Disruption of plasminogen activator inhibitor-1 gene enhances spontaneous enlargement of mouse airspace with increasing age.

Plasminogen activator inhibitor-1 (PAI-1) is the most effective protease inhibitor in the fibrinolysis system, and plays an important role in the remodeling of the extracellular matrix. We therefore explored whether PAI-1 is involved in the change of lung structure with increasing age. PAI-1 gene knockout mice and wild-type mice were sacrificed at age 3 weeks, 3 months, 6 months and 15 months for histopathology analysis, and assessed the relationship between PAI-1 and the change in lung structure with age. Six-month-old mice were chosen for further studies. Elastin in the lung was detected using Weigert staining. We measured the expression of matrix metalloproteinase-12 (MMP-12) that is a major protease in elastin degradation by real time PCR and immunostaining. Transforming growth factor-β1 (TGF-β1) expression was measured by western blot analysis. PAI-1 gene knockout mice showed significant increases in alveolar size with increasing age and damaged alveolar structure at the age of 15 months, compared with wild-type mice. At the age of 6 months, elastin protein was decreased in the lungs of PAI-1 gene knockout mice. PAI-1 null mice had higher MMP-12 mRNA expression, and lower expression level of active TGF-β1 in the lung. Taken together, these results indicate that the emphysema-like change attributed to PAI-1 deficiency might be facilitated with increased MMP-12 expression that accelerates elastin degradation in mice lungs, and TGF-β1 might be involved in the modulation of this process.