Lung Fibroblast Repair Functions in Patients with Chronic Obstructive Pulmonary Disease Are Altered by Multiple Mechanisms

• Published in: American journal of respiratory and critical care medicine 2008-08, Vol.178 (3), p.248-260
• Main Authors: Togo, Shinsaku, Holz, Olaf, Liu, Xiangde, Sugiura, Hisatoshi, Kamio, Koichiro, Wang, Xiangqi, Kawasaki, Shin, Ahn, Youngsoo, Fredriksson, Karin, Skold, C. Magnus, Mueller, Kai Christian, Branscheid, Detlef, Welker, Lutz, Watz, Henrik, Magnussen, Helgo, Rennard, Stephen I
• Format: Article
• Language: English
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Bioassays; Biological and medical sciences; C. Chronic Obstructive Pulmonary Disease; Case-Control Studies; Cells, Cultured; Chemotaxis - physiology; Chronic obstructive pulmonary disease; Chronic obstructive pulmonary disease, asthma; Cigarettes; Collagen; Dinoprostone - metabolism; Emphysema; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibroblasts; Fibroblasts - metabolism; Growth factors; Humans; Hypotheses; Intensive care medicine; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Ostomy; Pneumology; Pulmonary Disease, Chronic Obstructive - physiopathology; Transforming Growth Factor beta1 - metabolism
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200706-929OC

Fibroblasts are believed to be the major cells responsible for the production and maintenance of extracellular matrix. Alterations in fibroblast functional capacity, therefore, could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate maintenance of tissue structure. To evaluate the hypothesis that deficient fibroblast repair characterizes cells obtained from individuals with chronic obstructive pulmonary disease (COPD) compared with control subjects. Fibroblasts were cultured from lung tissue obtained from individuals undergoing thoracotomy and were characterized in vitro. Fibroblasts from individuals with COPD, defined by reduced FEV(1), manifested reduced chemotaxis toward fibronectin and reduced contraction of three-dimensional collagen gels, two bioassays associated with fibroblast repair function. At least two mechanisms appear to account for these differences. Prostaglandin E (PGE), a known inhibitor of fibroblast repair functions, was produced in increased amount by fibroblasts from subjects with COPD, which also expressed increased amounts of the receptors EP2 and EP4, both of which signal through cyclic AMP. Incubation of fibroblasts with indomethacin or with the PKA inhibitor KT-5720 partially restored COPD subject fibroblast function. In addition, fibroblasts from subjects with COPD produced more transforming growth factor (TGF)-beta1, but manifested reduced response to TGF-beta1. The functional alterations in fibroblasts correlated with both lung function assessed by FEV(1) and, for the data available, with severity of emphysema assessed by Dl(CO). Fibroblasts from individuals with COPD have reduced capability to sustain tissue repair, which suggests that this may be one mechanism that contributes to the development of emphysema.