TY - JOUR AU - Abdo, M.* AU - Trinkmann, F.* AU - Ewert, R.* AU - Obst, A.* AU - Völzke, H.* AU - Flexeder, C. AU - Heier, M. AU - Peters, A. AU - Herth, F.* AU - Watz, H.* AU - Rabe, K.F.* AU - Stubbe, B.* AU - Karrasch, S.* C1 - 75548 C2 - 58040 TI - High oscillometry-derived airway resistance is associated with FEV1 decline and future abnormal spirometry in smokers with initially normal spirometry. JO - Am. J. Respir. Crit. Care Med. PY - 2025 SN - 1073-449X ER - TY - JOUR AB - RATIONALE Lung adenocarcinoma (LUAD) frequently harbors KRAS mutations and is highly aggressive and resistant to conventional therapies. KRAS mutations drive tumorigenesis by altering pathways like NF-κB, suggesting that CCL2, VCAN and IL-1ß signaling within the tumor microenvironment is important to LUAD's etiology. Using Isunakinra, a potent IL-1 receptor antagonist, we tested whether these signaling pathways and immune cell recruitment contribute to suppressing the pro-tumorigenic environment fostered by KRAS mutations. METHODS and RESULTS Here we developed a bioluminescence-based reporting system (NF-κB.GFP.Luc; pNGL) to monitor NF-κB activity in four KRAS-mutant lines (KM: LLC, MC38, AE17, FULA1) and two KRAS wild-type lines (KW: B16F10, PANO2). When treated with Isunakinra, NF-κB activity was significantly inhibited in KM vs KW cell lines (p<0.001). FVB mice were injected subcutaneously with KM or KW and treated with Isunakinra (n= 5-6/cell line) for 7 days Tumor growth, pulmonary metastasis and malignant pulmonary effusion were all significantly decreased by Isunakinra (KM vs KW, p<0.001). Next, mice were treated with urethane (1g/kg/mouse, n=10/group), a reliable system for generating KRAS-mutant tumors. Isunakinra (20mg/kg; twice-weekly) was administered for 30 days either early during the first month post-induction or later during the fifth month post-induction. Tumor number and burden were assessed, and KRAS mutations (Q61 and G12/G13) were identified using ddPCR. Immunofluorescent labeling of lung sections was used to assess the presence of macrophages and CCL2/VCAN protein expression. Early treatment reduced both tumor number and burden by approximately 25% (vs non-treated, p < 0.05), while late treatment achieved a 40% reduction (p < 0.05), with no differences between early and late timing. KRAS mutations were confirmed in our model, and subtypes remained unchanged across groups (p > 0.05). CD68+ macrophages increased within the tumor area during late treatment (p= 0.053), while peritumor CD68+ macrophages decreased significantly (p < 0.05). CCR2 expression in tumor regions was reduced by 40% in the late-treated group (vs non-treated, p = 0.051). Interestingly, late-treated mice increased CCL2 expression, correlating with reduced tumor number and burden in early-treated mice (p<0.05) and suggesting compensatory changes in chemokine-receptor dynamics. VCAN levels were not significantly altered. CONCLUSIONS Overall, our data suggest that Isunakinra effectively influences the KRAS tumorgenicity via CCL2 signaling loop, reducing tumor growth by modulating the immune microenvironment. These results support its further investigation as a modulator of immune signaling and immune cell recruitment, and as a therapeutic approach for KRAS-mutated LUAD. AU - Deng, B. AU - Trassl, L. AU - Jia, J. AU - Skiadas, G.* AU - Ntaliarda, G.* AU - Behrend, S.J. AU - Schamberger, A.C. AU - Yildirim, A.Ö. AU - Stathopoulos, G.T. AU - Asarian, L. AU - Chateau, M.d.* AU - Fernandez, I.E.* C1 - 74704 C2 - 57664 SP - A3105 - A3105 TI - Targeting KRAS-mutant Lung Adenocarcinoma Tumors Through IL-1ß Inhibition. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - Single-cell RNA sequencing has greatly enhanced our understanding of the lungs and airways, although rare cell types and unique subtypes are often overlooked in individual studies. Recently, the Human Lung Cell Atlas (HLCA) was developed to identify these rare cell types in human studies and to standardize cell type identification across various datasets. However, there is a notable lack of references for mouse single-cell studies, especially concerning disease states. In response, we developed The Mouse Lung Disease Cell Atlas (MLDCA), which integrates 17 single-cell datasets encompassing 200 mice and a total of 773,732 cells across 24 disease models. To ensure the best integration of our datasets, we utilized the scIB benchmarking analysis, which identified the scArches scANVI pipeline as the most effective method. We determined 2,000 highly variable genes (HVGs) across our studies for this integration. After performing the integration, we analysed gene signature profiles, including those related to interferon response, and conducted multiple reclustering to identify unique cell types. These findings were further validated through spatial transcriptomics. In total, we categorized 5 hierarchical cell type annotations, with our most detailed definitions primarily consisting of immune cells and incorporating 53 unique cell types. This includes rare cells such as mast cells, neutrophils, pericytes, and plasmacytoid dendritic cells (pDCs), as well as cell types specific to certain disease states. Notably, our atlas identified viral and smoking-specific cell subtypes present only during viral infections (such as COVID-19, influenza, and herpesvirus) and cigarette smoke exposure, respectively. Furthermore, we developed a deconvolution reference matrix to accurately predict cell types in bulk RNA sequencing data of mouse lungs, which we validated against histological results. Our analysis revealed that biological factors, particularly age, have a greater influence on the composition of single-cell datasets in mice than technical factors, such as total RNA counts and sequencing platforms. Nevertheless, the choice of sequencing platform remains crucial when rare cell types are of interest. In addition to providing a comprehensive atlas, the MLDCA offers publicly available resources that allow other researchers to annotate and map cell types and define candidate genes across mouse models in single-cell datasets. AU - Faiz, A.* AU - Idrees, S.* AU - Johansen, M.* AU - Kovács, K.J.* AU - Boedijono, F.* AU - Chen, H.* AU - Galvao, I.* AU - Donovan, C.* AU - Kim, R.* AU - Sikkema, L. AU - Strobl, D.C. AU - Belz, G.T.* AU - Segal, L.N.* AU - Chotirmall, S.H.* AU - Nawijn, M.C.* AU - Lehmann, M.* AU - Kapellos, T. AU - Gallego‐Ortega, D.* AU - Hansbro, P.M.* C1 - 74712 C2 - 57672 SP - A5276 - A5276 TI - The Mouse Single Cell Lung Disease Atlas. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - Background: With an increasing percentage of extremely immature infants surviving, cardiopulmonary complications have become the most prevalent morbidity in this patient group. The underlying pathology of vascular disease (PVD) in preterms with chronic lung disease (BPD, bronchopulmonary dysplasia), associated with a high risk for progression into pulmonary hypertension (PH), is only incompletely understood and early, non-invasive biomarkers indicating early-stage disease are missing.Methods and Results: We prospectively included 190 preterm infants born <32 weeks postmenstrual age in the AIRR (Attention to Infants at Respiratory Risks) study (DRKS00004600) after informed parental consent. Identification of pathologic pulmonary artery flow and right heart strain by cardiopulmonary magnetic resonance imaging (MRI) at near-term age enabled us to identify plasma markers associated with PVD early after birth from proteomic screening. The differential regulation of IL-7 and its receptor IL7R, observed together with markers known from endothelial injury and remodeling , was confirmed by RNA scope analysis in human lung tissue (Vanderbilt University) from preterms with and without BPD and/or BPD-PH. Both vascular expression as well as cross talk to distinct immune cell populations was observed. Analysis of genetic data providing background information to this phenomenon is ongoing.Conclusion: Showcasing the regulation of IL-7R expression in infants with BPD indicates a role of IL7 signaling in PVD pathophysiology and outlines its potential as a disease marker and future therapeutic target. AU - Hilgendorff, A.* AU - Kindt-Dunjko, A.* AU - Häfner, F. AU - Förster, K.* AU - Heydarian, M. AU - Hauck, S.M. AU - Flemmer, A.W.* AU - von Toerne, C. AU - Sophia, S.* AU - Toshner, M.* AU - Sucre, J.M.S.* C1 - 74706 C2 - 57668 SP - A7319 - A7319 TI - Interleukin 7 Signaling as an Indicator of Pulmonary Vascular Disease in Preterm Infants Identified by Proteomic Screening and MRI Analysis. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AU - Merl-Pham, J. AU - Knüppel, L. AU - Binzenhöfer, L.* AU - Hennen, E. AU - Kaminski, N.* AU - Hatz, R.* AU - Behr, J.* AU - Hauck, S.M. AU - Hilgendorff, A. AU - Eickelberg, O.* AU - Staab-Weijnitz, C.A. C1 - 75384 C2 - 57955 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1889-1892 TI - Collagen post-translational modifications are altered in IPF including within ECM receptor binding motifs. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - 10 PB - Amer Thoracic Soc PY - 2025 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Human precision-cut lung slices (hPCLS) are a unique platform for functional, mechanistic, and drug discovery studies in respiratory research. Their relevance lies in their ability to maintain all resident cellular compartments (epithelial, mesenchymal, and immune cells) as well as the extracellular matrix (ECM) in their native three-dimensional structure. However, tissue availability, transportation, generation, and cultivation time represent important challenges for their usage. To address this, the present study aimed to evaluate the efficacy of a specifically designed tissue preservation solution (TiProtec) in the absence (-) or presence (+) of iron chelators as an alternative for long-term cold storage of hPCLS. METHODS: 500 µm hPCLS were generated and stored either in DMEM/F-12 medium or TiProtec (-/+) for up to 28 days. Viability, metabolic activity, and tissue structure were longitudinally determined. Bulk-RNA sequencing was used to study transcriptional changes, regulated signaling pathways, and changes in cellular composition after cold storage. Moreover, the induction of cold storage-associated cellular senescence was determined by transcriptomics and immunofluorescence (IF). To evaluate their potential for mechanistic studies in lung research, we evaluated the response to a previously described fibrotic cocktail after 7 and 14 days of cold storage in TiProtec (-/+) by IF and RT-qPCR. RESULTS: We demonstrated that TiProtec (+) preserves the viability, metabolic activity, transcriptional profile, and cellular composition of hPCLS for up to 14 days when compared to freshly sliced hPCLS. Moreover, cold storage did not significantly induce cellular senescence in hPCLS. Notably, TiProtec (+) downregulated pathways associated with cell death and inflammation while activating pathways protective against oxidative stress. Finally, cold-stored hPCLS remained responsive for up to 14 days to a fibrotic cocktail upregulating the expression of fibrosis-associated proteins such as fibronectin, alpha-smooth muscle actin, and alpha-1 type I collagen. CONCLUSION: This study provides for the first time insights into the transcriptional and functional changes associated with cold storage preservation of hPCLS. Moreover, it contributes to an optimized use of hPCLS, enabling banking, sharing, and on-demand processing and usage of hPCLS for translational lung research. AU - Narvaez, M.M.* AU - Gölitz, F.* AU - Jain, E. AU - Gote-Schniering, J.* AU - Stoleriu, M.G.* AU - Bertrams, W.* AU - Schmeck, B.* AU - Yildirim, A.Ö. AU - Rauen, U.* AU - Wille, T.* AU - Lehmann, M.* C1 - 74708 C2 - 57573 SP - A7646 - A7646 TI - Cold Storage of Human Precision-cut Lung Slices Preserves Cellular and Transcriptional Identity Enabling Optimized On-demand Translational Lung Research. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - CONF AB - Introduction Asthma is distinctly sexually dimorphic. Young males report higher asthma rates than females. This reverses at puberty, where females present increased incidence, reduced therapeutic effectiveness and worse asthma symptoms. The underlying molecular mechanisms causing this remain unknown. Biological DNA methylation (DNAm) clocks correlate with worse outcomes in chronic diseases such as asthma. The DNAm profile of males and females with asthma in the context of DNAm aging (DNAge) is yet to be explored. As such, we aimed to characterise and explore the DNA methylation profile associated with DNAge and biological sex in asthma. Methods Nasal brushings from the paediatric ALLIANCE cohort (n = 46F/74M; asthma = 73/ healthy = 31/ wheeze = 16; avg age = 11 yr range = 3 - 20 yr) were collected and DNAm processed and analysed by Illumina EPIC array using R software (v4.1; watermelon, minfi). DNAge was calculated using the established skinHorvath clock. The association between DNAge, sex, symptom severity or frequency of inhaled corticosteroid (ICS) use was analysed. Differential methylation analysis (DMA) comparing pathway enrichment analyses was completed using R packages (limma, minfi, methylGSA). Differential DNAm significance was determined at a false discovery rate (FDR) < 0.05. Results Highly symptomatic females with asthma are enriched for an accelerated DNAge compared to their male counterparts (p = 0.03). DNAge-accelerated females present increased asthma symptom frequency compared to DNAge-decelerated females and both male groups (p < 0.0001) despite equivalent ICS use. Focussing on highly symptomatic asthmatics, DMA comparing accelerated vs normal DNAged females and males revealed 459 differentially methylated sites (FDR < 0.05). Pathway analysis reported enrichment for Toll-like receptor, MAPK and Wnt signalling pathways as well as interferon type I, virus defence and mitochondrial response pathways (FDR < 0.05). Conclusions Here, we highlight a unique subset of female asthma patients who experience more asthma symptoms despite an equivalent use of ICS. In addition, this DNAged female sub-cohort carries a distinct DNAm profile from the male counterparts, with enrichment for pathologically relevant signalling and cellular differentiation pathways. This may present a novel foundation and support for the use of the DNAge clock as a tool for the characterisation of asthma patient sub-groups. AU - Reddy, K.* AU - Buccholz, S.* AU - Bohnhorst, A.* AU - Biedermann, S.B.* AU - Schaub, B.* AU - Hansen, G.* AU - Kopp, M.* AU - Mutius, E.V.* AU - Maison, N. AU - Bahmer, T.* AU - Rabe, K.F.* AU - Schmidt-Weber, C.B. AU - Jakwerth, C.* AU - Dittrich, A.* AU - Trojan, T.* AU - Alcázar, M.A.A.* AU - Grychtol, R.* AU - Brinkmann, F.* AU - Weckmann, M.* C1 - 74705 C2 - 57570 SP - A5172 - A5172 TI - Biologically aged females present a distinct symptom and DNA methylation asthma profile. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Early-life lung function trajectories predict long-term respiratory health, including COPD risk. Club Cell protein 16 (CC16) is a key determinant of lung health, with low levels associated with impaired lung development, reduced lung function, and COPD. Cigarette smoking lowers CC16, but it is unknown whether maternal smoking leads to persistent CC16 deficiency from early life, thereby disrupting lung development and predisposing to COPD risk and progression Methods: CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene [n=1,062] and ECLIPSE [n=2,164]), nasal brushings (ALLIANCE [n=63]), and peripheral lung sections (LTRC [n=44]) from participants with and without a history of maternal smoking exposure. Lung histology and respiratory mechanics were assessed in WT and Cc16-/- mice with and without maternal smoking exposure. Recombinant human (rh)CC16 effects on lung maturation were assessed in embryonic murine lung explants. RESULTS: Maternal smoking was linked to reduced circulating and airway CC16 in COPD patients, controls, and a preclinical murine COPD model. In human adults, lower CC16 correlated with accelerated lung function decline and emphysema progression, while in children it was associated with obstructive physiology and early small airway impairment. In both mice and humans, maternal smoking-induced CC16 reduction was accompanied by greater epithelial injury (fibrosis, inflammation, apoptosis, oxidative stress). In murine explants, smoking impaired lung branching, whereas rhCC16 restored branching via α2-integrin binding Conclusions: Maternal smoking reduces CC16 levels, disrupting lung development in ways that predispose to lifelong impairment of lung function and worse COPD outcomes. Defining the mechanisms by which CC16 regulates lung maturation is essential for establishing reliable outcome measures and designing trials aimed at preventing early COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). AU - Rojas-Quintero, J.* AU - Faner, R.* AU - Chiu, C.Y.* AU - Kue, J.T.* AU - Zhang, Y.* AU - Sanz Rubio, D.* AU - Colborg, A.S.* AU - Jakwerth, C.A.* AU - Schmidt-Weber, C.B. AU - Maitland-van der Zee, A.H.* AU - Abdel-Aziz, M.I.* AU - Pilon, A.L.* AU - Owen, C.A.* AU - Plosa, E.J.* AU - Kinney, G.L.* AU - Mc-Grath Morrow, S.* AU - Gazzaneo, M.G.* AU - Cortes Santiago, N.* AU - Lingappan, K.* AU - Ledford, J.* AU - Spence, J.* AU - Sucre, J.M.S.* AU - Sauler, M.* AU - Wu, T.D.* AU - Agusti, A.* AU - Wheelock, Å.M.* AU - Illi, S. AU - von Mutius, E. AU - Bowler, R.P.* AU - Celli, B.R.* AU - Abman, S.H.* AU - Wells, J.M.* AU - Polverino, F.* C1 - 75715 C2 - 57990 TI - Maternal smoking and CC-16: Implications for lung development and COPD across the lifespan. JO - Am. J. Respir. Crit. Care Med. PY - 2025 SN - 1073-449X ER - TY - JOUR AB - Rationale: Inflammation often persists even after smoking cessation, suggesting a self-sustaining pathogenic process similar to autoimmune diseases. However, the specific role of B cells in COPD onset and progression remains underexplored. Methods: We analyzed lung and peripheral blood samples from 61 COPD patients and healthy controls using single-cell transcriptomics to characterize B cell subpopulations and their association with emphysema severity. High emphysema was defined as greater than 5% lobar emphysema and greater than 15% total emphysema. B cell receptor (BCR) sequencing and clonal analysis assessed mutational frequency, clonal expansion, variable gene usage, and CDR3 region diversity. Autoantigen microarrays evaluated autoantibodies in the blood and the lung associated with different clinical characteristics. In contrast, mass spectrometry-based differential antigen capture assays evaluated plasma proteins reactive to lung self-antigens. Analyses were conducted in R, and statistical tests were corrected for multiple-hypothesis testing. Results: Lung B cells were significantly enriched in patients with high emphysema, with quantitative correlations observed between B cell abundance, emphysema severity, and pulmonary function tests (p< 0.05; Figure 1A-D). Within B cell subpopulations, MZ-like cells - defined as highly expressing IGHM and NR4A with enrichment in TNFα-NFκB and STAT3 pathways - were enriched in patients with increased emphysema (p=7.7e-11; Figure 1C-E). Spatial transcriptomics demonstrated these MZ-like cells were increased in lung follicles and airways. Furthermore, immunofluorescence and flow cytometry confirm the presence of this cell type in patients' lung tissue. B cell receptor sequencing analysis indicated a higher mutational frequency in IGHM isotypes (p=2.9e-6) and shorter CDR3 regions (p=0.0089) among patients with severe emphysema. Clonally expanded cells in patients with emphysema were more common in MZ-like cells (p=2.0e-8), with expanded clones shared in both the lungs and blood (Figure 1F-I). Similar CDR3 motifs were also shared across patients with clonally expanded MZ-like cells. Additionally, patients with high emphysema demonstrated recurrent usage of specific variable genes, including IGHV1-69 and IGHV4-34 (Figure 1J). Autoantigen microarrays revealed that patients with elevated lung MZ-like cell counts also had IGHM-predominant autoantibodies in the lungs and blood (p<0.05; Figure 1K-L). Patients' sera were also autoreactive to lung IGHM in patients with increased MZ-like cells. Conclusions: This study identifies a novel immune cell population - MZ-like B cells - enriched in severe emphysema. These cells may drive local and systemic autoantibody production, reminiscent of autoimmune diseases. Targeting MZ-like B cells or modulating IGHM autoantibody production presents a promising therapeutic avenue for addressing B cell-mediated mechanisms in COPD. AU - Zhao, A.* AU - Rojas, J.J.* AU - Cao, C.* AU - Zhang, Y.* AU - Semenova, A. AU - Schiller, H. AU - Estépar, R.S.J.* AU - Bhattacharya, D.* AU - Sauler, M.* AU - Polverino, F.* C1 - 74711 C2 - 57673 SP - A5246 - A5246 TI - Lung Marginal Zone-like B Cells: A Novel Pathogenic Immune Cell Population in Chronic Obstructive Pulmonary Disease. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - Rationale: The airway epithelium serves as the first protective barrier against cigarette smoke (CS), which is a major cause of chronic lung disease (CLD). While transient and persistent transcriptomic changes in the bronchial epithelium as a result of CS exposure have been described, proteomic studies are lacking in this context. Objective: To uncover CS-induced effects on the human airway proteome and identify the cellular source of transient and persistent changes. Methods: Label-free tandem mass spectrometry-based proteomics data of bronchoalveolar lavage fluid (BALF) from a CLD patient cohort mainly composed of interstitial lung disease (ILD) patients (n=124; 16 idiopathic pulmonary fibrosis (IPF), 79 non-IPF ILD, 29 non-ILD1) was analyzed in respect of patients' smoking history (ex-, active- and never-smokers). Results were compared to the proteome of chronically CS-exposed primary human bronchial epithelial cells (phBECs) relative to unexposed controls. Cellular sources of persistent protein changes were explored using immunofluorescent stainings of human lung tissue and whole lung single cell RNA-Seq analysis. Results: Smoking was associated with transient (up in active but lost in ex-smokers) and persistent (up in active and sustained in ex-smokers) protein changes in the BALF samples. We observed an overlap between CS-induced protein changes in phBECs and transient changes in BALF. Proteins associated with the persistent response primarily localized to macrophages as well as to basal and ciliated cells, but not to secretory cells, in the bronchial epithelium. Conclusion: CS triggers both transient and persistent protein changes in BALF of CLD patients. While the transient expression changes likely originate from the bronchial epithelium, persistent changes stem from both bronchial epithelial cells and macrophages. The results warrant further investigation into the relevance of these changes for onset and progression of CS-associated CLD. 1Mayr CH, et al. Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers. EMBO Mol Med 13: e12871, 2021. AU - Zöller, M. AU - Mayr, C.H. AU - Mastalerz, M. AU - Dick, E. AU - Chakraborty, A. AU - Nakayma, M. AU - Simon, L. AU - Merl-Pham, J. AU - Behr, J.* AU - Hilgendorff, A. AU - Schmid, O. AU - Hauck, S.M. AU - Schiller, H. AU - Staab-Weijnitz, C.A.* C1 - 74713 C2 - 57671 SP - A6856 - A6856 TI - Transient and Persistent Airway Proteome Changes Induced by Cigarette Smoke. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - Rationale: The airway epithelium serves as the first line of defense against cigarette smoke (CS), a major risk factor for chronic lung diseases. To the best of our knowledge, a comprehensive proteomic assessment of CS-induced changes in primary human bronchial epithelial cells (phBECs) differentiated at the air-liquid interface (ALI) has not been reported. Also, the relevance of CS-induced pathways for idiopathic pulmonary fibrosis (IPF) is poorly understood. An improved understanding thereof may unravel novel preventive strategies. Objective: To uncover novel key regulators and molecular pathways induced by CS in phBECs including such that may be relevant to IPF pathogenesis. Methods: Chronically CS-exposed, fully differentiated phBECs were analyzed by label-free tandem mass spectrometry (MS/MS)-based proteomics followed by pathway enrichment analysis using Ingenuity Pathway Analysis (IPA). Selected results were validated by ELISA and immunoblotting. The function of Nuclear protein 1 (NUPR1) was further explored in control and IPF-derived phBECs with and without CS-exposure using the NUPR1-specific inhibitor ZZW-115. Gene expression, cell type composition, barrier integrity, cytotoxicity, and cell death mechanisms were assessed using quantitative PCR, immunofluorescent stainings, transepithelial electrical resistance measurement, lactate dehydrogenase, BODIPY assay, and flow cytometry. Results: Out of 4861 detected proteins, proteomics revealed significantly altered levels for 186 proteins (adj. p<0.05) in response to CS. Subsequent pathway enrichment analysis suggested 11 key regulators. Results included many known CS-responsive genes involved in xenobiotic metabolism and antioxidant defense as well as activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Aryl hydrocarbon receptor (AhR) dependent pathways, validating the overall approach. Interestingly, IPA suggested NUPR1 as the top activated key regulator. In cultured phBECs, NUPR1 localized to basal and ciliated cells. NUPR1 inhibition with ZZW-115 in phBECs confirmed regulation of selected NUPR1 target genes suggested by IPA and revealed modulation of ferroptosis-associated genes. Inhibition of NUPR1 dose-dependently induced cell death and loss of epithelial integrity, with the underlying mechanisms varying across donor-derived cells, not consistently tied to a specific cell death type, and surprisingly little affected by prior CS exposure. Interestingly, IPF-derived phBECs showed a higher susceptibility to cytotoxicity after NUPR1 inhibition relative to control cells. Conclusion: Our proteomics analysis identified NUPR1 as a multifaceted regulator of cell death in differentiated phBECs. The results warrant further investigation of the function of NUPR1 in IPF airways. AU - Zöller, M. AU - Mastalerz, M. AU - Dick, E. AU - Hennen, E. AU - Chakraborty, A. AU - Merl-Pham, J. AU - Marchi, H. AU - Le Gleut, R. AU - Jeridi, A. AU - Prasse, A.* AU - Jäger, B.* AU - Santofimia‐Castaño, P.* AU - Stoleriu, M.-G. AU - Hilgendorff, A. AU - Yildirim, A.Ö. AU - Hauck, S.M. AU - Staab-Weijnitz, C.A.* C1 - 74714 C2 - 57670 SP - A6855 - A6855 TI - Quantitative Proteomics Identifies Nuclear Protein 1 as a Regulator of Cell Death in Differentiated Primary Human Bronchial Epithelial Cells. JO - Am. J. Respir. Crit. Care Med. VL - 211 IS - Abstracts PY - 2025 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Microplastics are a pressing global concern and inhalation of microplastic fibers has been associated with interstitial and bronchial inflammation in flock workers. However, how microplastic fibers affect the lungs is unknown. OBJECTIVES: Our aim was to assess the effects of 12x31 µm nylon 6,6 (nylon) and 15x52 µm polyethylene terephthalate (polyester) textile microplastic fibers on lung epithelial growth and differentiation. METHODS: We used human and murine alveolar and airway-type organoids as well as air-liquid interface cultures derived from primary lung epithelial progenitor cells and incubated these with either nylon or polyester fibers or nylon leachate. In addition, mice received one dose of nylon fibers or nylon leachate and 7 days later organoid-forming capacity of isolated epithelial cells was investigated. MEASUREMENTS AND MAIN RESULTS: We observed that nylon microfibers, more than polyester, inhibited developing airway organoids and not established ones. This effect was mediated by components leaching from nylon. Epithelial cells isolated from mice exposed to nylon fibers or leachate, also formed fewer airway organoids, suggesting long-lasting effects of nylon components on epithelial cells. Part of these effects were recapitulated in human air-liquid interface cultures. Transcriptome analysis revealed upregulation of Hoxa5 post-exposure to nylon fibers. Inhibiting Hoxa5 during nylon exposure restored airway organoid formation, confirming Hoxa5's pivotal role in the effects of nylon. CONCLUSIONS: These results suggest that components leaching from nylon 6,6 may especially harm developing airways and/or airways undergoing repair and we strongly encourage to characterize both hazard of and exposure to microplastic fibers in more detail. AU - Song, S.* AU - van Dijk, F.* AU - Vasse, G.F.* AU - Liu, Q. AU - Gosselink, I.F.* AU - Weltjens, E.* AU - Remels, A.H.* AU - de Jager, M.H.* AU - Bos, S.* AU - Li, C. AU - Stöger, T. AU - Rehberg, M. AU - Kutschke, D. AU - van Eck, G.* AU - Wu, X.* AU - Willems, S.H.* AU - Boom, D.* AU - Kooter, I.M.* AU - Spierings, D.* AU - Wardenaar, R.* AU - Cole, M.* AU - Nawijn, M.C.* AU - Salvati, A.* AU - Gosens, R.* AU - Melgert, B.N.* C1 - 68771 C2 - 54981 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 427-443 TI - Inhalable textile microplastic fibers impair airway epithelial differentiation. JO - Am. J. Respir. Crit. Care Med. VL - 209 IS - 4 PB - Amer Thoracic Soc PY - 2024 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes. OBJECTIVES: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus. METHODS: Genome-wide transcriptome analysis of nasal brushes from 261 children (78 healthy, 79 preschool wheezers, 104 asthmatics) within the ALLIANCE cohort, with a median age of 10.0 [1.0-20.0], was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology employed to measure IFN-protein levels. MEASUREMENTS AND MAIN RESULTS: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Elevated GSDMB expression correlated with the activation of a type-1 pro-inflammatory, cell-lytic immune, and NK signature, encompassing key genes linked to an IFN-type-II-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN-type-I and type-III expression signatures at both mRNA and protein levels. CONCLUSIONS: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions. AU - Jakwerth, C.A. AU - Weckmann, M.* AU - Illi, S. AU - Charles, H. AU - Zissler, U.M.* AU - Oelsner, M.* AU - Guerth, F. AU - Omony, J. AU - Nemani, S.S.P.* AU - Grychtol, R.* AU - Dittrich, A.M.* AU - Skevaki, C.* AU - Foth, S.* AU - Weber, S.* AU - Alejandre Alcazar, M.A.* AU - van Koningsbruggen-Rietschel, S.* AU - Brock, R.* AU - Blau, S.* AU - Hansen, G.* AU - Bahmer, T.* AU - Rabe, K.F.* AU - Brinkmann, F.* AU - Kopp, M.V.* AU - Chaker, A.M.* AU - Schaub, B.* AU - Von Mutius, E.* AU - Schmidt-Weber, C.B. C1 - 68936 C2 - 53778 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 947-959 TI - 17q21 variants disturb mucosal host defense in childhood asthma. JO - Am. J. Respir. Crit. Care Med. VL - 209 IS - 8 PB - Amer Thoracic Soc PY - 2023 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Exposure to ambient air pollution has been associated with adverse effects on morbidity and mortality. However, the evidence for ultrafine particles (UFP; 10-100nm) based on epidemiological studies remains scarce and inconsistent. OBJECTIVES: We examined associations between short-term exposures to UFP and total particle number concentrations (PNC; 10-800nm) and cause-specific mortality in the three German cities Dresden, Leipzig, and Augsburg. METHODS: We obtained daily counts of natural, cardiovascular, and respiratory mortality between 2010 and 2017. UFP and PNC were measured at six sites and fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were collected from routine monitoring. We applied station-specific confounder-adjusted Poisson regression models. We investigated air pollutant effects at aggregated lags (0-1, 2-4, 5-7, and 0-7) and used a novel multilevel meta-analytical method to pool the results. Additionally, we assessed interdependencies between pollutants using two-pollutant models. MEASUREMENTS AND MAIN RESULTS: For respiratory mortality, we found a delayed increase in relative risk of 4.46% [95% confidence interval: 1.52%, 7.48%] per 3,223 particles/cm3 increment 5 to 7 days after UFP exposure. Effects for PNC showed smaller but comparable estimates consistent with the observation that the smallest UFP fractions showed the largest effects. No clear associations were found for cardiovascular or natural mortality. UFP effects were independent of PM2.5 in two-pollutant models. CONCLUSIONS: We found delayed effects for respiratory mortality within a week after exposure to UFP and PNC but no associations for natural or cardiovascular mortality. This finding adds to the evidence on independent health effects of UFP. AU - Schwarz, M. AU - Schneider, A.E. AU - Cyrys, J. AU - Bastian, S.* AU - Breitner-Busch, S. AU - Peters, A. C1 - 67556 C2 - 54068 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1334-1344 TI - Impact of ambient ultrafine particles on cause-specific mortality in three German cities. JO - Am. J. Respir. Crit. Care Med. VL - 207 IS - 10 PB - Amer Thoracic Soc PY - 2023 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Small airway disease is an important pathophysiological feature of COPD. Recently, pre-COPD has been put forward as potential precursor stage of COPD, defined by abnormal spirometry or significant emphysema on CT in the absence of airflow obstruction. METHODS: We collected whole lungs/lung lobes from patients with emphysematous pre-COPD (n=10), COPD GOLD I (n=6), GOLD II (n=6), GOLD III/IV (n=7) and controls (n=10) which were analyzed using CT and microCT. The degree of emphysema and the number and morphology of small airways was compared between the different groups and further correlations were investigated with physiologic measures. Airway and parenchymal pathology was also validated with histopathology. MEASUREMENTS AND MAIN RESULTS: The number of transitional bronchioles (TrB)/mL and terminal bronchioles (TB)/mL was significantly lower in pre-COPD, GOLD I, GOLD II and GOLD III/IV compared to controls. In addition, the number of alveolar attachments of the TrB and TB was also lower in pre-COPD and all COPD groups compared to controls. We did not find any differences between the pre-COPD and COPD group in either CT or microCT measures. The % of emphysema on CT showed the strongest correlation with the number of small airways, also in patients without airflow obstruction. Histopathology showed an increase in the mean chord length and a decrease in the alveolar surface density in pre-COPD and all GOLD stages compared to control. CONCLUSION: Lungs of patients with emphysematous pre-COPD already show lower small airway number and airway remodeling and in the absence of physiologic airway obstruction. AU - Verleden, S.E.* AU - Hendriks, J.M.H.* AU - Snoeckx, A.* AU - Mai, C.* AU - Mentens, Y.* AU - Callebaut, W.* AU - De Belie, B.* AU - Van Schil, P.E.* AU - Verplancke, V.* AU - Janssens, A.C.* AU - Jacob, J.* AU - Pakzad, A.* AU - Conlon, T.M. AU - Guvenc, G. AU - Yildirim, A.Ö. AU - Pauwels, P.* AU - Koljenovic, S.* AU - Kwakkel-Van-Erp, J.M.* AU - Lapperre, T.* C1 - 68946 C2 - 53785 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 683-692 TI - Small airways disease in Pre-COPD with emphysema: A cross-sectional study. JO - Am. J. Respir. Crit. Care Med. VL - 209 IS - 6 PB - Amer Thoracic Soc PY - 2023 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. OBJECTIVES: We aimed to examine the relationship between occupational benzene exposure and lung cancer. METHODS: Subjects from 14 case-control studies across Europe and Canada were pooled. We used a quantitative job-exposure matrix to estimate benzene exposure. Logistic regression models assessed lung cancer risk across different exposure indices. We adjusted for smoking and five main occupational lung carcinogens and stratified analyses by smoking status and lung cancer subtypes. MEASUREMENTS AND MAIN RESULTS: Analyses included 28048 subjects (12329 cases, 15719 controls). Lung cancer odds ratios ranged from 1.12 (95% CI: 1.03-1.22) to 1.32 (95% CI: 1.18-1.48) (Ptrend=0.002) for groups with the lowest and highest cumulative occupational exposure, respectively, compared to unexposed subjects. We observed an increasing trend of lung cancer with longer duration of exposure (Ptrend<0.001) and decreasing trend with longer time since last exposure (Ptrend=0.02). These effects were seen for all lung cancer subtypes, regardless of smoking status, and were not influenced by specific occupational groups, exposures, or studies. CONCLUSION: We found consistent and robust associations between different dimensions of occupational benzene exposure and lung cancer after adjusting for smoking and main occupational lung carcinogens. These associations were observed across different subgroups, including non-smokers. Our findings support the hypothesis that occupational benzene exposure increases the risk of developing lung cancer. Consequently, there is a need to revisit published epidemiological and molecular data on the pulmonary carcinogenicity of benzene. AU - Wan, W.* AU - Peters, S.* AU - Portengen, L.* AU - Olsson, A.* AU - Schüz, J.* AU - Ahrens, W.* AU - Schejbalova, M.* AU - Boffetta, P.* AU - Behrens, T.* AU - Brüning, T.* AU - Kendzia, B.* AU - Consonni, D.* AU - Demers, P.A.* AU - Fabianova, E.* AU - Fernandez-Tardon, G.* AU - Field, J.K.* AU - Forastiere, F.* AU - Foretova, L.* AU - Guénel, P.* AU - Gustavsson, P.* AU - Jöckel, K.H.* AU - Karrasch, S. AU - Landi, M.T.* AU - Lissowska, J.* AU - Barul, C.* AU - Mates, D.* AU - McLaughlin, J.R.* AU - Merletti, F.* AU - Migliore, E.* AU - Richiardi, L.* AU - Pándics, T.* AU - Pohlabeln, H.* AU - Siemiatycki, J.* AU - Swiatkowska, B.* AU - Wichmann, H.E.* AU - Zaridze, D.* AU - Ge, C.* AU - Straif, K.* AU - Kromhout, H.* AU - Vermeulen, R.* C1 - 68679 C2 - 54885 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 185-196 TI - Occupational benzene exposure and lung cancer risk: A pooled analysis of 14 case-control studies. JO - Am. J. Respir. Crit. Care Med. VL - 209 IS - 2 PB - Amer Thoracic Soc PY - 2023 SN - 1073-449X ER - TY - JOUR AB - Rationale: Although type II alveolar epithelial cells (AEC2s) are chronically injured in idiopathic pulmonary fibrosis (IPF), they contribute to epithelial regeneration in IPF. Objectives: We hypothesized that Notch signaling may contribute to AEC2 proliferation, dedifferentiation characterized by loss of surfactant processing machinery, and lung fibrosis in IPF. Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, quantitative PCR, and proliferation and surface activity analysis to study epithelial differentiation, proliferation, and matrix deposition in vitro (AEC2 lines, primary murine/human AEC2s), ex vivo (human IPF-derived precision-cut lung slices), and in vivo (bleomycin and pepstatin application, Notch1 [Notch receptor 1] intracellular domain overexpression). Measurements and Main Results: We document here extensive SP-B and -C (surfactant protein-B and -C) processing defects in IPF AEC2s, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of endoplasmic reticulum stress in AEC2s. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK (Janus kinase)/Stat (signal transducer and activator of transcription) signaling in AEC2s. Conversely, inhibition of Notch signaling in IPF-derived precision-cut lung slices improved the surfactant processing capacity of AEC2s and reversed fibrosis. Conclusions: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation and loss of Napsin A and of surfactant proprotein processing, and it contributes to fibroproliferation. AU - Wasnick, R.* AU - Korfei, M.* AU - Piskulak, K.* AU - Henneke, I.* AU - Wilhelm, J.* AU - Mahavadi, P.* AU - Dartsch, R.C.* AU - von der Beck, D.* AU - Koch, M.* AU - Shalashova, I.* AU - Weiss, A.R.* AU - Klymenko, O.* AU - Askevold, I.* AU - Fink, L.* AU - Witt, H.* AU - Hackstein, H.* AU - El Agha, E.* AU - Bellusci, S.* AU - Klepetko, W.* AU - Königshoff, M. AU - Eickelberg, O.* AU - Schermuly, R.T.* AU - Braun, T.* AU - Seeger, W.* AU - Ruppert, C.* AU - Guenther, A.* C1 - 69505 C2 - 53870 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 283-299 TI - Notch1 induces defective epithelial surfactant processing and pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 207 IS - 3 PB - Amer Thoracic Soc PY - 2023 SN - 1073-449X ER - TY - JOUR AB - BACKGROUND: In murine models microbial exposures induce protection from experimental allergic asthma through innate immunity. Our aim was to assess the association of early life innate immunity with the development of asthma in children at risk. METHODS: In the PASTURE farm birth cohort innate, Th2, Th1 and Th17 cytokine expression at age 1 year was measured after stimulation of PBMCs with lipopolysaccharide (LPS) in N=445 children. Children at risk of asthma were defined based on single-nucleotide polymorphisms at the 17q21 asthma gene locus. Specifically, we used the SNP rs7216389 in the GSDMB gene. Wheeze in the 1st year of life was assessed by weekly diaries and asthma by questionnaire at age 6 years. RESULTS: Not all cytokines were detectable in all children after LPS-stimulation. When classifying detectability of cytokines by latent class analysis, carrying the 17q21 risk allele rs7216389 was associated with risk of wheeze only in the class with the lowest level of LPS-induced activation, odds ratio (OR)=1.89, 95%-CI 1.13-3.16, p=0.015. In contrast, in children with high cytokine activation after LPS-stimulation no association of the 17q21 risk allele with wheeze (OR=0.63, 95%-CI 0.29-1.40, p=0.258, p=0.034 for interaction) or school age asthma was observed. In these children consumption of unprocessed cow's milk was associated with higher cytokine activation (OR=3.37, 95%-CI 1.56-7.30, p=0.002), which was in part mediated by the gut microbiome. CONCLUSIONS: These findings suggest that within the 17q21 genotype asthma risk can be mitigated by activated immune responses after innate stimulation, which is partly mediated by a gut-immune axis. AU - Illi, S. AU - Depner, M. AU - Pfefferle, P.I.* AU - Renz, H.* AU - Roduit, C.* AU - Taft, D.H.* AU - Kalanetra, K.M.* AU - Mills, D.A.* AU - Farquharson, F.M.* AU - Louis, P.* AU - Schmaußer-Hechfellner, E. AU - Divaret-Chauveau, A.* AU - Lauener, R.* AU - Karvonen, A.M.* AU - Pekkanen, J.* AU - Kirjavainen, P.V.* AU - Roponen, M.* AU - Riedler, J.* AU - Kabesch, M.* AU - Schaub, B.* AU - von Mutius, E. C1 - 63906 C2 - 51678 SP - 641-650 TI - Immune responsiveness to LPS determines risk of childhood wheeze and asthma in 17q21 risk allele carriers. JO - Am. J. Respir. Crit. Care Med. VL - 205 IS - 6 PY - 2022 SN - 1073-449X ER - TY - JOUR AU - Lehmann, M. AU - Rojas, M.* C1 - 65457 C2 - 52308 SP - 372-373 TI - IPF: Let's keep the focus on the A(ge)TII cell. JO - Am. J. Respir. Crit. Care Med. VL - 206 IS - 4 PY - 2022 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: The associations between ambient coarse particulate matter (PM2.5-10) and daily mortality is not fully understood at a global scale. OBJECTIVES: To evaluate the short-term associations between PM2.5-10 and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide. METHODS: We collected daily mortality (total, cardiovascular, respiratory) and air pollution data from 205 cities in 20 countries/regions. Concentrations of PM2.5-10 were computed as the difference between inhalable and fine particulate matter. A two-stage time-series analytic approach was applied, with over-dispersed generalized linear models and multilevel meta-analysis. We fitted two-pollutant models to test the independent effect of PM2.5-10 from co-pollutants (fine particulate matter, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide). Exposure-response relationship curves were pooled and regional analyses were conducted. MEASUREMENTS AND MAIN RESULTS: A 10 μg/m3 increase in PM2.5-10 concentration on lag 0-1 day was associated with increments of 0.51% (95% confidence interval [CI]: 0.18%, 0.84%), 0.43% (95%CI: 0.15%, 0.71%) and 0.41% (95%CI: 0.06%, 0.77%) in total, cardiovascular, and respiratory mortality, respectively. The associations varied by country and region. These associations were robust to adjustment by all co-pollutants in two-pollutant models, especially for PM2.5. The exposure-response curves for total, cardiovascular, and respiratory mortality were positive, with steeper slopes at lower exposure ranges and without discernible thresholds. CONCLUSIONS: This study provides novel global evidence on the robust and independent associations between short-term exposure to ambient PM2.5-10 and total, cardiovascular and respiratory mortality, suggesting the need to establish a unique guideline or regulatory limit for daily concentrations of PM2.5-10. AU - Liu, C.* AU - Cai, J.* AU - Chen, R.* AU - Sera, F.* AU - Guo, Y.* AU - Tong, S.* AU - Li, S.* AU - Lavigne, E.* AU - Correa, P.M.* AU - Ortega, N.V.* AU - Orru, H.* AU - Maasikmets, M.* AU - Jaakkola, J.J.K.* AU - Ryti, N.* AU - Breitner-Busch, S. AU - Schneider, A.E. AU - Katsouyanni, K.* AU - Samoli, E.* AU - Hashizume, M.* AU - Honda, Y.* AU - Ng, C.F.S.* AU - Diaz, M.H.* AU - Valencia, C.C.* AU - Rao, S.* AU - Palomares, A.D.* AU - Silva, S.P.D.* AU - Madureira, J.* AU - Holobâc, I.H.* AU - Fratianni, S.* AU - Scovronick, N.* AU - Garland, R.M.* AU - Tobias, A.* AU - Iñiguez, C.* AU - Forsberg, B.* AU - Åström, C.* AU - Vicedo-Cabrera, A.M.* AU - Ragettli, M.S.* AU - Guo, Y.L.* AU - Pan, S.C.* AU - Milojevic, A.* AU - Bell, M.L.* AU - Zanobetti, A.* AU - Schwartz, J.* AU - Gasparrini, A.* AU - Kan, H.