Tohoku J. Exp. Med., 2010, 222(4)

Disruption of Plasminogen Activator Inhibitor-1 Gene Enhances Spontaneous Enlargement of Mouse Airspace with Increasing Age

HUA HU,^1,3 YANYAN ZHAO,² YAO XIAO,³ RUXIN ZHANG¹ and HOUYAN SONG³

¹Department of ENT, Huadong Hospital, Shanghai Medical School, Fudan University, Shanghai, P.R. China
²Department of neurology, Xinhua Hospital (Chong Ming), Shanghai Jiaotong University, Shanghai, P.R. China
³Department of Molecular Genetics and the Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical School, Fudan University, Shanghai, P.R. China

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.

keywords —— Plasminogen activator inhibitor-1; Age; Matrix metalloproteinase-12; transforming growth factor-β1; Elastin

© 2010 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2010, 222, 291-296

Correspondence: Ruxin Zhang, Department of ENT, Huadong Hospital, Shanghai Medical School, Fudan University, Shanghai, 200040, P.R. China.

e-mail: ruxzhang@gmail.com, rxzhang@x263.net