Pro‐inflammatory phenotype of COPD fibroblasts not compatible with repair in COPD lung

Jing Zhang,Jie‐Ming Qu,Mervyn J Merrilees,Peter N Black,Chun‐Xue Bai,Lian Wu

doi:10.1111/j.1582-4934.2011.01492.x

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by loss of elastic fibres from small airways and alveolar walls, with the decrease in elastin increasing with disease severity. It is unclear why there is a lack of repair of elastic fibres. We have examined fibroblasts cultured from lung tissue from subjects with or without COPD to determine if the secretory profile explains lack of tissue repair. In this study, fibroblasts were cultured from lung parenchyma of patients with mild COPD [Global initiative for chronic Obstructive Lung Disease (GOLD) 1, n= 5], moderate to severe COPD (GOLD 2–3, n= 12) and controls (non-COPD, n= 5). Measurements were made of proliferation, senescence-associated β-galactosidase-1, mRNA expression of IL-6, IL-8, MMP-1, tropoelastin and versican, and protein levels for IL-6, IL-8, PGE2, tropoelastin, insoluble elastin, and versican. GOLD 2–3 fibroblasts proliferated more slowly (P < 0.01), had higher levels of senescence-associated β-galactosidase-1 (P < 0.001) than controls and showed significant increases in mRNA and/or protein for IL-6 (P < 0.05), IL-8 (P < 0.01), MMP-1 (P < 0.05), PGE2 (P < 0.05), versican (P < 0.05) and tropoelastin (P < 0.05). mRNA expression and/or protein levels of tropoelastin (P < 0.01), versican (P < 0.05), IL-6 (P < 0.05) and IL-8 (P < 0.05) were negatively correlated with FEV1% of predicted. Insoluble elastin was not increased. In summary, fibroblasts from moderate to severe COPD subjects display a secretory phenotype with up-regulation of inflammatory molecules including the matrix proteoglycan versican, and increased soluble, but not insoluble, elastin. Versican inhibits assembly of tropoelastin into insoluble elastin and we conclude that the pro-inflammatory phenotype of COPD fibroblasts is not compatible with repair of elastic fibres.

Highlights

Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction in the small airways [1, 2], involves both small airway remodelling and emphysematous changes
Twenty-two patients met the criteria for the study and were divided into three groups according to the results of spirometry: control, mild COPD (GOLD stage 1, n ϭ 5) and moderate to severe COPD (GOLD stage 2–3, n ϭ 12) (Table 2)
This study demonstrates that fibroblasts derived from the peripheral parenchyma of lungs of patients with moderate to severe COPD (GOLD stages 2–3) have a distinctly different phenotype from fibroblasts cultured from patients with mild COPD (GOLD stage 1) or without COPD

Summary

Introduction

Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction in the small airways [1, 2], involves both small airway remodelling and emphysematous changes. The majority of research on COPD has focussed on the idea that emphysema can be explained by progressive destruction of the alveolar walls but there are several lines of evidence to suggest. Vol 16, No 7, 2012 that inhibition of repair may be important in the pathogenesis of COPD [7, 8]. When damage occurs as a result of smoking there may be differences in the ability to repair this damage, and individuals with impaired repair mechanisms may be more likely to develop COPD. Does not appear to be due to the inability to synthesize structural matrix proteins such as elastin and collagen

Methods

Results

Conclusion