TY - JOUR AB - Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery b = 0.0561, Q = 4.05 3 10210; b = 0.0421, Q = 1.12 3 1023; and b = 0.0358, Q = 1.67 3 1023, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q, 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; b = 24.3 ml/yr, Q = 0.049; b = 26.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD. AU - Ngo, D.* AU - Pratte, K.A.* AU - Flexeder, C. AU - Petersen, H.* AU - Dang, H.* AU - Ma, Y.* AU - Keyes, M.J.* AU - Gao, Y.* AU - Deng, S.* AU - Peterson, B.D.* AU - Farrell, L.A.* AU - Bhambhani, V.M.* AU - Palacios, C.* AU - Quadir, J.* AU - Gillenwater, L.* 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.C.* 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.G.* AU - Comellas, A.P.* AU - Silverman, E.K.* AU - Crapo, J.D.* AU - Larson, M.G.* AU - Vasan, R.S.* AU - Wang, T.J.* AU - Correa, A.* AU - Sims, M.* AU - Wilson, J.G.* AU - Gerszten, R.E.* AU - O’Connor, G.T.* AU - Barr, R.G.* 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 - 68366 C2 - 54667 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1124-1135 TI - Systemic markers of lung function and forced expiratory volume in 1 second decline across diverse cohorts. JO - Ann. Am. Thorac. Soc. VL - 20 IS - 8 PB - Amer Thoracic Soc PY - 2023 SN - 2329-6933 ER - TY - JOUR AB - Rationale Vaccination is the most effective protection against influenza. Patients with interstitial lung diseases (ILD) represent a high-risk group for influenza complications. Thus, yearly influenza vaccination is recommended, but evidence on its effects is sparse. Objective This study aimed to compare all-cause mortality and all-cause and respiratory-related hospitalization between vaccinated and unvaccinated patients with ILD. Methods Using data from the largest German statutory health insurance fund (about 27 million insurees in 2020), we analyzed four influenza seasons from 2014/15 to 2017/18 and compared vaccinated to unvaccinated ILD patients. Starting from September 1 of each year we matched vaccinated to unvaccinated patients in a 1:1 ratio using a rolling cohort design. Mortality and hospitalization were compared with Kaplan-Meier plots and effects were calculated during the influenza season (in-season) with risk ratios (RR). Results Both, the vaccinated and the unvaccinated cohort included 7,503 patients in 2014/15, 10,318 in 2015/16, 12,723 in 2016/17, and 13,927 in 2017/18. Vaccination rates were low with 43.2% in season 2014/15 and decreased over time to 39.9% in season 2017/18. The RR for all-cause mortality were 0.79 (95%CI: 0.65, 0.97; p = 0.02) in season 2014/15, 0.66 (95%CI: 0.54, 0.80; p < 0.001) in 2015/16, 0.89 (95%CI: 0.76, 1.04; p = 0.15) in 2016/17, and 0.95 (95%CI: 0.81, 1.12; p = 0.57) in 2017/18. The effects on all-cause hospitalization and respiratory-related hospitalization were similar in all seasons. Conclusions Although an unequivocally beneficial impact of influenza vaccination in patients with ILD could not be demonstrated, we observed promising results regarding avoidance of all-cause mortality in half of the seasons observed. Given the low vaccination rates, further efforts are necessary to improve rates in ILD patients. AU - Marijic, P. AU - Schwarzkopf, L. AU - Maier, W. AU - Trudzinski, F.* AU - Schwettmann, L. AU - Kreuter, M.* C1 - 64623 C2 - 52350 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 1479-1488 TI - Effects of influenza vaccination in patients with interstitial lung diseases: An epidemiological claims data analysis. JO - Ann. Am. Thorac. Soc. VL - 19 IS - 9 PB - Amer Thoracic Soc PY - 2022 SN - 2329-6933 ER - TY - JOUR AB - RATIONALE: Exposure to air pollution is associated with adverse respiratory effects. Omega-3 polyunsaturated fatty acids (n-3 FA) appear to attenuate the health effects to air pollution. OBJECTIVE: This panel study evaluated whether n-3 FA intake and blood levels of omega-6 