* C1 - 65458 C2 - 52309 SP - 999-1007 TI - Coarse particulate air pollution and daily mortality: A global study in 205 cities. JO - Am. J. Respir. Crit. Care Med. VL - 206 IS - 8 PY - 2022 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Ambient air pollution exposure has been linked to mortality from chronic cardiorespiratory diseases, while evidence on respiratory infections remains more limited. OBJECTIVES: We examined the association between long-term exposure to air pollution and pneumonia related mortality in adults in a pool of eight European cohorts. METHODS: Within the multicenter project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from eight cohorts among six European countries. Annual mean residential concentrations in 2010 for fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), and ozone (O3) were estimated using Europe-wide hybrid land use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and pneumonia, influenza, and acute lower respiratory infections (ALRI) mortality. MEASUREMENTS AND MAIN RESULTS: Of 325,367 participants, 712 died from pneumonia and influenza combined, 682 from pneumonia, and 695 from ALRI during a mean follow-up of 19.5 years. NO2 and BC were associated with 10-12% increases in pneumonia and influenza combined mortality, but 95% confidence intervals included unity [hazard ratios: 1.12 (0.99-1.26) per 10 µg/m3 for NO2; 1.10 (0.97-1.24) per 0.5 10-5m-1 for BC]. Associations with pneumonia and ALRI mortality were almost identical. We detected effect modification suggesting stronger associations with NO2 or BC in overweight, employed, or currently smoking participants compared to normal weight, unemployed, or non-smoking participants. CONCLUSIONS: Long-term exposure to combustion-related air pollutants NO2 and BC may be associated with mortality from lower respiratory infections, but larger studies are needed to estimate these associations more precisely. AU - Liu, S.* AU - Lim, Y.H.* AU - Chen, J.* AU - Strak, M.* AU - Wolf, K. AU - Weinmayr, G.* AU - Rodopolou, S.* AU - de Hoogh, K.* AU - Bellander, T.* AU - Brandt, J.* AU - Concin, H.* AU - Zitt, E.* AU - Fecht, D.* AU - Forastiere, F.* AU - Gulliver, J.* AU - Hertel, O.* AU - Hoffmann, B.* AU - Hvidtfeldt, U.A.* AU - Verschuren, W.M.M.* AU - Jöckel, K.H.* AU - Jørgensen, J.T.* AU - So, R.* AU - Amini, H.* AU - Cole-Hunter, T.* AU - Mehta, A.J.* AU - Mortensen, L.H.* AU - Ketzel, M.* AU - Lager, A.* AU - Leander, K.* AU - Ljungman, P.* AU - Severi, G.* AU - Boutron-Ruault, M.C.* AU - Magnusson, P.K.E.* AU - Nagel, G.* AU - Pershagen, G.* AU - Peters, A. AU - Raaschou-Nielsen, O.* AU - Rizzuto, D.* AU - van der Schouw, Y.T.* AU - Schramm, S.* AU - Sørensen, M.* AU - Stafoggia, M.* AU - Tjønneland, A.* AU - Katsouyanni, K.* AU - Huang, W.* AU - Samoli, E.* AU - Brunekreef, B.* AU - Hoek, G.* AU - Andersen, Z.J.* C1 - 64503 C2 - 51927 SP - 1429-1439 TI - Long-term air pollution exposure and pneumonia related mortality in a large pooled European cohort. JO - Am. J. Respir. Crit. Care Med. VL - 205 IS - 12 PY - 2022 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Kass, D.J.* C1 - 61482 C2 - 50310 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 9-11 TI - Do circulating monocytes promote and predict IPF progression? JO - Am. J. Respir. Crit. Care Med. VL - 204 IS - 1 PB - Amer Thoracic Soc PY - 2021 SN - 1073-449X ER - TY - JOUR AB - Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 mu g/m(3) were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship betweenECexposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers. AU - Ge, C.* AU - Peters, S.* AU - Olsson, A.* AU - Portengen, L.* AU - Schüz, J.* AU - Almansa, J.* AU - Ahrens, W.* AU - Bencko, V.* AU - Benhamou, S.* AU - Boffetta, P.* AU - Bueno-de-Mesquita, B.* AU - Caporaso, N.* AU - Consonni, D.* AU - Demers, P.* AU - Fabiánová, E.* AU - Fernández-Tardón, G.* AU - Field, J.* AU - Forastiere, F.* AU - Foretova, L.* AU - Guénel, P.* AU - Gustavsson, P.* AU - Janout, V.* AU - Jöckel, K.H.* AU - Karrasch, S. AU - Landi, M.T.* AU - Lissowska, J.* AU - Luce, D.* AU - Mates, D.* AU - McLaughlin, J.* AU - Merletti, F.* AU - Mirabelli, D.* AU - Pándics, T.* AU - Parent, M.* AU - Plato, N.* AU - Pohlabeln, H.* AU - Richiardi, L.* AU - Siemiatycki, J.* AU - Świątkowska, B.* AU - Tardón, A.* AU - Wichmann, H.-E. AU - Zaridze, D.* AU - Straif, K.* AU - Kromhout, H.* AU - Vermeulen, R.* C1 - 58934 C2 - 48519 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 402-411 TI - Diesel engine exhaust exposure, smoking, and lung cancer subtype risks a pooled exposure-response analysis of 14 case-control studies. JO - Am. J. Respir. Crit. Care Med. VL - 202 IS - 3 PB - Amer Thoracic Soc PY - 2020 SN - 1073-449X ER - TY - JOUR AB - Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend, 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend <= 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype. AU - Ge, C.* AU - Peters, S.* AU - Olsson, A.* AU - Portengen, L.* AU - Schüz, J.* AU - Almansa, J.* AU - Behrens, T.* AU - Pesch, B.* AU - Kendzia, B.* AU - Ahrens, W.* AU - Bencko, V.* AU - Benhamou, S.* AU - Boffetta, P.* AU - Bueno-de-Mesquita, B.* AU - Caporaso, N.* AU - Consonni, D.* AU - Demers, P.* AU - Fabiánová, E.* AU - Fernández-Tardón, G.* AU - Field, J.* AU - Forastiere, F.* AU - Foretova, L.* AU - Guénel, P.* AU - Gustavsson, P.* AU - Ho, V.* AU - Janout, V.* AU - Jöckel, K.H.* AU - Karrasch, S. AU - Landi, M.T.* AU - Lissowska, J.* AU - Luce, D.* AU - Mates, D.* AU - McLaughlin, J.* AU - Merletti, F.* AU - Mirabelli, D.* AU - Plato, N.* AU - Pohlabeln, H.* AU - Richiardi, L.* AU - Rudnai, P.* AU - Siemiatycki, J.* AU - Świątkowska, B.* AU - Tardón, A.* AU - Wichmann, H.-E.* AU - Zaridze, D.* AU - Brüning, T.* AU - Straif, K.* AU - Kromhout, H.* AU - Vermeulen, R.* C1 - 58935 C2 - 48521 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 412-421 TI - Respirable crystalline silica exposure, smoking, and lung cancer subtype risks A pooled analysis of case-control studies. JO - Am. J. Respir. Crit. Care Med. VL - 202 IS - 3 PB - Amer Thoracic Soc PY - 2020 SN - 1073-449X ER - TY - JOUR AU - Mathei, S.K.* AU - Cardwell, J.* AU - Metzger, F.* AU - Powers, J.* AU - Walts, A.D.* AU - Kropski, J.A.* AU - Eickelberg, O.* AU - Hauck, S.M. AU - Yang, I.V.* AU - Schwartz, D.A.* C1 - 60899 C2 - 49727 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1720-1724 TI - Preclinical pulmonary fibrosis circulating protein biomarkers. JO - Am. J. Respir. Crit. Care Med. VL - 202 IS - 12 PB - Amer Thoracic Soc PY - 2020 SN - 1073-449X ER - TY - JOUR AU - Ngo, D.* AU - Pratte, K.A.* AU - Flexeder, C. AU - Petersen, H.* AU - Dang, H.* AU - Ma, Y.* AU - Keyes, M.J.* AU - Petersonl, B.D.* AU - Sitars, V.* AU - Gillenwater, L.A.* AU - Xu, H.* AU - Emson, C.* AU - Gieger, C. AU - Suhre, K.* AU - Graumann, J.* AU - Jain, D.* AU - Conomos, M.P.* AU - Tracy, R.P.* AU - Guo, X.* AU - Liu, Y.* AU - Johnson, W.* AU - Cornell, E.* AU - Durda, P.* AU - Taylor, K.D.* AU - Papanicolaou, G.J.* AU - Rich, S.S.* AU - Rotter, J.I.* AU - Rennard, S.I.* AU - Curtis, J.L.* AU - Woodruff, P.* AU - Comellas, A.P.* AU - Silverman, E.K.* AU - Crapo, J.D.* AU - Larson, M.G.* AU - Ramachandran, V.S.* AU - Wang, T.J.* AU - Gerszten, R.E.* AU - O'Connor, G.T.* AU - Barr, R.* AU - Couper, D.* AU - Dupuis, J.* AU - Manichaikul, A.* AU - O'Neal, W.K.* AU - Tesfaigzi, Y.* AU - Schulz, H. AU - Bowler, R.P.* C1 - 60247 C2 - 49832 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Systemic biomarkers of lung function and FEV1 decline across multiple cohorts. JO - Am. J. Respir. Crit. Care Med. VL - 201 PB - Amer Thoracic Soc PY - 2020 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Güneş, G. AU - Sarker, R.S. AU - Fehrenbach, H.* AU - Yildirim, A.Ö. C1 - 56116 C2 - 46828 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Arginine methylation epigenetically regulates airway epithelial cell injury in COPD pathogenesis. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Greiffo, F.R. AU - Viteri-Alvarez, V. AU - Bastidas, I. AU - Roy, R.* AU - Frankenberger, M. AU - Behr, J.* AU - Forrest, A.* AU - Hilgendorff, A. AU - Eickelberg, O.* C1 - 56126 C2 - 46823 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Myeloid-derived suppressor cells orchestrate immunosuppressive networks in idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Gunsel, G.G.* AU - Conlon, T.M. AU - Sarker, R.* AU - Jia, J.* AU - Heinzelmann, K. AU - Tasdemir, D.* AU - Bayram, H.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 56122 C2 - 46834 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Metabolomic regulation of B cells drives the pathogenesis of COPD. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Heinzelmann, K. AU - Ulke, H.M. AU - Mutze, K. AU - Wagner, D.E.* AU - Ren, W.* AU - Guenther, A.* AU - Eickelberg, O.* AU - Koenigshoff, M.* C1 - 56124 C2 - 46825 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Epithelial cell transforming sequence 2 contributes to alveolar epithelial cell reprogramming in idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Korfei, M.* AU - Smaida, M.* AU - Klymenko, O.* AU - Ruppert, C.* AU - Henneke, I.* AU - Shalashova, I.* AU - Huehn, M.* AU - Mahavadi, P.* AU - Herold, S.* AU - Seeger, W.* AU - Adler, H. AU - Guenther, A.* C1 - 56115 C2 - 46829 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Increased susceptibility to gammaherpesvirus-induced lung fibrosis of transgenic mice with conditional overexpression of the pro-apoptotic ER-stress-factor chop in alveolar epithelium. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Lehmann, M. AU - Klee, S. AU - Wagner, D.E.* AU - Koenigshoff, M.* C1 - 56127 C2 - 46822 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Wnt1-inducible signaling protein 1 (WISP1) augments nuclear factor (NF)-kB signaling in primary human lung fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Mathai, S.K.* AU - Metzger, F. AU - Cardwell, J.* AU - Kropski, J.A.* AU - Powers, J.* AU - Walts, A.D.* AU - Markin, C.* AU - Brown, K.K.* AU - Steele, M.P.* AU - Schwarz, M.I.* AU - Lynch, D.A.* AU - Eickelberg, O.* AU - Fingerlin, T.E.* AU - Loyd, J.E.* AU - Hauck, S.M. AU - Yang, I.V.* AU - Schwartz, D.A.* C1 - 56125 C2 - 46824 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Circulating plasma proteins differentially detected in idiopathic pulmonary fibrosis and in subjects with pre-clinical pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AB - Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease.Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests.Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 x 10(-295)). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals.Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. AU - Moore, C.* AU - Blumhagen, R.Z.* AU - Yang, I.V.* AU - Walts, A.* AU - Powers, J.* AU - Walker, T.* AU - Bishop, M.* AU - Russell, P.* AU - Vestal, B.* AU - Cardwell, J.* AU - Markin, C.R.* AU - Mathai, S.K.* AU - Schwarz, M.I.* AU - Steele, M.P.* AU - Lee, J.* AU - Brown, K.K.* AU - Loyd, J.E.* AU - Crapo, J.D.* AU - Silverman, E.K.* AU - Cho, M.H.* AU - James, J.A.* AU - Guthridge, J.M.* AU - Cogan, J.D.* AU - Kropski, J.A.* AU - Swigris, J.J.* AU - Bair, C.* AU - Soon Kim, D.* AU - Ji, W.* AU - Kim, H.* AU - Song, W.J.* AU - Maier, L.A.* AU - Pacheco, K.A.* AU - Hirani, N.* AU - Poon, A.S.* AU - Li, F.* AU - Jenkins, R.G.* AU - Braybrooke, R.* AU - Saini, G.* AU - Maher, T.M.* AU - Molyneaux, P.L.* AU - Saunders, P.* AU - Zhang, Y.* AU - Gibson, K.F.* AU - Kass, D.J.* AU - Rojas, M.* AU - Sembrat, J.* AU - Wolters, P.J.* AU - Collard, H.R.* AU - Sundy, J.S.* AU - O'Riordan, T.* AU - Strek, M.E.* AU - Noth, I.* AU - Ma, S.F.* AU - Porteous, M.K.* AU - Kreider, M.E.* AU - Patel, N.B.* AU - Inoue, Y.* AU - Hirose, M.* AU - Arai, T.* AU - Akagawa, S.* AU - Eickelberg, O. AU - Fernandez, I.E. AU - Behr, J.* AU - Mogulkoc, N.* AU - Corte, T.J.* AU - Glaspole, I.* AU - Tomassetti, S.* AU - Ravaglia, C.* AU - Poletti, V.* AU - Crestani, B.* AU - Borie, R.* AU - Kannengiesser, C.* AU - Parfrey, H.* AU - Fiddler, C.* AU - Rassl, D.* AU - Molina-Molina, M.* AU - Machahua, C.* AU - Montes Worboys, A.* AU - Gudmundsson, G.* AU - Isaksson, H.J.* AU - Lederer, D.J.* AU - Podolanczuk, A.J.* AU - Montesi, S.B.* AU - Bendstrup, E.* AU - Danchel, V.* AU - Selman, M.* AU - Pardo, A.* AU - Henry, M.T.* AU - Keane, M.P.* AU - Doran, P.* AU - Vašáková, M.* AU - Sterclova, M.* AU - Ryerson, C.J.* AU - Wilcox, P.G.* AU - Okamoto, T.* AU - Furusawa, H.* AU - Miyazaki, Y.* AU - Laurent, G.* AU - Baltic, S.* AU - Prele, C.* AU - Moodley, Y.* AU - Shea, B.S.* AU - Ohta, K.* AU - Suzukawa, M.* AU - Narumoto, O.* AU - Nathan, S.D.* AU - Venuto, D.C.* AU - Woldehanna, M.L.* AU - Kokturk, N.* AU - de Andrade, J.A.* AU - Luckhardt, T.* AU - Kulkarni, T.* AU - Bonella, F.* AU - Donnelly, S.C.* AU - McElroy, A.* AU - Armstrong, M.E.* AU - Aranda, A.* AU - Carbone, R.G.* AU - Puppo, F.* AU - Beckman, K.B.* AU - Nickerson, D.A.* AU - Fingerlin, T.E.* AU - Schwartz, D.A.* C1 - 55950 C2 - 46713 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 199-208 TI - Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 200 IS - 2 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Srivastava, B.* AU - Conlon, T.M. AU - Mitula, E.* AU - Sarker, R.S. AU - Yildirim, A.Ö. C1 - 56121 C2 - 46827 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Developing oxysterol inhibitors as a novel therapeutic target for iBALT driven chronic pulmonary diseases. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Staab-Weijnitz, C.A. AU - Merl-Pham, J. AU - Basak, T.* AU - Knüppel, L. AU - Ramanujam, D.* AU - Athanason, M.* AU - Behr, J.* AU - Engelhardt, S.* AU - Eickelberg, O.* AU - Hauck, S.M. AU - Vanacore, R.* C1 - 56123 C2 - 46826 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Quantitative proteomic profiling of extracellular matrix and collagen posttranslational modifications in an in vitro model of lung fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 199 PB - Amer Thoracic Soc PY - 2019 SN - 1073-449X ER - TY - JOUR AU - Bahmer, T.* AU - Watz, H.* AU - Pedersen, F.* AU - Kirsten, A.* AU - Waschki, B.* AU - Von Mutius, E.* AU - Hansen, G.* AU - Kopp, M.V.* AU - Rabe, K.F.* AU - Fuchs, O.* AU - Weckmann, M.* AU - Koenig, I.R.* AU - Thiele, D.* AU - Chaker, A.* AU - Schmidt-Weber, C.B. AU - Zissler, U.M. C1 - 54843 C2 - 45915 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Nasal cytokine patterns in patients with asthma. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Sarker, R.S. AU - Jia, J. AU - Heinzelmann, K. AU - Tasdemir, D.* AU - Bayram, H.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 54878 C2 - 45910 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Immuno-metabolomic regulation of B cell guided iBALT positioning drives cigarette smoke-induced COPD. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Contreras, Z.A.* AU - Chen, Z.* AU - Roumeliotaki, T.* AU - Annesi-Maesano, I.* AU - Baïz, N.* AU - von Berg, A.* AU - Bergstrom, A.* AU - Bindslev-Jensen, C.* AU - Crozier, S.* AU - Duijts, L.* AU - Ekström, S.* AU - Eller, E.* AU - Fantini, M.* AU - Forastiere, F.* AU - Gerhard, B.* AU - Gori, D.* AU - Harskamp-van Ginkel, M.W.* AU - Heinrich, J. AU - Iñiguez, C.* AU - Inskip, H.* AU - Keil, T.* AU - Kogevinas, M.* AU - Lau, S.* AU - Lehmann, I.* AU - Maier, D.* AU - van Meel, E.* AU - Mommers, M.* AU - Murcia, M.* AU - Porta, D.* AU - Smit, H.* AU - Standl, M. AU - Stratakis, N.* AU - Sunyer, J.* AU - Thijs, C.* AU - Torrent, M.* AU - Vrijkotte, T.* AU - Wijga, A.* AU - Berhane, K.* AU - Gilliland, F.* AU - Chatzi, L.* C1 - 54832 C2 - 45896 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Early childhood asthma and the risk of new onset obesity: An individual participant meta-analysis of 16 European Birth Cohorts. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Costa, R. AU - Wagner, D.E. AU - De Santis, M. AU - Bailey, K.E.* AU - Doryab, A. AU - Schorpp, K.K. AU - Rothenaigner, I. AU - Ota, C. AU - Baarsma, H.A. AU - Campillos, M. AU - Hadian, K. AU - Koenigshoff, M.* C1 - 54849 C2 - 45848 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Drug repurposing for WNT/beta-catenin induced lung repair in chronic obstructive pulmonary disease. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Sun, N. AU - Wei, M. AU - Witting, M. AU - Aichler, M. AU - Verleden, S.* AU - Schmitt-Kopplin, P. AU - Eickelberg, O.* AU - Walch, A.K. C1 - 54889 C2 - 45870 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Pharmacometabolic response to pirfenidone treatment in pulmonary fibrosis detected by high resolution MALDI FTICR-mass spectrometry imaging. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Foerster, K.* AU - Sass, S. AU - Pomschar, A.* AU - Ehrhardt, H.* AU - Naehrlich, L.* AU - Schulze, A.* AU - Flemmer, A.* AU - Huebener, C.* AU - Eickelberg, O.* AU - Theis, F.J. AU - Dietrich, O.* AU - Ertl-Wagner, B.* AU - Hilgendorff, A. C1 - 54833 C2 - 45895 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Diagnosis of bronchopulmonary dysplasia using magnetic resonance imaging analysis. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Foerster, K.* AU - Ertl-Wagner, B.* AU - Sass, S. AU - Stoecklein, S.* AU - Schoeppe, F.* AU - Dietrich, O.* AU - Pomschar, A.* AU - Schulze, A.* AU - Huebener, C.* AU - Theis, F.J. AU - Ehrhardt, H.* AU - Flemmer, A.* AU - Hilgendorff, A. C1 - 54876 C2 - 45905 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Quantitative MRI measurements to detect pulmonary hypertension in bronchopulomnary dysplasia. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Förster, K. AU - Sass, S. AU - Ehrhardt, H.* AU - Mous, D.S.* AU - Rottier, R.J.* AU - Oak, P. AU - Schulze, A.* AU - Flemmer, A.W.* AU - Gronbach, J.* AU - Hübener, C.* AU - Desai, T.* AU - Eickelberg, O. AU - Theis, F.J. AU - Hilgendorff, A. C1 - 52168 C2 - 43788 SP - 1076-1080 TI - Early identification of bronchopulmonary dysplasia using novel biomarkers by proteomic screening. JO - Am. J. Respir. Crit. Care Med. VL - 197 IS - 8 PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Heinzelmann, K. AU - Gerckens, M. AU - Lindner, M.* AU - Hatz, R.* AU - Behr, J.* AU - Eickelberg, O.* AU - Hilgendorff, A. C1 - 54884 C2 - 45871 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - DPPIV expression in human lung fibroblasts affects phenotypic changes in fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Hu, Y.* AU - Skronska-Wasek, W. AU - Ota, C. AU - Mutze, K. AU - Baarsma, H.A. AU - Wagner, D.E. AU - Lehmann, M. AU - Bracke, K.R.* AU - Brusselle, G.G.* AU - Yildirim, A.Ö. AU - Koenigshoff, M.* C1 - 54836 C2 - 45894 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - The progenitor cell marker LGR5 is reduced in epithelial cells in emphysema. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Knüppel, L. AU - Merl-Pham, J. AU - Hennen, E. AU - Hatz, R.* AU - Behr, J.* AU - Eickelberg, O.* AU - Hauck, S.M. AU - Staab-Weijnitz, C.A. C1 - 54842 C2 - 45916 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - A proteomic analysis of extracellular matrix from idiopathic pulmonary fibrosis patient-derived fibroblasts in response to transforming growth factor beta 1. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Kreuter, M.* AU - Witt, S. AU - Polke, M.* AU - Waelscher, J.* AU - Schwarzkopf, L. C1 - 54837 C2 - 45899 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Financial burden of interstitial lung disease -a claims data based study. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Kreuter, M.* AU - Herth, F.J.F.* AU - Witt, S. AU - Kabitz, H.* AU - Hagmeyer, L.* AU - Hammerl, P.* AU - Esselmann, A.* AU - Wiederhold, C.* AU - Skowasch, D.* AU - Stolpe, C.* AU - Joest, M.* AU - Veitshans, S.* AU - Leidl, R. AU - Hellmann, A.* AU - Pfeifer, M.* AU - Behr, J.* AU - Guenther, A.* AU - Markart, P.* C1 - 54886 C2 - 45872 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Diagnosis and management of patients with interstitial lung disease (ILD) in clinical practice in Germany: Exciting-ILD registry. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Lehmann, M. AU - Klee, S. AU - Kaufmann, G.* AU - Koenigshoff, M.* C1 - 54841 C2 - 45917 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Human anti-Wnt1-inducible signaling protein (WISP) 1 antibodies attenuate experimental lung fibrosis ex vivo. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Lopez, C.B. AU - Conlon, T.M. AU - Ertuz, Z. AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 54840 C2 - 45918 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - The novel notch ligand DNER modulates IFN. Levels in recruited macrophages by enhancing non-canonical notch during COPD progression. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AB - Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo) fibroblast activation, and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT (wingless/integrated) proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remain unexplored.Objectives: To characterize EVs and study the role of EV-bound WNT signaling in IPF.Methods: We isolated EVs from BAL fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non-IPF interstitial lung disease (ILD), non-ILD, and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, quantitative PCR, and Western blotting upon WNT gain- and loss-of-function studies.Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from patients with IPF. WNT5A was secreted on EVs in lung fibrosis and induced by transforming growth factor-beta in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF BALF induced phLF proliferation, which was mediated by WNT5A.Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis. AU - Martin-Medina, A. AU - Lehmann, M. AU - Burgy, O.* AU - Hermann, S. AU - Baarsma, H.A. AU - Wagner, D.E. AU - De Santis, M. AU - Ciolek, F. AU - Hofer, T.P. AU - Frankenberger, M. AU - Aichler, M. AU - Lindner, M.* AU - Gesierich, W.* AU - Guenther, A.* AU - Walch, A.K. AU - Coughlan, C.* AU - Wolters, P. * AU - Lee, J.S.* AU - Behr, J. AU - Königshoff, M. C1 - 54002 C2 - 45191 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1527-1538 TI - Increased extracellular vesicles mediate WNT5A signaling in idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 198 IS - 12 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Meiners, S.* AU - Kammerl, I.E.* AU - Caniard, A.M.* AU - Merl-Pham, J. AU - Ben-Nissan, G.* AU - Mossina, A.* AU - Geerlof, A. AU - Eickelberg, O.* AU - Hauck, S.M. AU - Sharon, M.* C1 - 54874 C2 - 45908 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Dissecting the molecular effects of cigarette smoke on proteasome function. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Morrone, C. AU - Smirnova, N.F.* AU - Kneidinger, N.* AU - Mann, M.* AU - Schiller, H.B.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 54875 C2 - 45907 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Increased peribronchiolar and perivascular cysteine protease activity is associated with bronchiolitis obliterans syndrome. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Nawijn, M.C.* AU - Rajagopal, J.* AU - Koppelman, G.H.* AU - van den Berge, M.* AU - Rose-Zerilli, M.J.* AU - Holloway, J.W.* AU - Schultze, J.L.* AU - Barbry, P.* AU - Teichmann, S.A.* AU - Prabhakar, S.* AU - Theis, F.J. AU - Schiller, H. B. C1 - 54834 C2 - 45893 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - The human lung cell atlas: A comprehensive reference map for all cell types in the healthy human lung. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Ngo, D.* AU - Jacobson, S.* AU - Flexeder, C. AU - Petersen, H.* AU - Keyes, M.* AU - Herzig, M.* AU - Manichaikul, A.* AU - Oelsner, E.* AU - Gerszten, R.E.* AU - Gieger, C. AU - Kechris, K.* AU - Comellas, A.P.* AU - John, J.E.* AU - Barr, R.* AU - Couper, D.* AU - Tesfaigzi, Y.* AU - Schulz, H. AU - Bowler, R.P.* C1 - 54873 C2 - 45906 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Proteomic profiling identifies novel circulating markers associated with lung function. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Oak, P. AU - Koschlig, M. AU - Pritzke, T. AU - Foerster, K.* AU - Ahnert, P.* AU - Windhorst, A.* AU - Reicherzer, T.* AU - Ehrhardt, H.* AU - Hilgendorff, A. C1 - 54885 C2 - 45869 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Gender specific response of the neonatal lung to postnatal injury. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Preisendörfer, S. AU - Knüppel, L. AU - Ishikawa, Y.* AU - Binzenhöfer, L. AU - Fernandez, I.E. AU - Juan-Guardela, B.M.* AU - Ruppert, C.* AU - Guenther, A.* AU - Hatz, R.* AU - Behr, J.* AU - Kaminski, N.* AU - Schepers, A. AU - Bachinger, H.* AU - Eickelberg, O.* AU - Staab-Weijnitz, C.A. C1 - 54847 C2 - 45849 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - FK506 binding protein 11, a plasma cell-specific antibody folding catalyst, is increased in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Preissler, G.* AU - Nößner, E. AU - Warnecke, G.* AU - Knoefel, A.* AU - Schramm, R.* AU - Hatz, R.* AU - Haverich, A.* AU - Strobl, N.* C1 - 54838 C2 - 45920 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Systemic treg levels are associated with functional treg differences and correlate with the immunological risk in lung transplant recipients. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Schittny, J.C.* AU - Möller, W. AU - Holzwarth, U.* AU - Hirn, S. AU - Wenk, A. AU - Schleh, C. AU - Schäffler, M. AU - Haberl, N. AU - Gibson, N.* AU - Kreyling, W.G. C1 - 54877 C2 - 45909 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Age-dependent deposition patterns and quantitative biokinetics of inhaled 20nm gold nanoparticles in rat lungs. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Schmid, O. AU - Möller, W. AU - Stelzl, A. AU - Lund, J.* AU - Yildirim, A.Ö. AU - Krauss-Etschmann, S.* AU - Robichaud, A.* C1 - 54846 C2 - 45914 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Preclinical experiments support recent clinical switch to delivered dose during methacholine bronchoprovocation testing. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Smirnova, N.F. AU - Eickelberg, O.* C1 - 52755 C2 - 44300 SP - 981-983 TI - Epithelial progenitor cells take center stage in lung transplantation. JO - Am. J. Respir. Crit. Care Med. VL - 197 IS - 8 PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Smirnova, N.F. AU - Morrone, C. AU - Conlon, T.M. AU - von Toerne, C. AU - Hauck, S.M. AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 54880 C2 - 45913 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - A quantitative proteomics profiling of murine lung grafts indicates novel pathways associated with chronic lung allograft dysfunction. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Yu, B.* AU - Flexeder, C. AU - Wyss, A.* AU - North, K.E.* AU - Boerwinkle, E.* AU - Schulz, H. AU - London, S.* C1 - 54839 C2 - 45919 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa TI - Untargeted metabolomics analysis identifies novel biomarkers for pulmonary function in multi-ethnic populations. JO - Am. J. Respir. Crit. Care Med. VL - 197 PB - Amer Thoracic Soc PY - 2018 SN - 1073-449X ER - TY - JOUR AU - Alsafadi, H.N. AU - Lehmann, M. AU - Lindner, M.* AU - Peschel, B. AU - Königshoff, M. AU - Wagner, D.E. C1 - 51328 C2 - 42944 CY - New York TI - An ex vivo human model of idiopathic pulmonary fibrosis using precision cut lung slices. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Baarsma, H.A. AU - Skronska-Wasek, W. AU - Mutze, K. AU - Ciolek, F. AU - Wagner, D.E. AU - John-Schuster, G. AU - Heinzelmann, K. AU - Guenther, A.* AU - Bracke, K.R.* AU - Dagouassat, M.* AU - Boczkowski, J.* AU - Brusselle, G.G.* AU - Smits, R.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. AU - Königshoff, M. C1 - 51324 C2 - 42941 CY - New York TI - Non-canonical Wnt-5a signaling impairs endogenous lung repair in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ciolek, F.* AU - Heinzelmann, K. AU - Eickelberg, O. AU - Königshoff, M.* AU - Baarsma, H.* C1 - 51341 C2 - 43014 CY - New York TI - Regulation and function of non-canonical Wnt-5a in human lung fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Hackl, M. AU - Bartel, J. AU - Krumsiek, J. AU - Irmler, M. AU - Beckers, J. AU - Theis, F.J. AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 51334 C2 - 43021 CY - New York TI - 2d cross-omics integrated enrichment analysis of human and mice COPD lungs reveal novel pathological mechanisms of disease progression. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Jia, J. AU - Gao, J. AU - Heinzelmann, K. AU - Tasdemir, D.* AU - Bayram, H.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 51335 C2 - 43019 CY - New York TI - Loss of the cholesterol metabolizing enzyme Ch25h protects against cigarette smoke-induced COPD. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ege, M.J. C1 - 50765 C2 - 42743 CY - New York SP - 546-548 TI - Asthma and prenatal inflammation. JO - Am. J. Respir. Crit. Care Med. VL - 195 IS - 5 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Roy, R.* AU - Greiffo, F.R. AU - Frankenberger, M. AU - Behr, J.* AU - Forrest, A.R.* AU - Eickelberg, O.* C1 - 51332 C2 - 43023 CY - New York TI - Quantitative proteomics reveals novel fibrotic networks of myeloid-derived suppressor cell and monocytes in ipf. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ganguly, K.* AU - George, L.* AU - Thimraj, T.A.* AU - Upadhyay, S.* AU - Schulz, H. AU - Stöger, T. C1 - 51326 C2 - 42945 CY - New York TI - Skewed alveolar macrophage polarization signature in mice with impaired pulmonary function following carbon nanoparticle exposure. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AB - Rationale: The evidence supporting an association between traffic related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. Objectives: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. Methods: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among, air pollution exposure, methylation, and transcriptomic patterns. Measurements and Main Results: In the European cohorts, 186 SNPs had an interaction P < 1 x 10(-4) and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 x 10(-4)). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc beta-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P =1.18 x 10(-17)). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. Conclusions: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2. AU - Gref, A.* AU - Merid, S.K.* AU - Gruzieva, O.* AU - Ballereau, S.* AU - Becker, A.* AU - Bellander, T.* AU - Bergstrom, A.* AU - Bosse, Y.* AU - Bottai, M.* AU - Chan-Yeung, M.* AU - Fuertes, E. AU - Ierodiakonou, D.* AU - Jiang, R.X.* AU - Joly, S.* AU - Jones, M.* AU - Kobor, M.S.* AU - Korek, M.* AU - Kozyrskyj, A.L.* AU - Kumar, A.* AU - Lemonnier, N.* AU - MacIntyre, E.A. AU - Menard, C.* AU - Nickle, D.C.* AU - Obeidat, M.* AU - Pellet, J.* AU - Standl, M. AU - Saaf, A.* AU - Söderhäll, C.* AU - Tiesler, C.M.T.* AU - van den Berge, M.* AU - Vonk, J.M.* AU - Vora, H.* AU - Xu, C.* AU - Antò, J.M.* AU - Auffray, C.* AU - Brauer, M.* AU - Bousquet, J.* AU - Brunekreef, B.* AU - Gauderman, W.J.* AU - Heinrich, J. AU - Kere, J.* AU - Koppelman, G.H.* AU - Postma, D.* AU - Carlsten, C.* AU - Pershagen, G.* AU - Melén, E.* C1 - 51215 C2 - 42880 CY - New York SP - 1373-1383 TI - Genome-wide interaction analysis of air pollution exposure and childhood asthma with functional follow-up. JO - Am. J. Respir. Crit. Care Med. VL - 195 IS - 10 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Greiffo, F.R. AU - Fernandez, I.E. AU - Frankenberger, M. AU - Ortega-Gomez, A.* AU - Behr, J.* AU - Soehnlein, O.* AU - Eickelberg, O.* C1 - 51330 C2 - 43016 CY - New York TI - Monocyte immunophenotyping reflects aberrant activation patterns in interstitial lung disease patients. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Griswold, E.D.* AU - Wrenn, S.M.* AU - Uhl, F.E.* AU - Coffey, A.L.* AU - Dearborn, J.S.* AU - Hommel, R.J.* AU - Ahlers, B.A.* AU - Deng, B.* AU - Lam, Y.W.* AU - Wagner, D.E. AU - Weiss, D.J.* C1 - 51337 C2 - 43018 CY - New York TI - Avian lung bioengineering. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Heinzelmann, K. AU - Noskovicova, N. AU - Lehmann, M. AU - Lindner, M.* AU - Hatz, R.* AU - Behr, J.* AU - Königshoff, M.* AU - Eickelberg, O.* C1 - 51331 C2 - 43024 CY - New York TI - Cd82 is a novel mediator of fibroblast proliferation. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Hilgendorff, A. AU - Foerster, K.* AU - Sass, S. AU - Stoecklein, S.* AU - Dietrich, O.* AU - Pomschar, A.* AU - Schulze, A.* AU - Huebener, C.* AU - Theis, F.J. AU - Erhardt, H.* AU - Flemmer, A.W.* AU - Ertl-Wagner, B.* C1 - 51320 C2 - 42937 CY - New York TI - Discrimination of pulmonary changes in neonatal chronic lung disease by a new Mri score. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Hilgendorff, A. AU - Pritzke, T. AU - Markmann, M.* AU - Oak, P. AU - Koschlig, M. AU - Hossain, H.* AU - Desai, T.* C1 - 51345 C2 - 42985 CY - New York TI - Time dependant effects of mechanical ventilation and hyperoxia on central signalling pathways in the developing lung identified by comprehensive transcriptome analysis. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Knowledge about the prevalence of objectively assessed peripheral artery disease (PAD) and its clinical relevance in patients with COPD is scarce. OBJECTIVES: We aimed (1) to assess the prevalence of PAD in COPD compared to distinct control groups and (2) to study the association between PAD and functional capacity as well as health status. METHODS: The ankle-brachial index (ABI) was used to diagnose PAD (ABI≤0.9). 6-Minute-Walk-Distance (6MWD), health status (St. George's Respiratory Questionnaire [SGRQ]), COPD Assessment Test [CAT] and EuroQol-5-Dimensions [EQ-5D-3L] were assessed in patients enrolled in the German COPD and Systemic Consequences-Comorbidities Network (COSYCONET) cohort study. Control groups were derived from the Study of Health in Pomerania (SHIP). MEASUREMENTS AND MAIN RESULTS: 2,088 patients with COPD (61.1% male, mean [SD] age 65.3 [8.2] years GOLD stage I,II,III,IV: 9.4%,42.5%,37.5%,10.5%, respectively) were included. 184 patients (8.8%; GOLD stage I,II,III,IV: 5.1%,7.4%,11.1%,9.5%, respectively, versus 5.9% in patients with GOLD stage 0 in COSYCONET) had PAD. In SHIP, PAD ranged from 1.8% to 4.2%. COPD patients with PAD had a significantly shorter 6MWD (356 [108] vs 422 [103] m, p<0.001) and worse health status (SGRQ: 49.7 [20.1] vs 42.7 [20.0] points, p<0.001, CAT: 19.6 [7.4] vs 17.9 [7.4] points, p=0.004, EQ-5D VAS: 51.2 (19.0) vs 7.2 (19.6), p<0.001). Differences remained significant after correction for several confounders. CONCLUSIONS: In a large cohort of patients with COPD, 8.8% were diagnosed with PAD which is higher than the prevalence in non-COPD controls. PAD was associated with a clinically relevant reduction in functional capacity and health status. AU - Houben-Wilke, S.* AU - Jörres, R.A.* AU - Bals, R.* AU - Franssen, F.M.* AU - Gläser, S.* AU - Holle, R. AU - Karch, A.* AU - Koch, A.* AU - Magnussen, H.* AU - Obst, A.* AU - Schulz, H. AU - Spruit, M.A.* AU - Wacker, M. AU - Welte, T.* AU - Wouters, E.F.* AU - Vogelmeier, C.* AU - Watz, H.* C1 - 49278 C2 - 41730 SP - 189-197 TI - Peripheral artery disease and its clinical relevance in patients with chronic obstructive pulmonary disease in the COPD and systemic consequences-comorbidities network study. JO - Am. J. Respir. Crit. Care Med. VL - 195 IS - 2 PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Houssaini, A.* AU - Breau, M.* AU - Kebe, K.* AU - Abid, S.* AU - Marcos, E.* AU - Lipskaia, L.* AU - Rideau, D.* AU - Parpaleix, A.* AU - Huang, J.* AU - Amsellem, V.* AU - Maitre, B.* AU - Bizard, E.* AU - Vienney, N.* AU - Luka, C. AU - Validyre, P.* AU - Boczkowski, J.* AU - Derumeaux, G.* AU - Bernard, D.* AU - Meiners, S. AU - Adnot, S.* C1 - 51318 C2 - 42935 CY - New York TI - Activation of the Mtor pathway drives lung cell senescence and emphysema in chronic obstructive pulmonary disease (COPD). JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Jarosch, I.* AU - Schneeberger, T.* AU - Gloeckl, R.* AU - Kreuter, M.* AU - Benstz, J.* AU - Frankenberger, M. AU - Neurohr, C.* AU - Prasse, A.* AU - Behr, J.* AU - Kenn, K.* C1 - 51336 C2 - 43020 CY - New York TI - Different effects of pulmonary rehabilitation in Anxious Vs. Non-Anxious patients with idiopathic pulmonary fibrosis - a pilot study. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - John-Schuster, G. AU - Conlon, T.M. AU - Günter, S. AU - Eickelberg, O.* AU - Heikenwalder, M.* AU - Yildirim, A.Ö. C1 - 51333 C2 - 43022 CY - New York TI - Lymphotoxin-beta-receptor blockade prevents cigarette smoke-induced COPD. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Kahnert, K.* AU - Lucke, T.* AU - Biertz, F.* AU - Lechner, A.* AU - Alter, P.* AU - Bals, R.* AU - Watz, H.* AU - Behr, J.* AU - Holle, R. AU - Huber, R.M.* AU - Karrasch, S.* AU - Stubbe, B.* AU - Wacker, M. AU - Söhler, S.* AU - Wouters, E.F.M.* AU - Vogelmeier, C.* AU - Jörres, R.* C1 - 51327 C2 - 42946 CY - New York TI - Transfer factor for carbon monoxide in patients with COPD and diabetes: Results from the German Cosyconet Cohort. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Kammerl, I.E. AU - Chen, S. AU - Vergara, E.E. AU - Irmler, M. AU - Beckers, J. AU - Muchamuel, T.* AU - Kirk, C.* AU - Florea, B.I.* AU - Overkleeft, H.S.* AU - Eickelberg, O. AU - Meiners, S. AU - Stöger, T. C1 - 51323 C2 - 42940 CY - New York TI - Deficiency of immunoproteasome subunits increases alternative polarization of alveolar macrophages. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Lehmann, M. AU - Buhl, L. AU - Klee, S. AU - Wagner, D.E. AU - Behr, J. AU - Lindner, M.* AU - Königshoff, M. C1 - 51342 C2 - 42984 CY - New York TI - Effects of nintedanib and pirfenidone on alveolar epithelial cells in 2d and 3d lung cultures. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Lopez, C.B. AU - Conlon, T.M. AU - Ertuez, Z. AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 51325 C2 - 42942 CY - New York TI - Inflammatory response of lung recruited macrophages is partly regulated by non-canonical notch pathway in chronic obstructive pulmonary diseases (COPD). JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Maldonado, M.* AU - Ortiz-Quintero, B.* AU - Herrera, I.* AU - Ramirez, R.* AU - Staab-Weijnitz, C.A. AU - Eickelberg, O.* AU - Salgado-Aguayo, A.* AU - Selman, M.* AU - Pardo, A.* C1 - 51339 C2 - 43015 CY - New York TI - Matrix metalloproteinase (mmp)-28 is expressed in alveolar epithelial cells in idiopathic pulmonary fibrosis and increases their proliferation and migration. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Medina, A.M.* AU - Vierkotten, S.* AU - Lehmann, M.* AU - Wagner, D.* AU - Baarsma, H.* AU - Höfer, T.* AU - Frankerberger, M.* AU - Behr, J.* AU - Aichler, M. AU - Walch, A.* AU - Königshoff, M.* C1 - 51315 C2 - 42933 CY - New York TI - Wnt5a is secreted by extracellular vesicles in pulmonary fibrosis and increases fibroblasts proliferation. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ng-Blichfeldt, J.* AU - Ota, C. AU - Stolk, J.* AU - Hiemstra, P.* AU - Gosens, R.* AU - Königshoff, M.* C1 - 51316 C2 - 42932 CY - New York TI - Wnt activity marks lung progenitors capable of forming spheres in vitro. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Noskovicova, N. AU - Heinzelmann, K. AU - Burgstaller, G. AU - Eickelberg, O.* C1 - 51329 C2 - 42943 CY - New York TI - Cub domain containing protein 1/transforming growth factor-beta 1 cross-talk regulates (myo)fibroblast differentiation. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Oak, P. AU - Pritzke, T. AU - Koschlig, M. AU - Windhorst, A.* AU - Jain, N. AU - Reicherzer, T.* AU - Ehrhardt, H.* AU - Frankenberger, M. AU - Schwarz, M.A.* AU - Hilgendorff, A. C1 - 51321 C2 - 42938 CY - New York TI - Monocyte-centred inflammatory response driving pulmonary injury in neonatal chronic lung disease. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Oak, P. AU - Kamgari, N. AU - Pritzke, T. AU - John-Schuster, G. AU - Jia, J. AU - Yildirim, A.Ö. AU - Hilgendorff, A. C1 - 51322 C2 - 42939 CY - New York TI - Enhanced vulnerability of the developing lungs by moderate prenatal cigarette smoke upon postnatal injury. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ota, C. AU - Ng-Blichfeldt, J.* AU - Mutze, K.* AU - Baarsma, H.* AU - Skronska-Wasek, W.* AU - Königshoff, M. C1 - 51344 C2 - 43012 CY - New York TI - Hopx-Wnt crosstalk regulates alveolar homeostasis. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ryerson, C.J.* AU - Corte, T.J.* AU - Lee, J.S.* AU - Richeldi, L.* AU - Walsh, S.L.F.* AU - Myers, J.L.* AU - Behr, J. AU - Cottin, V.* AU - Danoff, S.K.* AU - Flaherty, K.R.* AU - Lederer, D.J.* AU - Lynch, D.A.* AU - Martinez, F.J.* AU - Raghu, G.* AU - Travis, W.D.* AU - Udwadia, Z.* AU - Wells, A.U.* AU - Collard, H.R.* C1 - 52443 C2 - 43978 CY - New York SP - 1249-1254 TI - A standardized diagnostic ontology for fibrotic interstitial lung disease. An International Working Group Perspective. JO - Am. J. Respir. Crit. Care Med. VL - 196 IS - 10 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Sarker, R.S. AU - Conlon, T.M. AU - Dorer, J. AU - Burgstaller, G. AU - Merthan, L. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Bustin, M.* AU - Furusawa, T.* AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 51317 C2 - 42934 CY - New York TI - Epigenetic histone-1 modulator Hmgn5 regulates cellular apoptosis In COPD pathogenesis. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets. OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across endstage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis. METHODS: We collected samples of ILD tissue (n=45) and healthy donor controls (n=10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n=6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging. MEASUREMENTS AND MAIN RESULTS: We determined the abundance of >7900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteome comparison of lung and skin fibrosis identified a common upregulation of MZB1, the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG, and negatively with diffusing capacity of the lung for carbon monoxide (DLCO). CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1+ plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis (IPF). AU - Schiller, H. B. AU - Mayr, C.H. AU - Leuschner, G. AU - Strunz, M. AU - Staab-Weijnitz, C.A. AU - Preisendörfer, S. AU - Eckes, B.* AU - Moinzadeh, P.* AU - Krieg, T.* AU - Schwartz, D.A.* AU - Hatz, R.A.* AU - Behr, J.* AU - Mann, M.* AU - Eickelberg, O. C1 - 51416 C2 - 43217 CY - New York SP - 1298-1310 TI - Deep proteome profiling reveals common prevalence of MZB1-positive plasma B cells in human lung and skin fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 196 IS - 10 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. WNT/β-catenin signaling is reduced in COPD, however, the mechanisms thereof, specifically the role of WNT receptors Frizzled (FZD), remains unexplored. OBJECTIVE: To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. METHODS: FZD receptor expression was analyzed in lung homogenates and primary alveolar epithelial type II (ATII) cells of never-smokers, smokers, and COPD patients, as well as two experimental emphysema models by qRT-PCR, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on WNT/β-catenin signaling and FZD4 function were investigated in primary ATII cells and cell lines. Gain- and loss-of-function approaches were applied to determine the effects of increased/decreased FZD4 expression on alveolar epithelial cell viability, wound repair, and elastogenesis. MEASUREMENTS AND MAIN RESULTS: FZD4 receptor expression was reduced in human and experimental COPD lung tissues as well as primary human ATII cells from COPD patients. Cigarette smoke exposure downregulated FZD4 expression in vitro and in vivo, along with reduced WNT target gene expression. Inhibition of FZD4 decreased WNT/β-catenin activity and epithelial cell proliferation, and interfered with ATII to ATI cell trans-differentiation, whereas FZD4 overexpression augmented WNT/β-catenin signaling and epithelial cell proliferation. Moreover, FZD4 overexpression rescued the cigarette smoke-induced decrease in elastin expression. CONCLUSIONS: Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity. Thus, FZD4 represents a potential therapeutic target for COPD. AU - Skronska-Wasek, W. AU - Mutze, K. AU - Baarsma, H.A. AU - Alsafadi, H.N. AU - Lehmann, M. AU - Costa, R. AU - Wagner, D.E. AU - Yildirim, A.Ö. AU - Königshoff, M. C1 - 50630 C2 - 42542 CY - New York SP - 172-185 TI - Reduced frizzled receptor 4 expression prevents WNT/β-catenin-driven alveolar lung repair in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 196 IS - 2 PB - American Thoracic Society, HighWire Press PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Smirnova, N.F. AU - Conlon, T.M. AU - Yildirim, A.Ö. AU - Eickelberg, O.* C1 - 51319 C2 - 42936 CY - New York TI - Orthotopic lung transplantation in a single- mismatch-based mouse model shows signs of chronic lung allograft dysfunction (clad) associated to inducible bronchus-associated lymphoid tissue (ibalt) formation. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Smirnova, N.F.* AU - Schiller, H. B. AU - Kneidmger, N.* AU - Behr, J.* AU - Mann, M.* AU - Eickelberg, O.* C1 - 51338 C2 - 43017 CY - New York TI - Stratification of chronic lung allograft dysfunction phenotypes using proteomic profiling of bronchoalveolar lavage-fluid. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Ulke, H. AU - Mutze, K. AU - Wagner, D.E. AU - Stein, M.M. AU - Lindner, M.* AU - Behr, J.* AU - Günther, A.* AU - Königshoff, M.* C1 - 51340 C2 - 42983 CY - New York TI - Non-small cell lung cancer (nsclc) gene signature in idiopathic pulmonary fibrosis (ipf). JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Welk, V. AU - Meul, T. AU - Merl-Pham, J. AU - Korfei, M.* AU - Koch, I.* AU - Semren, N. AU - Guenther, A.* AU - Lindner, M.* AU - Hauck, S.M. AU - Eickelberg, O. AU - Meiners, S. C1 - 51343 C2 - 43013 CY - New York TI - Proteasomal activator 200 (pa200) regulates cellular proliferation: A putative role for Ipf and lung cancer pathogenesis. JO - Am. J. Respir. Crit. Care Med. VL - 195 PB - Amer Thoracic Soc PY - 2017 SN - 1073-449X ER - TY - JOUR AU - Alter, P.* AU - Watz, H.* AU - Welte, T.* AU - Gläser, S.* AU - Schulz, H. AU - Bals, R.