Disruption of the SERPINE2 Gene Results in COPD‐Related Lung Phenotypes

Overwhelming evidence suggests the presence of genetic factors, in addition to α1‐antitrypsin (serine proteinase inhibitor, clade A, member 1 or SERPINA1) deficiency, which contribute to the development of COPD in the general population. Using a combination of genetic linkage, microarray gene expression and genetic association studies, we have recently identified SERPINE2 as a novel candidate susceptibility gene for COPD. SERPINE2 is a cell and matrix‐associated inhibitor of thrombin and plasmin, but not elastase. Prominent immunolocalization in adult mouse and human lungs was observed in the conducting airway epithelium and vascular adventitia. Gene expression for SERPINE2 could be detected in isolated lung mesenchymal cells, alveolar epithelial cells and bronchio‐alveolar stem cells. We tested the hypothesis that SERPINE2 confers susceptibility to COPD pathogenesis by studying lung development and homeostasis in SERPINE2‐deficient mice. A significant mononuclear cell infiltration was observed adjacent to the airways and vasculature of ageing SERPINE2‐deficient mice. At 9 weeks of age, 50% of SERPINE2‐deficient mice (n=20) had notable peribronchial and perivascular mononuclear cell infiltration. At 32 weeks of age, all SERPINE2‐ deficient mice (n=7) showed large infiltrates resembling Bronchus‐Associated Lymphoid Tissue (BALT). These findings were absent in the lungs of the age‐matched wild type and littermate heterozygote animals. Histological assessment also revealed abnormally enlarged airspaces in SERPINE2‐deficient mice at 9 weeks old. Quantitative morphometry showed a significant increase in mean alveolar chord length (32.56 μm vs. 29.16 μm; p=0.018). These results suggest that SERPINE2 contributes to the control of pulmonary homeostasis by preventing inflammatory cell recruitment and maintaining alveolar structure.