polyunsaturated fatty acids (n-6 FA) can modulate the associations between respiratory effects and short-term exposure to ambient air pollution in healthy adults. METHODS: Sixty-two healthy adults were enrolled into either high or low n-3 groups based on n-3 FA intake and erythrocytes n-3 FA concentrations. Low and high n-6 groups were dichotomized on blood n-6 FA levels. Participants underwent 3-5 testing sessions separated by at least seven days. At each session, FVC, FEV1, plasma markers of inflammation (IL-6) and oxidative stress (ox-LDL) were measured. Associations between ambient ozone and fine particulate matter (PM2.5) levels and lung function and blood markers were assessed using mixed-effects models stratified by fatty acids levels. RESULTS: Average concentrations of ozone (40.8±11.1 ppb) and PM2.5 (10.2±4.1 µg/m3) were below national ambient air quality standards during the study period. FVC was positively associated with ozone at lag0 in the high n-3 group while the association was null in the low n-3 group [for an IQR increase in ozone, 1.8%(95% CI:0.5-3.2) vs. 0.0%(95% CI:-1.4-1.5)]; however, the association shifted to negative at lag4 [-1.9%(95% CI:-3.2- -0.5) vs. 0.2%(95% CI:-1.2-1.5)] and lag5 [-1.2%(95% CI:-2.4-0.0) vs. 0.9%(-0.4-2.3)]. A similar pattern was observed in the low n-6 group compared to the high n-6 group [lag0:1.7%(95% CI:0.3-3.0) vs. 0.5%(95% CI:-0.9-2.0) and lag4:-1.4%(95% CI:-2.8-0.0) vs. -0.5%(95% CI:-1.8-0.9)]. The associations between FEV1 and ozone and between FVC and PM2.5 also followed a similar pattern. Elevated ozone levels were associated with an immediate decrease in ox-LDL in the high n-3 group atlag0 [-12.3%(95% CI:-24.8-0.1)] while no change in the low n-3 group [-7.5%(95% CI: -21.4-6.5)], and a delayed increase in IL-6 in the high n-3 group compared with the low n-3 group [lag4: 66.9%(95% CI:27.9-106.0) vs. 8.9%(95% CI:-31.8-49.6), lag5: 58.2%(95% CI:22.4-94.1) vs. -7.4%(95% CI:-48.8-34.0), and lag6: 45.8%(95% CI:8.7-82.9) vs. -8.5%(95% CI:-49.7-32.6)]. CONCLUSIONS: We observed lag-dependent associations between short-term ambient air pollutants and lung function that were differentially modulated by n-3 and n-6 FAs, suggesting that n-3 and n-6 FAs counteract the respiratory response to low levels of ambient air pollution in healthy adults. Clinical trial registered with ClinicalTrials.gov (NCT02921048). AU - Tong, H.* AU - Zhang, S. AU - Shen, W.* AU - Chen, H.* AU - Salazar, C.* AU - Schneider, A.E. AU - Rappold, A.G.* AU - Diaz-Sanchez, D.* AU - Devlin, R.B.* AU - Samet, J.M.* C1 - 63637 C2 - 51647 SP - 583–593 TI - Lung function and short-term ambient air pollution exposure: Differential impacts of omega-3 and omega-6 fatty acids. JO - Ann. Am. Thorac. Soc. VL - 19 IS - 4 PY - 2022 SN - 2329-6933 ER - TY - JOUR AB - RATIONALE: Few longitudinal studies have assessed the relationship between occupational exposures and lung function decline in the general population, with sufficiently long follow-up. OBJECTIVES: Our objective was to examine this potential association in two large cohorts (ECRHS and SAPALDIA). METHODS: General population samples aged 18 to 62 were randomly selected in 1991-1993, and followed up approximately 10 and 20 years later. Spirometry (without bronchodilation) was performed at each visit. Coded complete job histories during follow-up visits were linked to a Job-Exposure Matrix, generating cumulative exposure estimates for 12 occupational exposures. FEV1 and FVC were jointly modelled in linear mixed-effects models, fitted in a Bayesian framework, taking into account age and smoking. RESULTS: A total of 40,024 lung function measurements from 17,833 study participants were analyzed. We found accelerated declines in FEV1 and the FEV1/FVC ratio for exposure to biological dust, mineral dust and metals (FEV1 -15.1ml, -14.4ml and -18.7ml respectively, and FEV1/FVC -0.52%, -0.43% and -0.36% respectively, per 25 intensity-years of exposure). These declines were comparable in magnitude to those associated with long-term smoking. No effect modification by sex or smoking status was identified. Findings were similar between the ECRHS and SAPALDIA cohorts. CONCLUSIONS: Our results greatly strengthen the evidence base implicating occupation, independent of smoking, as a risk factor for lung function decline. This highlights the need to prevent or control these exposures in the workplace. AU - Lytras, T.