title: The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice.
abstract: Plasminogen activator inhibitor-1 (PAI-1) is increased in the lungs of patients with pulmonary fibrosis, and animal studies have shown that experimental manipulations of PAI-1 levels directly influence the extent of scarring that follows lung injury. PAI-1 has 2 known properties that could potentiate fibrosis, namely an antiprotease activity that inhibits the generation of plasmin, and a vitronectin-binding function that interferes with cell adhesion to this extracellular matrix protein. To determine the relative importance of each PAI-1 function in lung fibrogenesis, we administered mutant PAI-1 proteins that possessed either intact antiprotease or vitronectin-binding activity to bleomycin-injured mice genetically deficient in PAI-1. We found that the vitronectin-binding capacity of PAI-1 was the primary determinant required for its ability to exacerbate lung scarring induced by intratracheal bleomycin administration. The critical role of the vitronectin-binding function of PAI-1 in fibrosis was confirmed in the bleomycin model using mice genetically modified to express the mutant PAI-1 proteins. We conclude that the vitronectin-binding function of PAI-1 is necessary and sufficient in its ability to exacerbate fibrotic processes in the lung.
authors: Division of Pulmonary and Critical Care Medicine. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Anthony J
authors: AJ
authors: Courey
authors: Jeffrey C
authors: JC
authors: Horowitz
authors: Kevin K
authors: KK
authors: Kim
authors: Timothy J
authors: TJ
authors: Koh
authors: Margaret L
authors: ML
authors: Novak
authors: Natalya
authors: N
authors: Subbotina
authors: Mark
authors: M
authors: Warnock
authors: Bing
authors: B
authors: Xue
authors: Andrew K
authors: AK
authors: Cunningham
authors: Yujing
authors: Y
authors: Lin
authors: Monica P
authors: MP
authors: Goldklang
authors: Richard H
authors: RH
authors: Simon
authors: Daniel A
authors: DA
authors: Lawrence
authors: Thomas H
authors: TH
authors: Sisson
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000097:blood / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D019096:Vitronectin; D001761:Bleomycin; D003094:Collagen; D006909:Hydroxyproline