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-alpha1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3alpha1) 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 1alpha1, and transforming growth factor-beta3) 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.

Figure 1.

(A) Photomicrograph showing a thickened small airway in close proximity to early centrilobular emphysematous destruction (CLE). (B–E) Process of laser capture microdissection (LCM). (B) A single small airway and surrounding tissue stained with hematoxylin and eosin before LCM. (C) The tissue surrounding the airway after the airway was removed by LCM. (D) The isolated small airway. (E) A higher magnification of boxed area in (D) showing the individual compartments of the isolated small airway wall (Bar = 100 μm).

Figure 2.

Matrix metalloproteinase (MMP)-2 activity compared with gene expression in whole lung tissue from patients with chronic obstructive pulmonary disease (COPD). (A) Gelatin zymogram showing MMP activity in lung tissue from five patients with COPD with low (L) and six with high (H) levels of MMP2 gene expression (lanes 1–11) and MMP2/MMP9 zymography standard including various forms and complexes (–20) (S, lane 12) as identified at the right of the zymogram. (B) Box plots of MMP2 gene expression (in normalized relative gene expression units) in the lungs of these two groups of patients with COPD. (C) The corresponding box plots of MMP2 activity (in relative densitometry units) in these two groups from the gelatin zymogram in (A). In the box plots, the middle horizontal line represent the median, boxes denote lower (Q1) and higher (Q3) quartiles, and whiskers denote range of the data; circles and diamonds represent the values from each sample tested. *Significantly different, P < 0.05.