* AU - Söhler, S.* AU - Karch, A.* AU - Vogelmeier, C.* AU - Jörres, R.A.* C1 - 50402 C2 - 42199 CY - New York TI - Spirometric and bodyplethysmographic lung function is associated with echocardiography-derived ventricular wall stress in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Baarsma, H.A. AU - Skronska-Wasek, W. AU - Mutze, K. AU - Ciolek, F. AU - John-Schuster, G. AU - Dagouassat, M.* AU - Günther, A.* AU - Boczkowski, J.* AU - Smits, R.* AU - Yildirim, A.Ö. AU - Königshoff, M. C1 - 50395 C2 - 42288 CY - New York TI - Non-canonical Wnt-5a compromises endogenous lung repair In COPD. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Idiopathic Pulmonary fibrosis (IPF) is a devastating disease, which remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: Matriptase expression was assessed in tissue specimens from IPF patients versus controls using qRT-PCR, immunohistochemistry and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptase-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate, or by genetic down regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: Matriptase expression and activity were upregulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by TGF-β. Further, matriptase elicited signaling via Protease-Activated Receptor-2 (PAR-2), and promoted fibroblast activation, proliferation and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor camostat mesilate or by genetic down-regulation, diminished lung injury, collagen production and TGF-β expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by camostat mesilate, which is already in clinical use for other diseases, may represent potential therapies for IPF. AU - Bardou, O.* AU - Menou, A.* AU - François, C.* AU - Duitman, J.W.* AU - von der Thüsen, J.H.* AU - Borie, R.* AU - Sales, K.U.* AU - Mutze, K. AU - Castier, Y.* AU - Sage, E.H.* AU - Liu, L.* AU - Bugge, T.H.* AU - Fairlie, D.P.* AU - Königshoff, M. AU - Crestani, B.* AU - Borensztajn, K.S.* C1 - 47406 C2 - 40575 CY - New York SP - 847-860 TI - Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis. JO - Am. J. Respir. Crit. Care Med. VL - 193 IS - 8 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Behr, J. AU - Wirtz, H.* AU - Prasse, A.* AU - Pittrow, D.* AU - Klotsche, J.* AU - Koschel, D.* AU - Andreas, S.* AU - Claussen, M.* AU - Grohe, C.* AU - Kreuter, M.* C1 - 50387 C2 - 42293 CY - New York TI - Predictors of mortality in patients with idiopathic pulmonary fibrosis under clinical practice conditions: Insights-Ipf registry. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Bonella, F.* AU - Kreuter, M.* AU - Hagmeyer, L.* AU - Neurohr, C. AU - Keller, C.* AU - Kohlhaeufl, M.* AU - Mueller-Quernheim, J.* AU - Milger, K. AU - Prasse, A.* C1 - 50384 C2 - 42223 CY - New York TI - Insights from a multi-centre real life experience in Germany with nintedanib for the Tteatment of idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Ciolek, F. AU - Königshoff, M. AU - Baarsma, H.A. C1 - 50389 C2 - 42294 CY - New York TI - Regulation of non-canonical Wnt-5a by primary human lung fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Merthan, L. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Furusawa, T.* AU - Bustin, M.* AU - Eickelberg, O. AU - Yildirim, A.Ö. C1 - 50394 C2 - 42287 CY - New York TI - Reduced expression of the epigenetic regulator Hmgn5 enhances susceptibility to emphysema. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Greiffo, F.R. AU - Frankenberger, M. AU - Heinzelmann, K. AU - Neurohr, C. AU - Hatz, R.* AU - Behr, J. AU - Eickelberg, O. C1 - 50403 C2 - 42281 CY - New York TI - Peripheral blood myeloid-derived suppressor cells reflect disease status In Ipf. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Ganguly, K.* AU - George, L.* AU - Irmler, M. AU - Mitra, A.* AU - Thimraj, T.A.* AU - Beckers, J. AU - Upadhyay, S.* AU - Schulz, H. AU - Leikauf, G.D.* C1 - 50393 C2 - 42286 CY - New York TI - Mouse lung developmental gene expression profiling study identifies novel candidate genes for pulmonary function. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Houssaini, A.* AU - Kebe, K.* AU - Breau, M.* AU - Marcos, E.* AU - Huang, J.* AU - Attwe, A.* AU - Bizard, E.* AU - Abid, S.* AU - Validire, P.* AU - Maitre, B.* AU - Meiners, S. AU - Amsellem, V.* AU - Adnot, S.* C1 - 50406 C2 - 42194 CY - New York TI - Targeting the mtor signaling pathway to inhibit lung cell senescence In chronic obstructive pulmonary disease (COPD). JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Jia, J. AU - Conlon, T.M. AU - Lopez, C.B. AU - Eickelberg, O. AU - Mall, M.A.* AU - Yildirim, A.Ö. C1 - 50383 C2 - 42218 CY - New York TI - Chronic bronchitis enhancement in newborn mice from exposure to environmental tobacco smoke. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Chronic obstructive pulmonary disease patients and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. OBJECTIVES: To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. METHODS: Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors, COPD, and IPF patients, as well as in cigarette smoke-exposed mice. Smoke-mediated alteration of immunoproteasome activity and MHC I surface expression were analysed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. MEASUREMENTS AND MAIN RESULTS: Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of COPD patients and in isolated alveolar macrophages of COPD and IPF patients. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. CONCLUSIONS: We here show for the first time that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF. AU - Kammerl, I.E. AU - Dann, A. AU - Mossina, A. AU - Brech, D. AU - Lukas, C. AU - Vosyka, O. AU - Nathan, P. AU - Conlon, T.M. AU - Wagner, D.E. AU - Overkleeft, H.S.* AU - Prasse, A.* AU - Rosas, I.O.* AU - Straub, T.* AU - Krauss-Etschmann, S.* AU - Königshoff, M. AU - Preissler, G.* AU - Winter, H.* AU - Lindner, M.* AU - Hatz, R.A.* AU - Behr, J. AU - Heinzelmann, K. AU - Yildirim, A.Ö. AU - Nößner, E. AU - Eickelberg, O. AU - Meiners, S. C1 - 47676 C2 - 39715 CY - New York SP - 1230-1241 TI - Impairment of immunoproteasome function by cigarette smoke and in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 193 IS - 11 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Keller, I.E. AU - Dann, A. AU - Lukas, C. AU - Brech, D. AU - Vosyka, O. AU - Nössner, E. AU - Eickelberg, O. AU - Meiners, S. C1 - 50391 C2 - 42290 CY - New York TI - Proteasome-dependent Mhc I antigen presentation is altered by cigarette smoke. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Klee, S. AU - Lehmann, M. AU - Wagner, D.E. AU - Baarsma, H.A. AU - Königshoff, M. C1 - 50404 C2 - 42263 CY - New York TI - Wisp1 mediates Il6-dependent proliferation in healthy and Ipf-derived primary human lung fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Knüppel, L. AU - Ishikawa, Y.* AU - Heinzelmann, K. AU - Hatz, R.* AU - Behr, J.* AU - Bachinger, H.* AU - Eickelberg, O. AU - Staab-Weijnitz, C.A. C1 - 50386 C2 - 42313 CY - New York TI - Effects of nintedanib and pirfenidone on expression and maturation of collagen - A comprehensive analysis. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Koschlig, M. AU - Tian, X.* AU - Sudheendra, D.* AU - Spiekerkoetter, E.F.* AU - Hilgendorff, A.* C1 - 50398 C2 - 42285 CY - New York TI - Enhanced effects of hyperoxia on Vessel development in newborn mice heterozygote for the bmp receptor 2. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Evidence on short-term effects of ultrafine particles (UFP) on health is still inconsistent and few multi-center studies have been conducted so far especially in Europe. OBJECTIVES: Within the UFIREG project, we investigated the short-term effects of UFP and fine particulate matter <2.5 µm (PM2.5) on daily cause-specific hospital admissions in five Central and Eastern European cities using harmonized protocols for measurements and analyses. METHODS: Daily counts of cause-specific hospital admissions were obtained for Augsburg and Dresden (Germany) 2011-2012, Chernivtsi (Ukraine) 2013-March 2014, Ljubljana (Slovenia) and Prague (Czech Republic) 2012-2013 focusing on cardiovascular and respiratory diseases. Air pollution and meteorological data were measured at fixed monitoring sites in all cities. We analyzed city-specific associations using confounder-adjusted Poisson regression models and pooled the city-specific effect estimates using meta-analyses methods. MAIN RESULTS: A 2,750 particles/cm3 increase (average interquartile range (IQR) across all cities) in the 6-day average of UFP indicated a delayed and prolonged increase in the pooled relative risk of respiratory hospital admissions (3.4% [95%-confidence interval:-1.7%;8.8%]). We also found increases in the pooled relative risk of cardiovascular (exposure average of lag 2-5: 1.8% [0.1%;3.4%]) and respiratory (6-day average exposure: 7.5% [4.9%;10.2%]) admissions per 12.4 µg/m3 increase (average IQR) in PM2.5. CONCLUSIONS: Our findings indicated delayed and prolonged effects of UFP exposure on respiratory hospital admissions in Central and Eastern Europe. Cardiovascular and respiratory hospital admissions increased in association with an increase in PM2.5. Further multi-center studies are needed using harmonized UFP measurements to draw definite conclusions on health effects of UFP. AU - Lanzinger, S. AU - Schneider, A.E. AU - Breitner-Busch, S. AU - Stafoggia, M.* AU - Erzen, I.* AU - Dostal, M.* AU - Pastorkova, A.* AU - Bastian, S.* AU - Cyrys, J. AU - Zscheppang, A.* AU - Kolodnitska, T.* AU - Peters, A. C1 - 48667 C2 - 41261 CY - New York SP - 1233-1241 TI - Ultrafine and fine particles and hospital admissions in Central Europe: Results from the UFIREG study. JO - Am. J. Respir. Crit. Care Med. VL - 194 IS - 10 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Lehmann, M. AU - Mutze, K. AU - Schiller, H.B. AU - Wagner, D.E. AU - Königshoff, M. C1 - 50388 C2 - 42292 CY - New York TI - Increased alveolar epithelial cell senescence in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Mummler, C. AU - Vierkotten, S. AU - Mutze, K. AU - Günther, A.* AU - Königshoff, M. C1 - 50401 C2 - 42198 CY - New York TI - Runt-related transcription factor 2 (runx2) regulates mesenchymal cell differentiation and extracellular matrix production in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Oak, P. AU - Koschlig, M. AU - Windhorst, A.* AU - Jain, N. AU - Reicherzer, T.* AU - Ehrhardt, H.* AU - Frankenberger, M. AU - Alvira, C.M.* AU - Schwarz, M.A.* AU - Eickelberg, O. AU - Hilgendorff, A. C1 - 50381 C2 - 42220 CY - New York TI - Monocyte-centred inflammatory response characterizing early stages of Bpd development in the preterm infant. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Platz, J.* AU - Bonenfant, N.R.* AU - Uhl, F.E.* AU - Coffey, A.* AU - McKnight, T.* AU - Parsons, C.* AU - Sokocevic, D.* AU - Borg, Z.D.* AU - Lam, Y.W.* AU - Deng, B.* AU - Fields, J.G.* AU - Desarno, M.* AU - Loi, R.* AU - Hoffmann, A.L.* AU - Bianchi, J.* AU - Dacken, B.* AU - Wagner, D.E. AU - Weiss, D.J.* C1 - 50382 C2 - 42219 CY - New York TI - Comparative decellularization and recellularization of wild type and alpha 1,3 galactosyltransferase knockout pig lungs: A model for ex vivo xenogeneic lung bioengineering and transplantation. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Psallidas, I.* AU - Kanellakis, N.I.* AU - Vreka, M.* AU - Giannou, A.D.* AU - Maniatis, L.* AU - Magkouta, S.* AU - Moschos, C.* AU - Giopanou, I.* AU - Agalioti, T.* AU - Lillis, I.* AU - Kalomenidis, I.* AU - Rahman, N.M.* AU - Stathopoulos, G.T. C1 - 50405 C2 - 42193 CY - New York TI - Osteopontin as an airway epithelial tumor promoter. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Schmid, O. AU - Möller, W. AU - Stelzl, A. AU - Amarie, O.V. AU - Eickelberg, O. AU - Yildirim, A.Ö. C1 - 50407 C2 - 42195 CY - New York TI - Towards standardized airway hyperresponsiveness measurements In mice. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Skronska-Wasek, W. AU - Mutze, K. AU - Baarsma, H.A. AU - Wagner, D.E. AU - Stornaiuolo, M.* AU - Königshoff, M. C1 - 50390 C2 - 42291 CY - New York TI - Cigarette smoke-induced downregulation of the epithelial cell enriched WNT receptor Fzd4 contributes to reduced Wnt/beta-catenin signaling and alveolar epithelial cell proliferation in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Staab-Weijnitz, C.A. AU - Schamberger, A.C. AU - Fernandez, I.E. AU - Schiller, H. B. AU - Heinzelmann, K. AU - Sterclova, M.* AU - Vasakova, M.* AU - Mann, M.* AU - Eickelberg, O. C1 - 50396 C2 - 42283 CY - New York TI - Expression and regulation of glutathione peroxidase 3 in interstitial lung disease. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Stelzer, D.* AU - Ihle, F. AU - Weber, A.* AU - Kneidinger, N. AU - Zimmermann, G. AU - Ceelen, F. AU - Schramm, R.* AU - Winter, H.* AU - Frey, L.* AU - Andraschko, M.* AU - Vogeser, M.* AU - Behr, J. AU - Neurohr, C. C1 - 50399 C2 - 42282 CY - New York TI - Impact of posaconazol liquid vs. tablet formulation on plasma trough levels in lung transplant recipients. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Strange, C.B.* AU - Herth, F.J.F.* AU - Valipour, A.* AU - Shah, P.L.* AU - Eberhardt, R.* AU - Grah, C.* AU - Egan, J.* AU - Ficker, J.H.* AU - Wagner, M.* AU - Witt, C.* AU - Liebers, U.* AU - Hopkins, P.N.* AU - Gesierich, W. AU - Phillips, M.A.* AU - Stanzel, F.* AU - McNulty, W.* AU - Petermann, C.* AU - Snell, G.I.* AU - Gompelmann, D.* C1 - 50379 C2 - 42222 CY - New York TI - Step-up randomized controlled trial of segmental vapor ablation in patients with severe emphysema: 6 month results. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Uhl, F.E.* AU - Zvarova, B.* AU - Fields, J.G.* AU - Deng, B.* AU - Lam, Y.W.* AU - Weiss, D.J.* AU - Wagner, D.E. C1 - 50392 C2 - 42289 CY - New York TI - Enhanced mass spectrometry-based proteomics can be used to distinguish differences in protein compositions of acellular emphysematous versus normal lungs. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Wacker, M.E. AU - Jörres, R.A.* AU - Schulz, H. AU - Heinrich, J. AU - Karrasch, S. AU - Karch, A.* AU - Koch, A.* AU - Leidl, R. AU - Vogelmeier, C.* AU - Holle, R. C1 - 50380 C2 - 42221 CY - New York TI - How do symptoms and comorbidities affect healthcare costs in patients with COPD? Results from the new German cosyconet cohort. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Wagner, D.E. AU - Mutze, K. AU - Schiller, H.B. AU - Costa, R. AU - Kaminski, N.* AU - Königshoff, M. C1 - 50385 C2 - 42279 CY - New York TI - Hippo signaling is deranged in idiopathic pulmonary fibrosis and correlates with disease severity. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Welk, V. AU - Semren, N. AU - Korfei, M.* AU - Günther, A.* AU - Eickelberg, O. C1 - 50397 C2 - 42284 CY - New York TI - Proteasome activator 200 (pa200) is dysregulated in fibrotic remodeling of the lung. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AB - Background: Pulmonary fibrosis encompasses a group of lung-scarring disorders that occur owing to known or unknown insults and accounts for significant morbidity and mortality. Despite intense investigation spanning decades, much remains to be learned about the natural history, pathophysiology, and biologic mechanisms of disease. Purpose: To identify the most pressing research needs in the lung fibrosis community and to provide a roadmap of priorities to investigators, funding agencies, patient advocacy groups, and other interested stakeholders. Methods: An ad hoc international working group of the American Thoracic Society with experience in clinical, translational, and bench-based research in fibrotic lung diseases was convened. The group used an iterative consensus process to identify successes and challenges in pulmonary fibrosis research. Measurements and Main Results: The group identified five main priority areas in which substantial resources should be invested to advance our understanding and to develop novel therapies for patients with pulmonary fibrosis. These priorities include develop newer models of human lung fibrosis, engage current and new stakeholders to provide sustained funding for the initiatives, create a global infrastructure for storing patient-derived materials, establish collaborative preclinical and clinical research networks in fibrotic lung disease, and create a global lung fibrosis initiative that unites these multifaceted efforts into a single virtual umbrella structure. Conclusions: Despite recent advances in the treatment of some forms of lung fibrosis, many gaps in knowledge about natural history, pathophysiology, and treatment remain. Investment in the research priorities enumerated above will help address these shortcomings and enhance patient care worldwide.   AU - White, E.S.* AU - Borok, Z.* AU - Brown, K.* AU - Eickelberg, O. AU - Guenther, A.* AU - Jenkins, R.* AU - Kolb, M.* AU - Martinez, F.J.* AU - Roman, J.* AU - Sime, P.* C1 - 50319 C2 - 42096 SP - 792-800 TI - An american thoracic society official research statement: Future directions in lung fibrosis research. JO - Am. J. Respir. Crit. Care Med. VL - 193 IS - 7 PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Wrenn, S.* AU - Coffey, A.* AU - Uhl, F.E.* AU - Bianchi, J.* AU - Dacken, B.* AU - Petersen, T.* AU - Wagner, D.E. AU - Boyson, J.E.* AU - Weiss, D.J.* C1 - 50400 C2 - 42197 CY - New York TI - Decellularized wild type and alpha-galactosyltransferase knockout pig lungs stimulate M2 phenotype in human monocyte/macrophages. JO - Am. J. Respir. Crit. Care Med. VL - 193 PB - Amer Thoracic Soc PY - 2016 SN - 1073-449X ER - TY - JOUR AU - Baarsma, H.A. AU - Boczkowski, J.* AU - Yildirim, A.Ö. AU - Königshoff, M. C1 - 48943 C2 - 41539 CY - New York TI - Age-related Wnt5a contributes to disturbed alveolar epithelial cell repair in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Conlon, T.M. AU - Adamski, J. AU - Eickelberg, O.* AU - Yildirim, A.Ö. C1 - 48939 C2 - 41542 CY - New York TI - L-carnitine supplementation attenuates elastase-induced emphysema progression. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Eickelberg, O. AU - Hunninghake, G.M.* C1 - 43288 C2 - 36565 SP - 366-368 TI - A first glimpse at the early origins of idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 191 IS - 4 PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Schiller, H.B.* AU - Conlon, T.M. AU - Yildirim, A.Ö. AU - Mann, M.* AU - Eickelberg, O. C1 - 48955 C2 - 41527 CY - New York TI - Proteome alterations in the aging murine lung affect basement membrane composition. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Fernandez, I.E. AU - Na, S. AU - Wei, M. AU - Aichler, M. AU - Walch, A.K. AU - Eickelberg, O. C1 - 48959 C2 - 41524 CY - New York TI - In-situ detection of pirfenidone and endogenous metabolites by maldi-imaging mass spectrometry in fibrotic tissue. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AB - RATIONALE AND OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1726 German sarcoidosis cases and 5482 controls were genotyped for 128,705 SNPs using the Illumina Immunochip for the screening step. The remaining 3955 cases, 7514 controls and 684 parents of affected offspring were used for validation and replication of 44 candidate and 2 established risk SNPs. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1) and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA-region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17-signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics. AU - Fischer, A.* AU - Ellinghaus, D.* AU - Nutsua, M.* AU - Hofmann, S.* AU - Montgomery, C.G.* AU - Iannuzzi, M.C.* AU - Rybicki, B.A.* AU - Petrek, M.* AU - Mrazek, F.* AU - Pabst, S.* AU - Grohe, C.* AU - Grunewald, J.* AU - Ronninger, M.* AU - Eklund, A.* AU - Padyukov, L.* AU - Mihailovic-Vucinic, V.* AU - Jovanovic, D.L.* AU - Sterclova, M.* AU - Homolka, J.* AU - Nöthen, M.M.* AU - Herms, S.* AU - Gieger, C. AU - Strauch, K. AU - Winkelmann, J. AU - Boehm, B.O.* AU - Brand, S.* AU - Büning, C.* AU - Schürmann, M.* AU - Ellinghaus, E.* AU - Baurecht, H.* AU - Lieb, W.* AU - Nebel, A.* AU - Müller-Quernheim, J.* AU - Franke, A.* AU - Schreiber, S.* C1 - 45130 C2 - 37246 SP - 727-736 TI - Identification of immune-relevant factors conferring sarcoidosis genetic risk. JO - Am. J. Respir. Crit. Care Med. VL - 192 IS - 6 PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Heinzelmann, K. AU - Bretschneider, N.* AU - Scherf, M.* AU - Seifert, M.* AU - Lindner, M.* AU - Preissler, G.* AU - Winter, H.* AU - Hatz, R.A.* AU - Behr, J.* AU - Eickelberg, O. C1 - 48940 C2 - 41541 CY - New York TI - RNA-sequencing identifies a unique cellular profile of COPD fbroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Heinzelmann, K. AU - Noskovicova, N. AU - Merl-Pham, J. AU - Lindner, M.* AU - Hatz, R.A.* AU - Behr, J.* AU - Hauck, S.M. AU - Eickelberg, O. C1 - 48947 C2 - 41535 CY - New York TI - TGF-beta affects nintedanib function via PDGFR alpha in primary human fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Holle, R. AU - Wacker, M. AU - Joerres, R.A.* AU - Schulz, H. AU - Heinrich, J. AU - Peters, A. AU - Koch, A.* AU - Leidl, R. AU - Vogelmeier, C.F.* C1 - 48942 C2 - 41540 CY - New York TI - Do comorbidities have a specific impact on generic Health-Related Quality of Life (HRQL) in COPD patients compared to controls? First results of the German COSYCONET cohort study. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Jia, J. AU - Lopez, C.B. AU - Conlon, T.M. AU - Eickelberg, O. AU - Mall, M.A.* AU - Yildirim, A.Ö. C1 - 48951 C2 - 41531 CY - New York TI - Cigarette smoke exposure is a risk factor for the development of obstructive bronchitis in enac overexpressing mouse. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - John-Schuster, G. AU - Hager, K. AU - Eickelberg, O. AU - Yildirim, A.Ö. C1 - 48962 C2 - 41521 CY - New York TI - Irreversible ibalt following smoking cessation prolonged emphysema development in a cigarette smoke-induced COPD mouse model. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Jörres, R.A.* AU - Biertz, F.* AU - Vogel, C.* AU - Kauczor, H.-U.* AU - Biederer, J.* AU - Jobst, B.* AU - Heinrich, J. AU - Koch, A.* AU - Watz, H.* AU - Welte, T.* AU - Vogelmeier, C.* C1 - 48946 C2 - 41536 CY - New York TI - Prediction of emphysema from lung function parameters and chest CT scans obtained in clinical routine: Results of the German COSYCONET study. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Kamgari, N. AU - Oak, P. AU - Gimm, T. AU - John-Schuster, G. AU - Yildirim, A.Ö. AU - Hilgendorff, A. C1 - 48954 C2 - 41528 CY - New York TI - Moderate prenatal cigarette smoke increases the risk for ventilation induced injury in the developing lung. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Keller, I.E. AU - Vosyka, O. AU - Dann, A. AU - Nathan, P. AU - Takenaka, S. AU - Overkleeft, H.S.* AU - Marcos, E.* AU - Adnot, S.* AU - Ruppert, C.* AU - Günther, A.