TY  - JOUR
AB  - BACKGROUND: Airway infection and inflammation play major roles in the progression of cystic fibrosis (CF) lung disease. In patients with mild disease, airway inflammation is a clinically relevant and often underdiagnosed feature. Lung function, sputum cell counts, and cytokine profiles in CF with mild disease might be different in patients with and without involvement of small airway disease (SAD). METHODS: Patients with mild CF (n=32) and 22 healthy controls were enrolled in this study. Patients with CF were assigned to two groups: (1) patients without SAD (n=19, median age 12.3years, MEF25>50% predicted), and (2) patients with SAD (n=13 median age, 13.2years, MEF25<50% predicted). Lung function parameters were measured, cells in induced sputum were counted, and cytokines/chemokines (IL-1β, IL-6, IL-8, TNF-α) were analyzed by real-time quantitative PCR (qRT-PCR) and cytometric bead array (CBA). RESULTS: Patients with CF had significant elevated levels of pro-inflammatory genes in qRT-PCR and secreted gene products in CBA compared to controls. Patients with CF and SAD had significantly increased trapped air (RV/TLC) and pronounced airway inflammation compared to controls as indicated by elevated levels of sputum biomarkers like total cells, neutrophils, and IL6. CONCLUSIONS: Our study demonstrated that patients with CF with mild disease defined by lung function might be further endotyped according to their involvement of SAD. In patients with CF and SAD, airway neutrophilic inflammation is more pronounced and is in part distinct from that seen in patients without SAD.
AU  - Eckrich, J.*
AU  - Zissler, U.M.
AU  - Serve, F.*
AU  - Leutz, P.*
AU  - Smaczny, C.*
AU  - Schmitt-Grohé, S.*
AU  - Fussbroich, D.*
AU  - Schubert, R.*
AU  - Zielen, S.*
AU  - Eickmeier, O.*
C1  - 48817
C2  - 41431
CY  - Amsterdam
SP  - 107-115
TI  - Airway inflammation in mild cystic fibrosis.
JO  - J. Cyst. Fibros.
VL  - 16
IS  - 1
PB  - Elsevier Science Bv
PY  - 2017
SN  - 1569-1993
ER  - 

TY  - JOUR
AB  - BACKGROUND: Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. METHODS: Sputa were collected from CF patients (n=5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. RESULTS: There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. CONCLUSION: Inhibitors of neutrophil and Pseudomonas-derived elastases might rescue mucus clearance and reverse airway obstruction in CF.
AU  - Chillappagari, S.*
AU  - Müller, C.*
AU  - Mahavadi, P.*
AU  - Guenther, A.*
AU  - Nahrlich, L.*
AU  - Rosenblum, J.*
AU  - Rubin, B.K.*
AU  - Henke, M.O.
C1  - 47188
C2  - 39158
CY  - Amsterdam
SP  - 325-331
TI  - A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation.
JO  - J. Cyst. Fibros.
VL  - 15
IS  - 3
PB  - Elsevier Science Bv
PY  - 2016
SN  - 1569-1993
ER  - 

TY  - JOUR
AB  - BACKGROUND: Neutrophilic inflammation causes lung damage in cystic fibrosis (CF). Recent data from animal models suggest that the migration of blood monocytes into the airway supports neutrophil-mediated tissue injury. CF may therefore be associated with increased airway levels of chemoattractants for pro-inflammatory monocytes. In this study, we sought to assess the levels of monocyte chemoattractants CCL2 and CX3CL1 in the blood and airways of patients with CF, and expression of their respective receptors CCR2 and CX3CR1 on blood monocytes. METHODS: Blood was obtained from 32 CF patients and 25 healthy controls. Induced sputum was obtained from a further 24 CF patients and 17 healthy controls. Expression of CCR2 and CX3CR1 on CD14++CD16- and CD14+CD16+ blood monocytes was determined by flow cytometry. CCL2 and CX3CL1 levels in blood and induced sputum were determined by ELISA. RESULTS: Total blood monocyte concentration was not different between CF and controls. CCR2 was absent, and CX3CR1 higher on CD14+CD16+ monocytes from both CF and controls when compared with expression on CD14++CD16- cells. There was no difference in expression of chemokine receptors by either monocyte subpopulation between CF and controls. Blood CCL2, but not CX3CL1, was increased in CF patients (p = 0.006). Similarly, CF was associated with increased induced sputum CCL2, but not CX3CL1 (190.6 vs. 77.3pg/mL; p = 0.029). CONCLUSION: CCL2, but not CX3CL1 is increased in the airway and blood of CF patients. Blood monocytes from CF patients are phenotypically competent to respond to CCL2, since they express normal levels of CCR2.  
AU  - Rao, S.*
AU  - Wright, A.K.*
AU  - Montiero, W.*
AU  - Ziegler-Heitbrock, L.
AU  - Grigg, J.*
C1  - 28406
C2  - 33369
SP  - 97-103
TI  - Monocyte chemoattractant chemokines in cystic fibrosis.
JO  - J. Cyst. Fibros.
VL  - 8
IS  - 2
PB  - Elsevier
PY  - 2009
SN  - 1569-1993
ER  -