Differential Expression of Tissue Repair Genes in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

Rationale: The airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction. Objectives: To examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair. Methods: The expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV 1 by linear regression analysis. Measurements and Main Results: After corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-a1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3a1) decreased in small airways in association with FEV 1 . In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1a1, and transforming growth factor-b3) decreased in the surrounding lung tissue in association with progression of COPD. Conclusions: The progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

“…We observed a novel association of TNF-a induced MMP9 mRNA expression with FEV1 % pred (table 3). This observation is consistent with previous data that demonstrated MMP9 expression increased in the lung parenchyma surrounding small airways as FEV1 % pred decreased [40]. There is also supportive evidence that MMP9 contributes to the development of emphysema from mouse models [41,42].…”

“…There is also supportive evidence that MMP9 contributes to the development of emphysema from mouse models [41,42]. Our data suggest that it is the level of MMP9 in response to specific pro-inflammatory stimuli that plays a critical role in the development of COPD, in agreement with studies showing that increases in TNF-a are associated with reductions in lung function [40] and that TNF-a plays an important role in cigarette smoke-induced emphysema [43].…”

Association of SERPINE2 With Asthma

“…32 Thus, it is plausible that genetic variants in SERPINE2 infl uence asthma and COPD through modulation of airway remodeling processes.…”

Matrix metalloproteinases in COPD

“…LAPAN et al [50] pointed out that MMP-12 levels in induced sputum tend to be relatively low and developed highly specific assays to detect it; they were able to find MMP-12, but could not identify differences between control and COPD patients. GOSSELINK et al [51] could not find any associations with parenchymal MMP-12 gene expression and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. LEE et al [52] investigated the potential association of single nucleotide polymorphisms (SNPs) in MMP-1, MMP-9 and MMP-12 with COPD in a Korean population and found that only the MMP-9 -1562CRT showed a (protective) correlation; the MMP-12 N357S SNP was not associated with differences in COPD frequency.…”