* AU - Krauss-Etschmann, S. AU - Adler, H. AU - Eickelberg, O. AU - Meiners, S. C1 - 48960 C2 - 41523 CY - New York TI - Impaired immunoproteasome function in COPD. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Koschlig, M. AU - Tian, X.* AU - Sudheendra, D.* AU - Spiekerkoetter, E.* AU - Hilgendorff, A. C1 - 48958 C2 - 41525 CY - New York TI - Fk506 restores reduced Bmp signaling in the lung of mechanically ventilated newborn mice. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Mutze, K. AU - Vierkotten, S. AU - Milosevic, J.* AU - Burgstaller, G. AU - Eickelberg, O. AU - Königshoff, M. C1 - 48953 C2 - 41529 CY - New York TI - Enolase 1 and protein disulfide isomerase associated 3 are novel regulators of Wnt/beta-catenin driven alveolar epithelial plasticity in lung injury and repair. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Oak, P. AU - Jain, N. AU - Koschlig, M. AU - Reicherzer, T.* AU - Ehrhardt, H.* AU - Hilgendorff, A. C1 - 48948 C2 - 41534 CY - New York TI - TGF-beta affects functional properties by altering PDGF signaling in stretched and unstretched neonatal lung (myo)fibroblast. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Schamberger, A.C. AU - Staab-Weijnitz, C.A. AU - Mise, N. AU - Eickelberg, O. C1 - 48957 C2 - 41526 CY - New York TI - Cigarette smoke extract shifts human bronchial basal cell differentiation towards a COPD-associated phenotype. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and timely controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodelling. Dysregulation of the proteasome has been reported for several chronic diseases of the heart, brain, and lung. We hypothesized that proteasome function is altered upon fibrotic lung remodelling, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis (IPF). METHODS: To investigate proteasome function during myofibroblast differentiation, we treated lung fibroblasts with TGF-β and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN RESULTS: We demonstrate that induction of myofibroblast differentiation by TGF-β involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-β-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 was detected during bleomycin-induced lung remodelling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the brochiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. CONCLUSION: Our study identifies Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo and suggests an important role in IPF pathogenesis. AU - Semren, N. AU - Welk, V. AU - Korfei, M.* AU - Keller, I.E. AU - Fernandez, I.E. AU - Adler, H. AU - Günther, A.* AU - Eickelberg, O. AU - Meiners, S. C1 - 46414 C2 - 37546 SP - 1089-1101 TI - Regulation of 26S proteasome activity in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 192 IS - 9 PY - 2015 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Increased abundance and stiffness of the extracellular matrix (ECM), in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which are described to lead to reduced ECM stiffness, e.g. in osteogenesis imperfecta. OBJECTIVES: To assess the expression and function of FKBP10 in IPF. METHODS: We assessed FKBP10 expression bleomycin-induced lung fibrosis (using qRT-PCR, Western Blot, and immunofluorescence), analysed microarray data from 99 IPF patients and 43 control subjects from a U.S. cohort, and performed Western Blot Analysis from 6 IPF patients and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by ER stress or TGF-β1, was analyzed by siRNA-mediated loss-of-function-experiments, qRT-PCR, Western Blot, and quantification of secreted collagens, in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the recently for IPF approved drugs nintedanib and pirfenidone. MEASUREMENTS AND MAIN RESULTS: FKBP10 expression was upregulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68+ macrophages. TGF-β1, but not ER stress, induced FKBP10 expression in phLF. The siRNA-mediated knockdown of FKBP10 attenuated expression of pro-fibrotic mediators and effectors, including collagens I and V and α-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF. CONCLUSIONS: FKBP10 might be a novel drug target for IPF. AU - Staab-Weijnitz, C.A. AU - Fernandez, I.E. AU - Knüppel, L. AU - Maul, J. AU - Heinzelmann, K. AU - Juan-Guardela, B.M.* AU - Hennen, E. AU - Preissler, G.* AU - Winter, H.* AU - Neurohr, C.* AU - Hatz, R.A.* AU - Lindner, M.* AU - Behr, J.* AU - Kaminski, N.* AU - Eickelberg, O. C1 - 45105 C2 - 37231 CY - New York SP - 455-467 TI - FK506-binding protein 10 is a potential novel drug target for idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 192 IS - 4 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Staab-Weijnitz, C.A. AU - Fernandez, I.E. AU - Maul, J. AU - Knüppel, L. AU - Heinzelmann, K. AU - Hennen, E. AU - Preissler, G.* AU - Winter, H.* AU - Hatz, R.A.* AU - Lindner, M.* AU - Behr, J.* AU - Kaminski, N.* AU - Eickelberg, O. C1 - 48937 C2 - 41543 CY - New York TI - The chaperones FKBP10 and FKBP11 are increased in pulmonary fibrosis and affect collagen synthesis and secretion in primary human fibroblasts. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Sterclova, M.* AU - Heinzelmann, K. AU - Fernandez, I.E. AU - Paluch, P.* AU - Eickelberg, O. AU - Vasakova, M.* C1 - 48950 C2 - 41532 CY - New York TI - Cigarette smoke may contribute to IPF pathogenesis by effect on Wnt-1, Wnt-3 and Mmp-7 production by cells present in alveoli of IPF patients. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AB - The aging of the population in the United States and throughout the developed world has increased morbidity and mortality attributable to lung disease, while the morbidity and mortality from other prevalent diseases has declined or remained stable. Recognizing the importance of aging in the development of lung disease, the American Thoracic Society (ATS) highlighted this topic as a core theme for the 2014 annual meeting. The relationship between aging and lung disease was discussed in several oral symposiums and poster sessions at the annual ATS meeting. In this article, we used the input gathered at the conference to develop a broad framework and perspective to stimulate basic, clinical, and translational research to understand how the aging process contributes to the onset and/or progression of lung diseases. A consistent theme that emerged from the conference was the need to apply novel, systems-based approaches to integrate a growing body of genomic, epigenomic, transcriptomic, and proteomic data and elucidate the relationship between biologic hallmarks of aging, altered lung function, and increased susceptibility to lung diseases in the older population. The challenge remains to causally link the molecular and cellular changes of aging with age-related changes in lung physiology and disease susceptibility. The purpose of this review is to stimulate further research to identify new strategies to prevent or treat age-related lung disease. AU - Thannickal, V.J.* AU - Murthy, M.* AU - Balch, W.E.* AU - Chandel, N.S.* AU - Meiners, S. AU - Eickelberg, O. AU - Selman, M.* AU - Pardo, A.* AU - White, E.S.* AU - Levy, B.D.* AU - Busse, P.J.* AU - Tuder, R.M.* AU - Antony, V.B.* AU - Sznajder, J.I.* AU - Budinger, G.R.* C1 - 43383 C2 - 36362 CY - New York SP - 261-269 TI - Blue journal conference : Aging and susceptibility to lung disease. JO - Am. J. Respir. Crit. Care Med. VL - 191 IS - 3 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Vierkotten, S. AU - Mutze, K. AU - Uhl, F. AU - Königshoff, M. C1 - 48945 C2 - 41537 CY - New York TI - Heparan sulfate proteoglycan alterations mediate Wnt/beta-catenin signaling in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Wacker, M. AU - Joerres, R.A.* AU - Schulz, H. AU - Heinrich, J. AU - Peters, A. AU - Koch, A.* AU - Leidl, R. AU - Vogelmeier, C.F.* AU - Holle, R. C1 - 48961 C2 - 41522 CY - New York TI - Work absenteeism and healthcare utilization in COPD: The clinical cohort COSYCONET compared with population-based controls. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Watz, H.* AU - Wilke, S.* AU - Bals, R.* AU - Karch, A.* AU - Koch, A.* AU - Schulz, H. AU - Welte, T.* AU - Vogelmeier, C.* AU - Jörres, R.* C1 - 48944 C2 - 41538 CY - New York TI - Prevalence of peripheral artery disease in patients with chronic obstructive pulmonary disease: Results of the COSYCONET study. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Welk, V. AU - Semren, N. AU - Korfei, M.* AU - Guenther, A.* AU - Eickelberg, O. AU - Meiners, S. C1 - 48952 C2 - 41530 CY - New York TI - Altered protein homeostasis in pulmonary fibrosis indicates a role for proteasome activator 200. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AU - Wilke, S.* AU - Watz, H.* AU - Bals, R.* AU - Franssen, F.* AU - Holle, R. AU - Karch, A.* AU - Koch, A.* AU - Schulz, H. AU - Spruit, M.A.* AU - Wacker, M. AU - Welte, T.* AU - Wouters, E.F.M.* AU - Joerres, R.A.* AU - Vogelmeier, C.* C1 - 48949 C2 - 41533 CY - New York TI - Impact of peripheral artery disease on functional capacity and health status in patients with chronic obstructive pulmonary disease: Results of the COSYCONET study. JO - Am. J. Respir. Crit. Care Med. VL - 191 PB - Amer Thoracic Soc PY - 2015 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously. OBJECTIVES: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma. METHODS: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case-control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking. MEASUREMENTS AND MAIN RESULTS: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [OR], 1.33; 95% confidence interval [CI], 1.20-1.48 and OR, 1.50; 95% CI, 1.21-1.87, respectively). A positive relationship was observed between lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33-4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis "only." Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter. CONCLUSIONS: Findings from this large international case-control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer. AU - Denholm, R.* AU - Schüz, J.* AU - Straif, K.* AU - Stücker, I.* AU - Jöckel, K.-H.* AU - Brenner, D.R.* AU - De Matteis, S.* AU - Boffetta, P.* AU - Guida, F.* AU - Brüske, I. AU - Wichmann, H.-E. AU - Landi, M.T.* AU - Caporaso, N.* AU - Siemiatycki, J.* AU - Ahrens, W.* AU - Pohlabeln, H.* AU - Zaridze, D.* AU - Field, J.K.* AU - McLaughlin, J.* AU - Demers, P.* AU - Szeszenia-Dabrowska, N.* AU - Lissowska, J.* AU - Rudnai, P.* AU - Fabianova, E.* AU - Dumitru, R.S.* AU - Bencko, V.* AU - Foretova, L.* AU - Janout, V.* AU - Kendzia, B.* AU - Peters, S.* AU - Behrens, T.* AU - Vermeulen, R.* AU - Brüning, T* AU - Kromhout, H.* AU - Olsson, A.C.* C1 - 32358 C2 - 34997 CY - New York SP - 549-559 TI - Is previous respiratory disease a risk factor for lung cancer? JO - Am. J. Respir. Crit. Care Med. VL - 190 IS - 5 PB - Amer Thoracic Soc PY - 2014 SN - 1073-449X ER - TY - JOUR AB - Rationale: Prospective cohort studies have shown that chronic exposure to particulate matter and traffic-related air pollution is associated with reduced survival. However, the effects on nonmalignant respiratory mortality are less studied, and the data reported are less consistent. Objectives: We have investigated the relationship of long-term exposure to air pollution and nonmalignant respiratory mortality in 16 cohorts with individual level data within the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE). Methods: Data from 16 ongoing cohort studies from Europe were used. The total number of subjects was 307,553. There were 1,559 respiratory deaths during follow-up. Measurements and Main Results: Air pollution exposure was estimated by land use regression models at the baseline residential addresses of study participants and traffic-proximity variables were derived from geographical databases following a standardized procedure within, the ESCAPE study. Cohort-specific hazard ratios obtained by Cox proportional hazard models from standardized individual cohort analyses were combined using metaanalyses. We found no significant associations between air pollution exposure and nonmalignant respiratory mortality. Most hazard ratios were slightly below unity, with the exception of the traffic-proximity indicators. Conclusions: In this study of 16 cohorts, there was no-association between air pollution exposure and nonmalignant respiratory mortality. AU - Dimakopoulou, K.* AU - Samoli, E.* AU - Beelen, R.* AU - Stafoggia, M.* AU - Andersen, Z.J.* AU - Hoffmann, B.* AU - Fischer, P.* AU - Nieuwenhuijsen, M.* AU - Vineis, P.* AU - Xun, W.* AU - Hoek, G.* AU - Raaschou-Nielsen, O.* AU - Oudin, A.* AU - Forsberg, B.* AU - Modig, L.* AU - Jousilahti, P.* AU - Lanki, T.* AU - Turunen, A.* AU - Oftedal, B.* AU - Nafstad, P.* AU - Schwarze, P.E.* AU - Penell, J.* AU - Fratiglioni, L.* AU - Andersson, N.* AU - Pedersen, N.* AU - Korek, M.* AU - de Faire, U.* AU - Eriksen, K.T.* AU - Tjonneland, A.* AU - Becker, T.* AU - Wang, M.* AU - Bueno-de-Mesquita, H.B.* AU - Tsai, M.* AU - Eeftens, M.* AU - Peeters, P.H.* AU - Meliefste, K.* AU - Marcon, A.* AU - Krämer, U.* AU - Kuhlbusch, T.A.J.* AU - Vossoughi, M.* AU - Key, T.* AU - de Hoogh, K.* AU - Hampel, R. AU - Peters, A. AU - Heinrich, J. AU - Weinmayr, G.* AU - Concin, H.* AU - Nagel, G.* AU - Ineichen, A.* AU - Jacquemin, B.* AU - Stempfelet, M.* AU - Vilier, A.* AU - Ricceri, F.* AU - Sacerdote, C.* AU - Pedeli, X.* AU - Katsoulis, M.* AU - Trichopoulou, A.* AU - Brunekreef, B.* AU - Katsouyanni, K.* C1 - 31196 C2 - 34278 CY - New York SP - 684-696 TI - Air pollution and nonmalignant respiratory mortality in 16 cohorts within the ESCAPE project. JO - Am. J. Respir. Crit. Care Med. VL - 189 IS - 6 PB - Amer Thoracic Soc PY - 2014 SN - 1073-449X ER - TY - JOUR AU - Herold, S.* AU - Staab-Weijnitz, C.A. C1 - 30921 C2 - 34018 CY - New York SP - 386-389 TI - Glutathione on the Fas track. A novel drug target for the treatment of pseudomonas infection? JO - Am. J. Respir. Crit. Care Med. VL - 189 IS - 4 PB - Amer Thoracic Soc PY - 2014 SN - 1073-449X ER - TY - JOUR AU - Jenne, D. C1 - 42880 C2 - 35642 SP - 1203-1204 TI - Off-target rewards of augmentation therapy with α1-antitrypsin. JO - Am. J. Respir. Crit. Care Med. VL - 190 IS - 11 PY - 2014 SN - 1073-449X ER - TY - JOUR AU - Königshoff, M. C1 - 43010 C2 - 35973 SP - 1339-1341 TI - Live and let die: Targeting alveolar epithelial cell proliferation in pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 190 IS - 12 PY - 2014 SN - 1073-449X ER - TY - JOUR AB - Rationale: The temporal stability of adult asthma phenotypes identified using clustering methods has never been addressed. Longitudinal cluster-based methods may provide novel insights in the study of the natural history of asthma. Objectives: To compare the stability of cluster-based asthma phenotype structures a decade apart in adults and to address the individuals' phenotypic transition across these asthma phenotypes. Methods: The latent transition analysis was applied on longitudinal data (twice, 10 yr apart) from 3,320 adults with asthma who took part in the European Community Respiratory Health Survey, the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, or the Epidemiological Study on Genetics and Environment of Asthma. Nine variables covering personal and phenotypic characteristics measured twice, 10 years apart, were simultaneously considered. Measurements and Main Results: Latent transition analysis identifies seven asthma phenotypes (prevalence range, 8.4-20.8%), mainly characterized by the level of asthma symptoms (low, moderate, high), the allergic status, and pulmonary function. Phenotypes observed 10 years apart showed strong similarities. The probability of membership in the same asthma phenotype at both times varied across phenotypes from 54 to 88%. Different transition patterns were observed across phenotypes. Transitions toward increased asthma symptoms were more frequently observed among nonallergic phenotypes as compared with allergic phenotypes. Results showed a strong stability of the allergic status over time. Conclusions: Adult asthma phenotypes identified by a clustering approach, 10 years apart, were highly consistent. This study is the first to model the probabilities of transitioning over time between comprehensive asthma phenotypes. AU - Boudier, A.* AU - Curjuric, I.* AU - Basagana, X.* AU - Hazgui, H.* AU - Antò, J.M.* AU - Bousquet, J.* AU - Bridevaux, P.O.* AU - Dupuis-Lozeron, E.* AU - Garcia-Aymerich, J.* AU - Heinrich, J. AU - Janson, C.* AU - Künzli, N.* AU - Leynaert, B.* AU - de Marco, R.* AU - Rochat, T.* AU - Schindler, C.* AU - Varraso, R.* AU - Pin, I.* AU - Probst-Hensch, N.* AU - Sunyer, J.* AU - Kauffmann, F.* AU - Siroux, V.* C1 - 27479 C2 - 32690 SP - 550-560 TI - Ten-year follow-up of cluster-based asthma phenotypes in adults. A pooled analysis of three cohorts. JO - Am. J. Respir. Crit. Care Med. VL - 188 IS - 5 PB - Amer. Thoracic Soc. PY - 2013 SN - 1073-449X ER - TY - JOUR AU - Gottardi, C.J.* AU - Königshoff, M. C1 - 23927 C2 - 31302 SP - 566-568 TI - Considerations for targeting β-catenin signaling in fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 187 IS - 6 PB - Amer. Thoracic Soc. PY - 2013 SN - 1073-449X ER - TY - JOUR AB - Rationale: Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). Objectives: We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. Methods: This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. Measurements and Main Results: FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. Conclusions: Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88). AU - Griese, M.* AU - Kappler, M.* AU - Eismann, C.* AU - Ballmann, M.* AU - Junge, S.* AU - Rietschel, E.* AU - van Koningsbruggen-Rietschel, S.* AU - Staab, D.* AU - Rolinck-Werninghaus, C.* AU - Mellies, U.* AU - Köhnlein, T.* AU - Wagner, T.* AU - König, S.* AU - Teschler, H.* AU - Heuer, H.E.* AU - Kopp, M.* AU - Heyder, S.* AU - Hammermann, J.* AU - Küster, P.* AU - Honer, M.* AU - Mansmann, U.* AU - Beck-Speier, I. AU - Hartl, D.* AU - Fuchs, C.* AU - Glutathione Study Group (*) AU - Hector, A.* C1 - 26206 C2 - 32122 SP - 83-89 TI - Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. JO - Am. J. Respir. Crit. Care Med. VL - 188 IS - 1 PB - Amer. Assoc. Critical Care Nurses PY - 2013 SN - 1073-449X ER - TY - JOUR AB - Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 x 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis. AU - Fischer, A.* AU - Schmid, B.* AU - Ellinghaus, D.* AU - Nothnagel, M.* AU - Gaede, K.I.* AU - Schürmann, M.* AU - Lipinski, S.* AU - Rosenstiel, P.* AU - Zissel, G.* AU - Höhne, K.* AU - Petrek, M.* AU - Kolek, V.* AU - Pabst, S.* AU - Grohe, C.* AU - Grunewald, J.* AU - Ronninger, M.* AU - Eklund, A.* AU - Padyukov, L.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Nebel, A.* AU - Franke, A.* AU - Müller-Quernheim, J.* AU - Hofmann, S.* AU - Schreiber, S.* C1 - 11490 C2 - 30685 SP - 877-885 TI - A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1. JO - Am. J. Respir. Crit. Care Med. VL - 186 IS - 9 PB - American Thoracic Society PY - 2012 SN - 1073-449X ER - TY - JOUR AB - Comment on: Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. [Am. J. Respir. Crit. Care Med. 2012] AU - Königshoff, M. AU - Rojas, M.* C1 - 7254 C2 - 29614 SP - 473-475 TI - Galectin-3: The bridge over troubled waters. JO - Am. J. Respir. Crit. Care Med. VL - 185 IS - 5 PB - Amer. Thoracic Soc. PY - 2012 SN - 1073-449X ER - TY - JOUR AB - Rationale: Although epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma, previous studies were not able to differentiate the effects of prenatal from postnatal exposure. Objectives: To assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma among preschool-age children. Methods: A pooled analysis was performed based on individual participant data from eight European birth cohorts. Cohort-specific effects of maternal smoking during pregnancy, but not during the first year, on wheeze and asthma at 4 to 6 years of age were estimated using logistic regression and then combined using a random effects model. Adjustments were made for sex, parental education, parental asthma, birth weight, and siblings. Measurements and Main Results: Among the 21,600 children included in the analysis, 735 children (3.4%) were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth. In the pooled analysis, maternal smoking only during pregnancy was associated with wheeze and asthma at 4 to 6 years of age, with adjusted odds ratios of 1.39 (95% confidence interval, 1.08-1.77) and 1.65 (95% confidence interval, 1.18-2.31), respectively. The likelihood to develop wheeze and asthma increased statistically significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy. Conclusions: Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth. AU - Neuman, A.* AU - Hohmann, C.* AU - Orsini, N.* AU - Pershagen, G.* AU - Eller, E.* AU - Kjaer, H.F.* AU - Gehring, U.* AU - Granell, R.* AU - Henderson, J.* AU - Heinrich, J. AU - Lau, S.* AU - Nieuwenhuijsen, M.* AU - Sunyer, J.* AU - Tischer, C.G. AU - Torrent, M.* AU - Wahn, U.* AU - Wijga, A.H.* AU - Wickman, M.* AU - Keil, T.* AU - Bergström, A.* C1 - 11374 C2 - 30648 SP - 1037-1043 TI - Maternal smoking in pregnancy and asthma in preschool children: A pooled analysis of eight birth cohorts. JO - Am. J. Respir. Crit. Care Med. VL - 186 IS - 10 PB - American Thoracic Society PY - 2012 SN - 1073-449X ER - TY - JOUR AU - Olsson, A.* AU - Vermeulen, R.* AU - Kromhout, H.* AU - Peters, S.* AU - Gustavsson, P.* AU - Brüske, I. AU - Siemiatycki, J.* AU - Pesch, B.* AU - Brüning, T* AU - Straif, K.* C1 - 8036 C2 - 29959 SP - 106-107 TI - The impact of selection bias due to increasing response rates among population controls in occupational case-control studies response. JO - Am. J. Respir. Crit. Care Med. VL - 185 IS - 1 PB - Amer. Thoracic Soc. PY - 2012 SN - 1073-449X ER - TY - JOUR AB - The exploration of the endogenous regenerative potential of the diseased adult human lung represents an innovative and exciting task. In this pulmonary perspective, we discuss three major components essential for endogenous lung repair and regeneration: epithelial progenitor populations, developmental signaling pathways that regulate their reparative and regenerative potential, as well as the surrounding extracellular matrix in the human diseased lung. Over the past years, several distinct epithelial progenitor populations have been discovered within the lung, all of which most likely respond to different injuries by varying degrees. It has become evident that several progenitor populations are mutually involved in maintenance and repair, which is highly regulated by developmental pathways, such as Wnt or Notch signaling. Third, endogenous progenitor cells and developmental signaling pathways act in close spatio-temporal synergy with the extracellular matrix. These three components define and refine the highly dynamic microenviroment of the lung, which is altered in a disease-specific fashion in several chronic lung diseases. The search for the right mixture to induce efficient and controlled repair and regeneration of the diseased lung is ongoing and will open completely novel avenues for the treatment of patients with chronic lung disease. AU - Rock, J.