title: Disruption of plasminogen activator inhibitor-1 gene enhances spontaneous enlargement of mouse airspace with increasing age.
abstract: 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.
authors.affiliation: Department of ENT, Huadong Hospital, Shanghai Medical School, Fudan University, Shanghai, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Hu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiao
authors.forename: Ruxin
authors.initials: R
authors.lastname: Zhang
authors.forename: Houyan
authors.initials: H
authors.lastname: Song
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D004549:Elastin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004549:Elastin; D053508:Matrix Metalloproteinase 12