* AU - Beckmeyer-Borowko, A.* AU - Kogevinas, M.* AU - Kromhout, H.* AU - Carsin, A.E.* AU - Antó, J.M.* AU - Bentouhami, H.* AU - Weyler, J.* AU - Heinrich, J. AU - Nowak, D.* AU - Urrutia, I.* AU - Martínez-Moratalla, J.* AU - Gullón, J.A.* AU - Pereira Vega, A.* AU - Raherison Semjen, C.* AU - Pin, I.* AU - Demoly, P.* AU - Leynaert, B.* AU - Villani, S.* AU - Gislason, T.* AU - Svanes, Ø.* AU - Holm, M.* AU - Forsberg, B.* AU - Norbäck, D.* AU - Mehta, A.J.* AU - Keidel, D.* AU - Vernez, D.* AU - Benke, G.* AU - Jõgi, R.* AU - Torén, K.* AU - Sigsgaard, T.* AU - Schlünssen, V.* AU - Olivieri, M.* AU - Blanc, P.D.* AU - Watkins, J.* AU - Bono, R.* AU - Squillacioti, G.* AU - Buist, A.S.* AU - Vermeulen, R.* AU - Jarvis, D.* AU - Probst-Hensch, N.* AU - Zock, J.P.* C1 - 60660 C2 - 49568 CY - 25 Broadway, 18 Fl, New York, Ny 10004 Usa SP - 238-246 TI - Cumulative occupational exposures and lung function decline in two large general population cohorts. JO - Ann. Am. Thorac. Soc. VL - 18 IS - 2 PB - Amer Thoracic Soc PY - 2021 SN - 2329-6933 ER - TY - JOUR AB - Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status. AU - Fernandez, I.E. AU - Heinzelmann, K. AU - Verleden, S.* AU - Eickelberg, O. C1 - 44099 C2 - 36780 SP - S34-S41 TI - Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction. JO - Ann. Am. Thorac. Soc. VL - 12 PY - 2015 SN - 2329-6933 ER - TY - JOUR AB - With the expected rapid growth of the aging population worldwide, there is a clear need to understand the complex process of aging to develop interventions that might extend the health span in this group of patients. Aging is associated with increased susceptibility to a variety of chronic diseases, and lung pathologies are no exception. The prevalence of lung diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease has been found to increase considerably with age. In October 2014, the Division of Pulmonary, Allergy, and Critical Care of the University of Pittsburgh cohosted the Pittsburgh-Munich Lung Conference focused in aging and lung disease with the Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ludwig-Maximilians University and Helmholtz Zentrum Munich Germany. The purpose of the conference was to disseminate novel concepts in aging mechanisms that have an impact in lung physiology and pathogenesis of pulmonary diseases that commonly occur in older populations. The conference included 28 presentations on diverse topics, which are summarized in this report. The participants identified priorities for future basic and translational investigations that will assist in the identification of molecular insights involved in the pathogenesis of age-related pulmonary diseases and the design of therapeutic interventions for these lung conditions. AU - Rojas, M.* AU - Mora, A.L.* AU - Kapetanaki, M.* AU - Weathington, N.* AU - Gladwin, M.* AU - Eickelberg, O. C1 - 47543 C2 - 40648 SP - S222-S227 TI - Aging and lung disease. Clinical impact and cellular and molecular pathways. JO - Ann. Am. Thorac. Soc. VL - 12 IS - 12 PY - 2015 SN - 2329-6933 ER - TY - JOUR AB - Transforming growth factor-β (TGF-β) is extensively involved in the development of fibrosis in different organs. Overproduction or potentiation of its profibrotic effects leads to an aberrant wound healing response during the initiation of fibrotic processes. Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating disease, in which TGF-βx{2013}induced disturbances of the homeostatic microenvironment are critical to promote cell activation, migration, invasion, or hyperplastic changes. In addition, excess extracellular matrix production contributes in a major way to disease pathogenesis. For this reason, this review will focus on discussing novel data and highlight growing interest in deepening the understanding of the profibrotic role of TGF-β and its direct or indirect targeting for disease modulation. AU - Fernandez, I.E. AU - Eickelberg, O. C1 - 7938 C2 - 29924 SP - 111-116 TI - The impact of TGF-β on lung fibrosis: From targeting to biomarkers. JO - Ann. Am. Thorac. Soc. VL - 9 IS - 3 PB - American Thoracic Society PY - 2012 SN - 2329-6933 ER - TY - JOUR AB - The transforming growth factor (TGF)-beta superfamily of secreted growth factors consists of more than 40 members, including the TGF-beta isoforms themselves, bone morphogenetic proteins, and activins. Most of these factors have been shown to be essential for proper organ development, a process often recapitulated in chronic diseases. Importantly, TGF-beta superfamily members are key regulators of extracellular matrix composition and alveolar epithelial cell and fibroblast function in the lung. Both during lung development and disease, TGF-betas therefore control lung homeostasis by providing the structural requirements and functional micromilieu needed for physiological epithelial cell function and proper gas exchange. Prolonged alterations of TGF-beta signaling have been shown to result in structural changes in the lung that compromise gas exchange and lung function, as seen in arrested lung development, a feature of bronchopulmonary dysplasia, lung fibrosis, and chronic obstructive pulmonary disease. All these syndromes share a loss of functional alveolar structures, which ultimately leads to a decreased life expectancy. In this review, we cover our current understanding of the impact of TGF-beta signaling on chronic lung disease. We focus on distorted TGF-beta signaling in bronchopulmonary dysplasia and chronic obstructive pulmonary disease as prototype diseases of the premature and matured lung, respectively, which are both characterized by functional and structural loss of alveolar units. AU - Morty, R.E.* AU - Königshoff, M. AU - Eickelberg, O. C1 - 195 C2 - 26819 SP - 607-613 TI - Transforming growth factor-β signaling across ages: From distorted lung development to chronic obstructive pulmonary disease. JO - Ann. Am. Thorac. Soc. VL - 6 IS - 7 PB - American Thoracic Society PY - 2009 SN - 2329-6933 ER - TY - JOUR AB - Biomedical imaging has become an important tool in the study of "-omics" fields by allowing the noninvasive visualization of functional and molecular events using in vivo staining and reporter gene approaches. This capacity can go beyond the understanding of the genetic basis and phenotype of such respiratory conditions as acute bronchitis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and asthma and investigate the development of disease and of therapeutic events longitudinally and in unperturbed environments. Herein, we show how the application of novel quantitative optical imaging methods, using transillumination and fluorescence molecular tomography (FMT), can allow visualization of pulmonary inflammation in small animals in vivo. The results confirm prior observations using a protease-sensitive probe. We discuss how this approach enables in vivo insights at the system level as to the dynamic role of proteases in respiratory pathophysiology and their potential as therapeutic targets. Overall, the proposed imaging method can be used with a significantly wider range of possible targets and applications in lung imaging. AU - Ntziachristos, V. C1 - 2812 C2 - 26804 SP - 416-418 TI - Optical imaging of molecular signatures in pulmonary inflammation. JO - Ann. Am. Thorac. Soc. VL - 6 PY - 2009 SN - 2329-6933 ER -