* AU - Königshoff, M. C1 - 11352 C2 - 30623 SP - 1213-1219 TI - Endogenous lung regeneration: Potential and limitations. JO - Am. J. Respir. Crit. Care Med. VL - 186 IS - 12 PB - American Thoracic Society PY - 2012 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Few studies have investigated the factors associated with the early inception of chronic obstructive pulmonary disease (COPD). OBJECTIVES: We investigated COPD risk factors in an international cohort of young adults using different spirometric definitions of the disease. Methods: We studied 4,636 subjects without asthma who had prebronchodilator FEV(1)/FVC measured in the European Community Respiratory Health Survey both in 1991 to 1993 (when they were 20-44 yr old) and in 1999 to 2002. COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease fixed cut-off criterion (FEV(1)/FVC < 0.70), and two criteria based on the Quanjer and LuftiBus reference equations (FEV(1)/FVC less than lower limit of normal). COPD determinants were studied using two-level Poisson regression models. Measurements and Main RESULTS: COPD incidence ranged from 1.85 (lower limit of normal [Quanjer]) to 2.88 (Global Initiative for Chronic Obstructive Lung Disease) cases/1,000/yr. Although about half of the cases had smoked less than 20 pack-years, smoking was the main risk factor for COPD, and it accounted for 29 to 39% of the new cases during the follow-up. Airway hyperresponsiveness was the second strongest risk factor (15-17% of new cases). Other determinants were respiratory infections in childhood and a family history of asthma, whereas the role of sex, age, and of being underweight largely depended on the definition of COPD used. CONCLUSIONS: COPD may start early in life. Smoking prevention should be given the highest priority to reduce COPD occurrence. Airway hyperresponsiveness, a family history of asthma, and respiratory infections in childhood are other important determinants of COPD. We suggest the need for a definition of COPD that is not exclusively based on spirometry.   AU - de Marco, R.* AU - Accordini, S.* AU - Marcon, A.* AU - Cerveri, I.* AU - Antò, J.M.* AU - Gislason, T.* AU - Heinrich, J. AU - Janson, C.* AU - Jarvis, D.* AU - Kuenzli, N.* AU - Leynaert, B.* AU - Sunyer, J.* AU - Svanes, C.* AU - Wjst, M. AU - Burney, P.* C1 - 5468 C2 - 27800 SP - 891-897 TI - Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults. JO - Am. J. Respir. Crit. Care Med. VL - 183 IS - 7 PB - American Thoracic Society PY - 2011 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/β-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/β-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative RT-PCR, immunohistochemistry, and Western blotting. The role of WNT/β-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/β-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear !-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/β-catenin signaling was downregulated in both experimental emphysema models. Preventive, as well as therapeutic, WNT/β-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSION: Decreased WNT/β-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/β-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/β-catenin activation as a future therapeutic approach for emphysema. AU - Kneidinger, N.* AU - Yildirim, A.Ö. AU - Callegari, J. AU - Takenaka, S. AU - Stein, M.M. AU - Dumitrascu, R.* AU - Bohla, A. AU - Bracke, K.R.* AU - Morty, R.E.* AU - Brusselle, G.G.* AU - Schermuly, R.T.* AU - Eickelberg, O. AU - Königshoff, M. C1 - 2037 C2 - 28062 SP - 723-733 TI - Activation of the WNT/β-catenin pathway attenuates experimental emphysema. JO - Am. J. Respir. Crit. Care Med. VL - 183 IS - 6 PB - American Thoracic Society PY - 2011 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Hormonal and metabolic status appears to influence lung health in women, and there are findings suggesting that early menarche may be related to asthma, cardiovascular disease, diabetes and breast cancer. OBJECTIVES: This study investigates whether age of menarche was related to adult lung function and asthma. MEASUREMENTS: Among participants in the European Community Respiratory Health Survey II, 3354 women aged 27-57 years from random population samples in 21 centers responded to a questionnaire concerning women's health (1998-2002). 2873 had lung function measurements, 2136 measurements of bronchial hyper reactivity (BHR) and 2743 IgE measurements. Logistic, linear and negative binomial regression analyses included adjustment for age, height, body mass index, education, smoking, family size and centre. MAIN RESULTS: Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were lower and asthma more common in women with early menarche. Women reporting menarche AU - Macsali, F.* AU - Real, F.G.* AU - Plana, E.* AU - Sunyer, J.* AU - Anto, J.* AU - Dratva, J.* AU - Janson, C.* AU - Jarvis, D.* AU - Omenaas, E.R.* AU - Zemp, E.* AU - Wjst, M. AU - Leynaert, B.* AU - Svanes, C.* C1 - 5467 C2 - 27799 SP - 8-14 TI - Early age of menarche, lung function and adult asthma. JO - Am. J. Respir. Crit. Care Med. VL - 183 IS - 1 PB - American Thoracic Society PY - 2011 SN - 1073-449X ER - TY - JOUR AB - Rationale: Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. Objectives: Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. Methods: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from 13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. Measurements and Main Results: Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95% confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and never-smokers, although not statistically significant. Conclusions: Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models and subgroup analyses. AU - Olsson, A.C.* AU - Gustavsson, P.* AU - Kromhout, H.* AU - Peters, S.* AU - Vermeulen, R.* AU - Brüske, I. AU - Pesch, B.* AU - Siemiatycki, J.* AU - Pintos, J.* AU - Brüning, T* AU - Cassidy, A.* AU - Wichmann, H.-E. AU - Consonni, D.* AU - Landi, M.T.* AU - Caporaso, N.* AU - Plato, N.* AU - Merletti, F.* AU - Mirabelli, D.* AU - Richiardi, L.* AU - Jöckel, K.-H.* AU - Ahrens, W.* AU - Pohlabeln, H.* AU - Lissowska, J.* AU - Szeszenia-Dabrowska, N.* AU - Zaridze, D.* AU - Stücker, I.* AU - Benhamou, S.* AU - Bencko, V.* AU - Foretova, L.* AU - Janout, V.* AU - Rudnai, P.* AU - Fabianova, E.* AU - Dumitru, RS.* AU - Gross, IM.* AU - Kendzia, B.* AU - Forastiere, F.* AU - Bueno-de-Mesquita, H.B.* AU - Brennan, P.* AU - Boffetta, P.* AU - Straif, K. C1 - 5940 C2 - 28418 CY - New York SP - 941-948 TI - Exposure to diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada. JO - Am. J. Respir. Crit. Care Med. VL - 183 IS - 7 PB - Amer. Thoracic Soc. PY - 2011 SN - 1073-449X ER - TY - JOUR AB - no Abstract AU - Schwarz, J. C1 - 6497 C2 - 28808 SP - 5-7 TI - Emerging role of c-kit⁺ progenitor cells in pulmonary hypertension. JO - Am. J. Respir. Crit. Care Med. VL - 184 IS - 1 PB - Amer Thoracic Soc PY - 2011 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)) CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score. AU - Soler Artigas, M.* AU - Wain, L.V.* AU - Repapi, E.* AU - Obeidat, M.* AU - Sayers, I.* AU - Burton, P.R* AU - Johnson, T.* AU - Zhao, J.H.* AU - Albrecht, E. AU - Dominiczak, A.F.* AU - Kerr, S.M.* AU - Smith, B.H.* AU - Cadby, G.* AU - Hui, J.* AU - Palmer, L.J.* AU - Hingorani, A.D.* AU - Wannamethee, S.G.* AU - Whincup, P.H.* AU - Ebrahim, S.* AU - Smith, G.D.* AU - Barroso, I.* AU - Loos, R.J.* AU - Wareham, N.J.* AU - Cooper, C.* AU - Dennison, E.* AU - Shaheen, S.O.* AU - Liu, J.Z.* AU - Marchini, J* AU - Medical Research Council NSHD Respiratory Study Team (*) AU - Dahgam, S.* AU - Naluai, A.T.* AU - Olin, A.C.* AU - Karrasch, S.* AU - Heinrich, J. AU - Schulz, S. AU - McKeever, T.M.* AU - Pavord, I.D.* AU - Heliövaara, M.* AU - Ripatti, S.* AU - Surakka, I.* AU - Blakey, J.D.* AU - Kähönen, M.* AU - Britton, J.R.* AU - Nyberg, F.* AU - Holloway, J.W.* AU - Lawlor, D.A.* AU - Morris, R.W.* AU - James, A.L.* AU - Jackson, C.M.* AU - Hall, I.P.* AU - Tobin, M.D* AU - SpiroMeta Consortium (*) C1 - 6700 C2 - 29137 SP - 786-795 TI - Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function. JO - Am. J. Respir. Crit. Care Med. VL - 184 IS - 7 PB - Amer Thoracic Soc PY - 2011 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Studies in humans and rodents have indicated a causative role for CD8(+) T cells in IgE-mediated allergic inflammation, but their function is still controversial. OBJECTIVES: To analyze the role of allergen-specific CD8(+) T cells during the development of allergic airway inflammation in two parallel but diverging outcome models. METHODS: We used H2-Kb SIINFEKL (OVA(257-264)) multimers to analyze induction, natural distribution, and phenotype of allergen-specific CD8(+) T cells in a murine C57BL/6 model of ovalbumin (OVA)-induced allergic airway inflammation using low-dose or high-dose OVA sensitization. MEASUREMENTS AND MAIN RESULTS: The low-dose protocol was characterized by a significant induction of total and OVA-specific IgE, eosinophilic airway inflammation, IL-4 levels in bronchoalveolar lavage fluid. And significant alterations in lung function. The high dose protocol was characterized by a significant reduction of the allergic phenotype. Using OVA(257-264) H2-Kb multimers, we observed lung and airway infiltrating OVA-specific CD8(+) T cells showing an effector/effector-memory phenotype. The high-dose protocol caused significantly higher infiltration of allergen-specific CD8(+) cells to the airways and enhanced their cytotoxicity. Adoptive transfer with CD8(+) T cells from transgenic OT-I mice to TAP1(-/-) or wild-type mice showed their migration to the lungs and TAP1-dependent proliferation after OVA-aerosol exposure. TAP1(-/-) mice defective in CD8(+) T cells showed exacerbated symptoms in the low-dose sensitization model. CONCLUSIONS: Allergen-specific CD8(+) T cells seem to protect from allergic inflammation in the lungs. Their number, which is dependent on the sensitization dose, appears to be a critical predictor for the severity of the allergic phenotype. AU - Aguilar-Pimentel, J.A.* AU - Alessandrini, F. AU - Huster, K.M. AU - Jakob, T.* AU - Schulz, S. AU - Behrendt, H. AU - Ring, J. AU - Hrabě de Angelis, M. AU - Busch, D.H. AU - Mempel, M. AU - Ollert, M.* C1 - 56 C2 - 27042 SP - 7-16 TI - Specific CD8 T cells in IgE-mediated allergy correlate with allergen dose and allergic phenotype. JO - Am. J. Respir. Crit. Care Med. VL - 181 IS - 1 PB - American Thoracic Society PY - 2010 SN - 1073-449X ER - TY - JOUR AU - Eickelberg, O. AU - Selman, M.* C1 - 2839 C2 - 27536 SP - 883-888 TI - Update in diffuse parenchymal lung disease 2009. JO - Am. J. Respir. Crit. Care Med. VL - 181 IS - 9 PB - American Thoracic Society PY - 2010 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed. OBJECTIVES: The objective of this study was to assess the possible contribution of the IL-13 system to IPAH. METHODS: Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC. MEASUREMENTS AND MAIN RESULTS: Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects. CONCLUSIONS: The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH. AU - Hecker, M.* AU - Zaslona, Z.* AU - Kwapiszewska, G.* AU - Niess, G.* AU - Zakrzewicz, A.* AU - Hergenreider, E.* AU - Wilhelm, J.* AU - Marsh, L.M.* AU - Sedding, D.* AU - Klepetko, W.* AU - Lohmeyer, J.* AU - Dimmeler, S.* AU - Seeger, W.* AU - Weissmann, N.* AU - Schermuly, R.T.* AU - Kneidinger, N.* AU - Eickelberg, O. AU - Morty, R.E.* C1 - 2140 C2 - 28063 SP - 805-818 TI - Dysregulation of the IL-13 receptor system: A novel pathomechanism in pulmonary arterial hypertension. JO - Am. J. Respir. Crit. Care Med. VL - 182 IS - 6 PB - American Thoracic Society PY - 2010 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in IPF. METHODS: RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. Measurements and Main RESULTS: Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00258544). AU - Pandit, K.V.* AU - Corcoran, D.* AU - Yousef, H.* AU - Yarlagadda, M.* AU - Tzouvelekis, A.* AU - Gibson, K.F.* AU - Konishi, K.* AU - Yousem, S.A.* AU - Singh, M.* AU - Handley, D.* AU - Richards, T.* AU - Selman, M.* AU - Watkins, S.C.* AU - Pardo, A.* AU - Ben-Yehudah, A.* AU - Bouros, D.* AU - Eickelberg, O. AU - Ray, P.* AU - Benos, P.V.* AU - Kaminski, N.* C1 - 109 C2 - 28077 SP - 220-229 TI - Inhibition and role of let-7d in idiopathic pulmonary fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 182 IS - 2 PB - Amer Thoracic Soc PY - 2010 SN - 1073-449X ER - TY - JOUR AB - Rationale Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. Objectives: To investigate whether therapeutic application of palifermin (Delta N23-KGF) is able to induce a regenerative response in distal lung parenchyma after induction of pulmonary emphysema. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg Delta N23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. AI Delta N23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanced differentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-beta 1, TGF-beta 2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. Delta N23-KGF induced the expression of TGF-beta 1 in and release of active TGF-beta 1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-beta 1 but not Delta N23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of Delta N23-KGF in LA-4/MLF cocultures.Conclusions: Our data demonstrate that therapeutic application of Delta N23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-beta 1. AU - Yildirim, A.Ö. AU - Muyal, V.* AU - John, G.* AU - Müller, B.* AU - Seifart, C.* AU - Kasper, M.* AU - Fehrenbach, H.* C1 - 6147 C2 - 28179 CY - New York, USA SP - 705-717 TI - Palifermin induces alveolar maintenance programs in emphysematous mice. JO - Am. J. Respir. Crit. Care Med. VL - 181 IS - 7 PB - Amer. Thorac. Society PY - 2010 SN - 1073-449X ER - TY - JOUR AB - Rationale: The effects of ultrafine particle inhalation on allergic airway inflammation are of growing interest. The mechanisms underlying these effects are currently under investigation. Objectives: To investigate the role of oxidative stress on the adjuvant activity of inhaled elemental carbon ultrafine particles (EC-UFPs) on allergic airway inflammation. Methods: Ovalbumin-sensitized mice were exposed to EC-UFPs (504 mu g/m(3) for 24 h) or filtered air immediately before allergen challenge and systemically treated with N-acetylcysteine or vehicle before and during EC-UFP inhalation. Allergic inflammation was measured up to 1 week after allergen challenge by means of bronchoalveolar lavage, cytokine/total protein assays, lung function, and histology. Isoprostane levels in lung tissue served to measure oxidative stress. Transmission electron microscopy served to localize ECUFPs in lung tissue and both electrophoretic mobility shift assay and immunohistochemistry to quantify/localize nuclear factor-kappa B (NF-kappa B) activation. Measurements and Main Results: In sensitized and challenged mice EC-UFP inhalation increased allergen-induced lung lipid peroxidation and NF-kappa B activation in addition to inflammatory infiltrate, cytokine release, and airway hyperresponsiveness. Prominent NF-kappa B activation was observed in the same cell types in which EC-UFPs were detected. N-acetylcysteine treatment significantly reduced the adjuvant activity of EC-UFPs. In nonsensitized or sensitized but not challenged mice EC-UFP exposure induced a moderate increase in isoprostanes but no significant effect on other parameters of lung inflammation. Conclusions: Our findings demonstrate a critical role for oxidative stress in EC-UFP-induced augmentation of allergen-induced lung inflammation, where EC-UFP exposure has potentiating effects in lung allergic inflammation. Our data support the concept that allergic individuals are more susceptible to the adverse health effects of EC-UFPs. AU - Alessandrini, F. AU - Beck-Speier, I. AU - Krappmann, D. AU - Weichenmeier, I. AU - Takenaka, S. AU - Karg, E.W. AU - Kloo, B. AU - Schulz, S. AU - Jakob, T. AU - Mempel, M. AU - Behrendt, H. C1 - 1220 C2 - 26094 SP - 984-991 TI - Role of oxidative stress in ultrafine particle-induced exacerbation of allergic lung inflammation. JO - Am. J. Respir. Crit. Care Med. VL - 179 IS - 11 PB - Amer Thoracic Soc PY - 2009 SN - 1073-449X ER - TY - JOUR AB - Rationale: Little is known about the long-term outcomes of individuals with mild/moderate chronic obstructive pulmonary disease (COPD) according to spirometric criteria. Objectives: To test whether nonsmokers and asymptomatic subjects with a spirometric diagnosis of COPD have a steeper decrease in lung function and higher hospitalization rates than subjects without airway obstruction. Methods: A total of 5,205 subjects without asthma (20-44 years of age) from the general population, with FEV1 >= 50% predicted at baseline, were followed for 9 years in the frame of an international cohort study. Percent decrease in FEV1 (Delta FEV1%) and the annual hospitalization rate for respiratory causes during the follow-up were assessed for each subject. Measurements and Main Results: At baseline, 324 (6.2%) subjects had the prebronchodilator FEV1/FVC ratio less than the lower limit of normal (LLN-COPD), and 105 (2.0%) subjects had the same ratio less than 0.70 (modified GOLD-COPD). At follow-up, smokers with LLN-COPD (n = 205) had a greater mean Delta FEV1% (1.7%; 95% confidence interval [CI], 0.8-2.7) and a higher hospitalization rate (rate ratio [RR], 2.52,95% Cl, 1.65-3.86) than normal subjects. Similarly, symptomatic subjects with LLN-COPD (n = 104) had Delta FEV1% (2.0%; 95% CI, 0.8-3.3) and the hospitalization rate (RR, 4.18; 95% CI, 2.43-7.21) higher than the reference group. By contrast, nonsmokers and asymptomatic subjects with LLN-COPD had outcomes that were similar or even better than normal subjects. Among subjects with LLN-COPD, the association of symptoms with Delta FEV1% varied according to smoking habits (P = 0.007); it was particularly strong in symptomatic smokers and disappeared in symptomatic nonsmokers. Similar results were found with the modified GOLD classification. Conclusions: In relatively young populations, COPD is associated with poor long-term outcomes in smokers and in symptomatic subjects only. AU - de Marco, R.* AU - Accordini, S.* AU - Antò, J.M.* AU - Gislason, T.* AU - Heinrich, J. AU - Janson, C.* AU - Jarvis, D.* AU - Künzli, N.* AU - Leynaert, B.* AU - Marcon, A.* AU - Sunyer, J.* AU - Svanes, C.* AU - Wjst, M. AU - Burney, P.* C1 - 280 C2 - 26937 CY - New York SP - 956-963 TI - Long-term outcomes in mild/moderate chronic obstructive pulmonary disease in the European community respiratory health survey. JO - Am. J. Respir. Crit. Care Med. VL - 180 IS - 10 PB - Amer Thoracic Soc PY - 2009 SN - 1073-449X ER - TY - JOUR AU - Karrasch, S. AU - Behr, J. AU - Ernst, K. AU - Heinrich, J. AU - Huber, R.M. AU - Joerres, R.A. AU - Nowak, D. AU - Wichmann, H.-E. AU - Schulz, H. C1 - 47052 C2 - 40469 TI - FENO and Influencing Factors in a Group of Randomly Selected Adults. JO - Am. J. Respir. Crit. Care Med. VL - 179 PY - 2009 SN - 1073-449X ER - TY - JOUR AB - RATIONALE: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. OBJECTIVES: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. METHODS: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-beta) was preemptively blocked in mice exposed to hyperoxia using TGF-beta-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. MEASUREMENTS AND MAIN RESULTS: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygen-injured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-beta signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. CONCLUSIONS: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-beta signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD. AU - Kumarasamy, A.* AU - Schmitt, I.* AU - Nave, A.H.* AU - Reiss, I.* AU - van der Horst, I. AU - Dony, E.* AU - Roberts, J.D.Jr.* AU - de Krijger, R.R.* AU - Tibboel, D.* AU - Seeger, W.* AU - Schermuly, R.T.* AU - Eickelberg, O. AU - Morty, R.E.* C1 - 27 C2 - 26712 SP - 1239-1252 TI - Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs. JO - Am. J. Respir. Crit. Care Med. VL - 180 IS - 1 PB - American Thoracic Society PY - 2009 SN - 1073-449X ER - TY - JOUR AB - Rationale: Ambient particulate matter has been associated with systemic inflammation indicated by blood markers such as fibrinogen, implicated in promoting atherothrombosis. Objectives: This study evaluated whether single-nucleotide polymorphisms (SNPs) within the fibrinogen genes modified the relationship between ambient particles and plasma fibrinogen. Methods: In 854 myocardial infarction survivors from five European cities plasma fibrinogen levels were determined repeatedly (n = 5,082). City-specific analyses were conducted to assess the impact of particulate matter on fibrinogen levels, applying additive mixed models adjusting for patient characteristics, time trend, and weather. City-specific estimates were pooled by meta-analysis methodology. Measurements and Main Results: Seven SNPs in the FGA and FGB genes shown to be associated with differences in fibrinogen levels were selected. Promoter SNPs within FGA and FG8 were associated with modifications of the relationship between 5-day averages of particulate matter with an aerodynamic diameter below 10 mu m (PM10) and plasma fibrinogen levels. The PM10-fibrinogen relationship for subjects with the homozygous minor allele genotype of FGB rs1800790 compared with subjects homozygous for the major allele was eightfold higher (P value for the interaction, 0.037). Conclusions: The data suggest that susceptibility to ambient particulate matter may be partly genetically determined by polymorphisms that alter early physiological responses such as transcription of fibrinogen. Subjects with variants of these frequent SNPs may have increased risks not only due to constitutionally higher fibrinogen concentrations, but also due to an augmented response to environmental inflammatory stimuli such as ambient particulate matter. AU - Peters, A. AU - Greven, S. AU - Heid, I.M. AU - Baldari, F.* AU - Breitner-Busch, S. AU - Bellander, T.* AU - Chrysohoou, C.* AU - Illig, T. AU - Jacquemin, B.* AU - Koenig, W.* AU - Lanki, T.* AU - Nyberg, F.* AU - Pekkanen, J.* AU - Pistelli, R.* AU - Rückerl, R. AU - Stefanadis, C.* AU - Schneider, A.E. AU - Sunyer, J.* AU - Wichmann, H.-E. C1 - 1588 C2 - 26182 SP - 484-491 TI - Fibrinogen genes modify the fibrinogen response to ambient particulate matter. JO - Am. J. Respir. Crit. Care Med. VL - 179 IS - 6 PB - Amer Thoracic Soc PY - 2009 SN - 1073-449X ER - TY - JOUR AB - Introduction/Rationale Epidemiological studies have shown that exposure to ambient particles is associated with increased respiratory symptoms and exacerbations in asthmatic patients. Ultrafine particles (UFP) may contribute to these negative health effects due to their highly reactive surface area and oxidant capacity. The aim of this study was to test the hypothesis that the allergic inflammation in the lung of allergic asthmatics will be enhanced due to the preexposure to UFP. Methods 14 mild allergic asthmatics were exposed for 2 hours to a controlled atmosphere of 50μg/m 3 spark−discharge generated carbon black UFP (Ø50nm) or clean air in a randomized, double−blind crossover design. The expositions were performed with a wash−out period of 30 days under intermittent bicycles ergometer exercise. 