title: Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury.
abstract: Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E-cadherin and zona occludens-1, whereas collagen-I and α-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells.
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Amarnath Satheesh
authors.initials: AS
authors.lastname: Marudamuthu
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Yashodhar Prabhakar
authors.initials: YP
authors.lastname: Bhandary
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Shwetha Kumari
authors.initials: SK
authors.lastname: Shetty
authors.affiliation: Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Venkatachalem
authors.initials: V
authors.lastname: Sathish
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ys
authors.initials: Y
authors.lastname: Prakash
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas. Electronic address: sreerama.shetty@uthct.edu.
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D015820:Cadherins / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000503:physiopathology; D012307:Risk Factors; D058258:Serpin E2 / Q000378:metabolism; D012907:Smoking; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C569043:Tjp1 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D062826:Zonula Occludens-1 Protein; D001761:Bleomycin; D014568:Urokinase-Type Plasminogen Activator