18 hours after the exposures segmental allergen challenges were performed by bronchoscopy. 42 hours after the expositions, during a second bronchoscopy, the previously challenged segments were lavaged and BAL−cells were obtained for differentiated FACS analysis and oxygen radical generation by chemiluminescence. Results The preexposition to UFP showed only a slight non significant short term effect after 42 hours on the allergic inflammation compared to the exposition with clean air. The subgroup of subjects however, which were exposed to UFP in the first period and to clean air in the second period showed after the allergen challenge in the second period a strong increase in the absolute numbers of eosinophils and oxygen radical generation by BAL−cells. Conclusions of the study The exposure to UFP 30 days prior to an allergen challenge had a strong pro−inflammatory effect on the allergic inflammation in allergic asthmatics. AU - Schaumann, F.* AU - Dijkstra, D.* AU - Frömke, C.* AU - Windt, H.* AU - Karg, E.W. AU - Müller, M.* AU - Braun, A.* AU - Hohlfeld, J.* AU - Koch, W.* AU - Schulz, H. AU - Krug, N.* C1 - 51161 C2 - 42670 TI - Prolonged pro-inflammatory effects of ultrafine particles in the lung of allergic asthmatics. JO - Am. J. Respir. Crit. Care Med. VL - 179 PY - 2009 SN - 1073-449X ER - TY - JOUR AB - Little is known about clearance of ultrafine carbon particles from the different regions of the human lung. These particles may accumulate and present a health hazard because of their high surface area. OBJECTIVES: Technetium Tc 99m ((99m)Tc)-radiolabeled 100-nm-diameter carbon particles were inhaled by healthy nonsmokers, asymptomatic smokers, and by patients with chronic obstructive pulmonary disease (COPD). METHODS: Using a bolus inhalation technique, particle deposition was targeted either to the airways or to the lung periphery, and retention, clearance, and translocation were measured using retained radiotracer imaging. MEASUREMENTS AND MAIN RESULTS: In vitro studies revealed that mean leaching of soluble (99m)Tc-radiotracer from the carbon particles was 4.1 (2.6 [SD]) % after 24 hours. Cumulative (99m)Tc activity in urine at 24 hours was 1.1 (1.3) % of activity deposited in the lungs. In the lung periphery, particle retention was not affected by smoking or pulmonary disease; retention was 96 (3) % after 24 hours. The small amount of clearance could be attributed to leaching of the (99m)Tc label, suggesting negligible particle clearance. In healthy nonsmokers, retention of particles targeted to the airways was 89 (6) and 75 (10) % after 1.5 and 24 hours, respectively. Radiolabel activity did not accumulate in the liver. CONCLUSIONS: Within the limits of detection of our experimental system, most inhaled ultrafine carbon particles are retained in the lung periphery and in the conducting airways without substantial systemic translocation or accumulation in the liver at 48 hours. Repeated exposure may result in significant pulmonary accumulation of ultrafine particles. AU - Möller, W. AU - Felten, K. AU - Sommerer, K.* AU - Scheuch, G.* AU - Meyer, G.* AU - Meyer, P. AU - Häussinger, K.* AU - Kreyling, W.G. C1 - 3203 C2 - 25131 SP - 426-432 TI - Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery. JO - Am. J. Respir. Crit. Care Med. VL - 177 IS - 4 PB - American Thoracic Society PY - 2008 SN - 1073-449X ER - TY - JOUR AB - In vitro studies, animal experiments, and human exposure studies have shown how ambient air pollution increases the risk of atopic diseases. However, results derived from observational studies are inconsistent. OBJECTIVES: To assess the relationship between individual-based exposure to traffic-related air pollutants and allergic disease outcomes in a prospective birth cohort study during the first 6 years of life. METHODS: We studied 2,860 children at the age of 4 years and 3,061 at the age of 6 years to investigate atopic diseases and allergic sensitization. Long-term exposure to particulate matter (PM(2.5)), PM(2.5) absorbance, and long-term exposure to nitrogen dioxide (NO(2)) was assessed at residential addresses using geographic information systems based regression models and air pollution measurements. The distance to the nearest main road was used as a surrogate for traffic-related air pollutants. MEASUREMENTS AND MAIN RESULTS: Strong positive associations were found between the distance to the nearest main road and asthmatic bronchitis, hay fever, eczema, and sensitization. A distance-dependent relationship could be identified, with the highest odds ratios (ORs) for children living less than 50 m from busy streets. For PM(2.5) absorbance, statistically significant effects were found for asthmatic bronchitis (OR, 1.56; 95% confidence interval [CI], 1.03-2.37), hay fever (OR, 1.59; 95% CI, 1.11-2.27), and allergic sensitization to pollen (OR, 1.40; 95% CI, 1.20-1.64). NO(2) exposure was associated with eczema, whereas no association was found for allergic sensitization. CONCLUSIONS: This study provides strong evidence for increased risk of atopic diseases and allergic sensitization when children are exposed to ambient particulate matter. AU - Morgenstern, V. AU - Zutavern, A. AU - Cyrys, J. AU - Brockow, I.* AU - Koletzko, S.* AU - Krämer, U.* AU - Behrendt, H. AU - Herbarth, O.* AU - von Berg, A.* AU - Bauer, C.P.* AU - Wichmann, H.-E. AU - Heinrich, J. AU - GINIplus Study Group (Wichmann, H.-E. AU - Heinrich, J. AU - Schoetzau, A. AU - Popescu, M. AU - Mosetter, M. AU - Schindler, J. AU - Franke, K. AU - Laubereau, B. AU - Sausenthaler, S. AU - Thaqi, A. AU - Traidl-Hoffmann, C.* AU - Zirngibl, A. AU - Zutavern, A. AU - Filipiak, B. AU - Gehring, U.) AU - LISAplus Study Group (Wichmann, H.-E. AU - Heinrich, J. AU - Bolte, G. AU - Belcredi, P. AU - Jacob, B. AU - Schoetzau, A. AU - Mosetter, M. AU - Schindler, J. AU - Höhnke, A. AU - Franke, K. AU - Laubereau, B. AU - Sausenthaler, S. AU - Thaqi, A. AU - Zirngibl, A. AU - Zutavern, A.) C1 - 4892 C2 - 25488 SP - 1331-1337 TI - Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. JO - Am. J. Respir. Crit. Care Med. VL - 177 IS - 12 PB - American Thoracic Society PY - 2008 SN - 1073-449X ER - TY - JOUR AB - The development of atopic diseases is characterized by skewed immune responses to common allergens. Only recently, interferons have been identified to play a crucial role in these mechanisms. OBJECTIVES: Because interferon regulatory factor (IRF)-1 is critical for interferon expression, we tested the hypotheses that genetic changes in this essential transcription factor may have consequences for the development of atopy. METHODS: The IRF-1 gene locus was resequenced in 80 human chromosomes. Association and haplotype analyses were performed in a cross-sectional study population of German children from Dresden (n = 1,940), and results were replicated in a second population sample from Munich (n = 1,159), both part of the ISAAC (International Study of Asthma and Allergy in Childhood) phase II. Promoter polymorphism effects were studied using electrophoretic mobility shift assay and colorimetric binding assays. Allele-specific IRF-1 gene expression was studied in vitro using luciferase reporter assays, whereas we assessed ex vivo expression of IRF-1 by real-time polymerase chain reaction and IFN-gamma protein by Luminex technology (Bio-Rad, Hercules, CA). Statistical analyses were performed using SAS/Genetics (SAS 9.1.3; SAS Institute, Cary, NC). MEASUREMENTS AND MAIN RESULTS: By resequencing, 49 polymorphisms were identified within the IRF-1 gene. Four blocks containing 11 polymorphisms were significantly associated with atopy, total IgE levels, or specific IgE levels in both populations (P < 0.05). Two polymorphisms changed transcription factor binding of nuclear factor (NF)-kappaB and EGR1 (early growth response 1) to the IRF-1 promoter, altered gene expression in vitro (P = 0.0004), and altered IRF-1 mRNA and IFN-gamma protein expression ex vivo. CONCLUSIONS: Our results suggest that functionally relevant IRF-1 polymorphisms influence atopy risk, potentially by altering transcription factor binding, IRF-1 gene expression, and IFN-gamma regulation. AU - Schedel, M.* AU - Pinto, LA.* AU - Schaub, B.* AU - Rosenstiel, P.* AU - Cherkasov, D.* AU - Cameron, L.* AU - Klopp, N. AU - Illig, T. AU - Vogelberg, C.* AU - Weiland, S.K.* AU - von Mutius, E.* AU - Lohoff, M.* AU - Kabesch, M.* C1 - 2662 C2 - 25277 SP - 613-621 TI - IRF-1 gene variations influence IgE regulation and atopy. JO - Am. J. Respir. Crit. Care Med. VL - 177 IS - 6 PB - American Thoracic Society PY - 2008 SN - 1073-449X ER - TY - JOUR AB - The association of asthma with sensitization and allergen exposure is known to be complex. There have been few studies of bronchial responsiveness in relation to both risk factors in adults. To determine the relation of bronchial responsiveness to allergen exposure and IgE sensitization in a community study taking into account the major determinants of bronchial responsiveness in adulthood. Cross-sectional data were drawn from 1,884 participants in 20 centers in the European Community Respiratory Health Survey follow-up, which included measurement of house dust mite and cat allergen in mattress dust samples, and IgE sensitization to four allergens. Bronchial responsiveness to methacholine was expressed as a continuous variable, and analyzed by multiple regression. The trend toward greater bronchial responsiveness with increasing exposure to cat allergen was greater in those sensitized to any of the four allergens than those not sensitized (p = 0.001); there was no significant interaction between cat sensitization and Fel d 1 exposure. No trend was found with house dust mite allergen exposure. The difference in bronchial responsiveness between those exposed to the highest levels compared with the lowest was approximately –2.02 doubling doses of PD20 (95% confidence interval, –3.06 to –0.97), and nearly as great in those exposed to more moderate levels. Cat allergen exposure at moderate levels may be harmful to all atopic adults. The clinical implication is that it is insufficient to test patients with asthma for cat sensitization; all atopic individuals may benefit from reduced cat exposure. AU - Chinn, S.* AU - Heinrich, J. AU - Antò, J.M.* AU - Janson, C.* AU - Norbäck, D.* AU - Olivieri, M.* AU - Svanes, C.* AU - Sunyer, J.* AU - Verlato, G.* AU - Wjst, M. AU - Zock, J.P.* AU - Burney, P.G.* AU - Jarvis, D.L.* C1 - 3955 C2 - 24602 SP - 20-26 TI - Bronchial responsiveness in atopic adults increases with exposure to cat allergen. JO - Am. J. Respir. Crit. Care Med. VL - 176 IS - 1 PB - American Thoracic Society PY - 2007 SN - 1073-449X ER - TY - JOUR AB - Rationale: The few prospective studies aimed at assessing the incidence of chronic obstructive pulmonary disease (COPD) in relation to the presence of chronic cough/phlegm have produced contrasting results. Objectives: To assess the incidence of COPD in a cohort of young adults and to test whether chronic cough/phlegm and dyspnea are independent predictors of COPD. Methods: An international cohort of 5,002 subjects without asthma (ages 20–44 yr) with normal lung function (FEV1/FVC ratio >= 70%) from 12 countries was followed from 1991–2002 in the frame of the European Community Respiratory Health Survey II. Incident cases of COPD were those who had an FEV1/FVC ratio less than 70% at the end of the follow-up, but did not report having had a doctor diagnose asthma during the follow-up. Main Results: The incidence rate of COPD was 2.8 cases/1,000/yr (95% confidence interval [CI], 2.3–3.3). Chronic cough/phlegm was an independent and statistically significant predictor of COPD (incidence rate ratio [IRR], 1.85; 95% CI, 1.17–2.93) after adjusting for smoking habits and other potential confounders, whereas dyspnea was not associated with the disease (IRR = 0.98; 95% CI, 0.64–1.50). Subjects who reported chronic cough/phlegm both at baseline and at the follow-up had a nearly threefold-increased risk of developing COPD with respect to asymptomatic subjects (IRR = 2.88; 95% CI, 1.44–5.79). Conclusions: The incidence of COPD is substantial even in young adults. The presence of chronic cough/phlegm identifies a subgroup of subjects with a high risk of developing COPD, independently of smoking habits. AU - de Marco, R.* AU - Accordini, S.* AU - Cerveri, I.* AU - Corsico, A.* AU - Antò, J.M.* AU - Künzli, N.* AU - Janson, C.* AU - Sunyer, J.* AU - Jarvis, D.* AU - Chinn, S.* AU - Vermeire, P.* AU - Svanes, C.* AU - Ackermann-Liebrich, U.* AU - Gislason, T.* AU - Heinrich, J. AU - Leynaert, B.* AU - Neukirch, F.* AU - Schouten, J.P.* AU - Wjst, M. AU - Burney, P.* C1 - 3849 C2 - 24243 SP - 32-39 TI - Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. JO - Am. J. Respir. Crit. Care Med. VL - 175 IS - 1 PB - American Lung Assoc. PY - 2007 SN - 1073-449X ER - TY - JOUR AB - Patients with allergic rhinitis have more frequent bronchial hyperresponsiveness (BHR) in cross-sectional studies. OBJECTIVES: To estimate the changes in BHR in nonasthmatic subjects with and without allergic rhinitis during a 9-year period. METHODS: BHR onset was studied in 3,719 subjects without BHR at baseline, who participated in the follow-up of the European Community Respiratory Health Survey. MEASUREMENTS AND MAIN RESULTS: BHR was defined as a >or=20% decrease in FEV(1) for a maximum dose of 1 mg of methacholine. Allergic rhinitis was defined as having a history of nasal allergy and positive specific IgE (>or=0.35 IU/ml) to pollen, cat, mites, or Cladosporium. The cumulative incidence of BHR was 9.7% in subjects with allergic rhinitis and 7.0% in subjects with atopy but no rhinitis, compared with 5.5% in subjects without allergic rhinitis and atopy (respective odds ratios [OR] and their 95% confidence intervals [95% CI] for BHR onset, 2.44 [1.73-3.45]; and 1.35 [0.86-2.11], after adjustment for potential confounders including sex, smoking, body mass index and FEV(1)). Subjects with rhinitis sensitized exclusively to cat or to mites were particularly at increased risk of developing BHR (ORs [95% CI], 7.90 [3.48-17.93] and 2.84 [1.36-5.93], respectively). Conversely, in subjects with BHR at baseline (n = 372), 35.3% of those with allergic rhinitis, compared with 51.8% of those without rhinitis had no more BHR at follow-up (OR [95% CI], 0.51 [0.33-0.78]). BHR "remission" was more frequent in patients with rhinitis treated by nasal steroids than in those not treated (OR [95% CI], 0.33 [0.14-0.75]). CONCLUSIONS: Allergic rhinitis was associated with increased onset of BHR, and less chance for remission except in those treated for rhinitis. AU - Shaaban, R.* AU - Zureik, M.* AU - Soussan, D.* AU - Antò, J.M.* AU - Heinrich, J. AU - Janson, C.* AU - Künzli, N.* AU - Sunyer, J.* AU - Wjst, M. AU - Burney, P.G.* AU - Neukirch, F.* AU - Leynaert, B.* C1 - 3531 C2 - 24879 SP - 659-666 TI - Allergic rhinitis and onset of bronchial hyperresponsiveness: A population-based study. JO - Am. J. Respir. Crit. Care Med. VL - 176 IS - 7 PB - American Thoracic Society PY - 2007 SN - 1073-449X ER - TY - JOUR AU - Hartl, D.* AU - Latzin, P.* AU - Zissel, G.* AU - Krane, M.* AU - Krauss-Etschmann, S. AU - Griese, M.* C1 - 1428 C2 - 24198 SP - 1370-1376 TI - Chemokines indicate allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 173 PY - 2006 SN - 1073-449X ER - TY - JOUR AU - Moshammer, H.* AU - Hoek, G.* AU - Luttmann-Gibson, H.* AU - Neuberger, M.A.* AU - Antova, T.* AU - Gehring, U. AU - Hruba, F.* AU - Pattenden, S.* AU - Rudnai, P.* AU - Slachtova, H.* AU - Zlotkowska, R.* AU - Fletcher, T.* C1 - 2311 C2 - 24256 SP - 1255-1263 TI - Parental smoking and lung function in children: An international study. JO - Am. J. Respir. Crit. Care Med. VL - 173 IS - 11 PY - 2006 SN - 1073-449X ER - TY - JOUR AU - Rückerl, R. AU - Ibald-Mulli, A. AU - Koenig, W.* AU - Schneider, A.E. AU - Woelke, G. AU - Cyrys, J. AU - Heinrich, J. AU - Marder, V.* AU - Frampton, M.* AU - Wichmann, H.-E. AU - Peters, A. C1 - 4710 C2 - 23611 SP - 432-441 TI - Air pollution and markers of inflammation and coagulation in patiens with coronary heart disease. JO - Am. J. Respir. Crit. Care Med. VL - 173 PY - 2006 SN - 1073-449X ER - TY - JOUR AU - Chinn, S.* AU - Heinrich, J. AU - Wjst, M. C1 - 2924 C2 - 23117 SP - 956-961 TI - An increase in bronchial responsiveness is associated with continuing or restarting smoking. JO - Am. J. Respir. Crit. Care Med. VL - 172 PY - 2005 SN - 1073-449X ER - TY - JOUR AU - Forastiere, F.* AU - von Klot, S. AU - Peters, A. C1 - 3944 C2 - 23263 SP - 1549-1555 TI - A case-crossover analysis of out-of-hospital coronary deaths and air pollution in Rome, Italy. JO - Am. J. Respir. Crit. Care Med. VL - 172 PY - 2005 SN - 1073-449X ER - TY - JOUR AU - Kormann, M.S.D.* AU - Carr, D.* AU - Klopp, N. AU - Illig, T. AU - Leupold, W.* AU - Fritzsch, C.* AU - Weiland, S.K.* AU - von Mutius, E.* AU - Kabesch, M.* C1 - 3394 C2 - 22987 SP - 1358-1362 TI - G-protein-coupled receptor polymorphisms are associated with asthma in a large German population. JO - Am. J. Respir. Crit. Care Med. VL - 171 PY - 2005 SN - 1073-449X ER - TY - JOUR AU - Reinhard, C. AU - Meyer, B.* AU - Fuchs, H. AU - Stöger, T. AU - Eder, G. AU - Ruschendorf, F.* AU - Heyder, J. AU - Nürnberg, P.* AU - Hrabě de Angelis, M. AU - Schulz, S. C1 - 3519 C2 - 22483 SP - 880-888 TI - Genomewide linkage analysis identifies novel genetic loci for lung function in mice. JO - Am. J. Respir. Crit. Care Med. VL - 171 PY - 2005 SN - 1073-449X ER - TY - JOUR AU - Gohlke, H. AU - Illig, T. AU - Bahnweg, M. AU - Klopp, N. AU - André, E. AU - Altmüller, J. AU - Herbon, N. AU - Werner, M. AU - Knapp, M.* AU - Pescollderungg, L.* AU - Boner, A.* C1 - 2763 C2 - 22289 SP - 1217-1223 TI - Association of the Interleukin-1 Receptor Antagonist Gene with Asthma. JO - Am. J. Respir. Crit. Care Med. VL - 169 PY - 2004 SN - 1073-449X ER - TY - JOUR AU - Griese, M.* AU - Ramakers, J.* AU - Krasselt, A.* AU - Starosta, V.* AU - van Koningsbruggen, S.* AU - Fischer, R.* AU - Ratjen, F.* AU - Müllinger, B.* AU - Huber, R.M.* AU - Maier, K.L. AU - Rietschel, E.* C1 - 3178 C2 - 22167 SP - 822-828 TI - Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis. JO - Am. J. Respir. Crit. Care Med. VL - 169 PY - 2004 SN - 1073-449X ER - TY - JOUR AU - Gryparis, A.* AU - Wichmann, H.-E. C1 - 2995 C2 - 22410 SP - 1080-1087 TI - Acute effects of ozone on mortality from the "Air pollution and health: A European approach" project. JO - Am. J. Respir. Crit. Care Med. VL - 170 PY - 2004 SN - 1073-449X ER - TY - JOUR AU - Raby, B.A.* AU - Lazarus, R.* AU - Silverman, E.K.* AU - Lake, S.* AU - Lange, C.* AU - Wjst, M. AU - Weiss, S.T.* C1 - 4630 C2 - 22299 SP - 1057-1065 TI - Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. JO - Am. J. Respir. Crit. Care Med. VL - 170 PY - 2004 SN - 1073-449X ER - TY - JOUR AU - Schaumann, F.* AU - Borm, P.J.A.* AU - Herbrich, A.* AU - Knoch, J.* AU - Pitz, M.* AU - Schins, R.P.F.* AU - Luettig, B.* AU - Hohlfeld, J.M.* AU - Heinrich, J. AU - Krug, N.* C1 - 2667 C2 - 22467 SP - 898-903 TI - Metal-rich ambient particles (particulate matter2.5) cause airway inflammation in healthy subjects. JO - Am. J. Respir. Crit. Care Med. VL - 170 PY - 2004 SN - 1073-449X ER - TY - JOUR AU - Heinrich, J. AU - Topp, R. AU - Brasche, S.* C1 - 9734 C2 - 21524 SP - 1243-1245 TI - Rhinitis and Blood Pressure in Adults. JO - Am. J. Respir. Crit. Care Med. VL - 168 PY - 2003 SN - 1073-449X ER - TY - JOUR AU - Brauer, M.* AU - Hoek, G.* AU - van Vliet, P.* AU - Meliefste, K.* AU - Fischer, P.H.* AU - Wijga, A.* AU - Koopmann, L.P.* AU - Neijens, H.J.* AU - Gerritsen, J.* AU - Kerkhof, M.* AU - Heinrich, J. AU - Bellander, T.* AU - Brunekreef, B.* C1 - 22072 C2 - 20711 SP - 1092-1098 TI - Air Pollution from Traffic and the Development of Respiratory Infections and Asthmatic and Allergic Symptoms in Children. JO - Am. J. Respir. Crit. Care Med. VL - 166 PY - 2002 SN - 1073-449X ER - TY - JOUR AU - Gehring, U. AU - Bischof, W.* AU - Fahlbusch, B.* AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 22073 C2 - 20712 SP - 939-944 TI - House Dust Endotoxin and Allergic Sensitization in Children. JO - Am. J. Respir. Crit. Care Med. VL - 166 PY - 2002 SN - 1073-449X ER - TY - JOUR AB - Dietary fat consumption is hypothesized to influence atopy development by modulation of IgE production. The aim of our study was to assess whether margarine consumption is associated with allergic sensitization and diseases in children. Data of a cross-sectional health survey in 1998-1999 comprising 2,348 children age 5 to 14 yr were analyzed, information on type of fat used as spread during the past 12 mo, children's health, and sociodemographic factors were gathered by questionnaire. Allergic sensitization to common aeroallergens was assessed by specific serum IgE. Compared with butter consumption, margarine consumption was associated with allergic sensitization (adjusted odds ratio 1.30 [95% confidence interval: 1.01 to 1.67]) and with rhinitis symptoms during the past 12 mo (1.41 [1.01 to 1.97]). Sex-stratified analysis showed that these associations were limited to boys (boys: sensitization 1.57 [1.12 to 2.20], rhinitis symptoms 1.76 [1.12 to 2.78]; girls: sensitization 0.99 [0.67 to 1.46], rhinitis symptoms 1.03 [0.63 to 1.70]). No statistically significant relation was observed between exclusive margarine consumption and ever physician-diagnosed hay fever or asthma in all children. In conclusion, the sex difference in the association of margarine consumption with allergic sensitization was in accordance with the higher IgE concentrations and atopy prevalence in boys compared with girls. Increased intake of certain polyunsaturated fatty acids might further stimulate IgE production in boys. AU - Bolte, G. AU - Frye, C. AU - Hoelscher, B. AU - Meyer, I. AU - Wjst, M. AU - Heinrich, J. C1 - 9733 C2 - 19877 SP - 277-279 TI - Margarine Consumption and Allergy in Children. JO - Am. J. Respir. Crit. Care Med. VL - 163 IS - 1 PB - American Thoracic Society PY - 2001 SN - 1073-449X ER - TY - JOUR AU - Heinrich, J. AU - Hoelscher, B.* AU - Wichmann, H.-E. C1 - 21580 C2 - 19706 SP - 1930-1936 TI - Decline of Ambient Air Pollution and Respiratory Symptoms in Children. JO - Am. J. Respir. Crit. Care Med. VL - 161 PY - 2000 SN - 1073-449X ER - TY - JOUR AU - Ulbrecht, M.* AU - Hergeth, M.* AU - Wjst, M. AU - Heinrich, J. AU - Bickeböller, H.* AU - Wichmann, H.-E. AU - Weiss, E.H.* C1 - 21317 C2 - 19432 SP - 469-474 TI - Association of ß2-Adrenoreceptor Variants with Bronchial Hyperresponsiveness. JO - Am. J. Respir. Crit. Care Med. VL - 161 PY - 2000 SN - 1073-449X ER -