title: Plasminogen activator inhibitor-1 suppresses profibrotic responses in fibroblasts from fibrotic lungs.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive interstitial scarification. A hallmark morphological lesion is the accumulation of myofibroblasts or fibrotic lung fibroblasts (FL-fibroblasts) in areas called fibroblastic foci. We previously demonstrated that the expression of both urokinase-type plasminogen activator (uPA) and the uPA receptor are elevated in FL-fibroblasts from the lungs of patients with IPF. FL-fibroblasts isolated from human IPF lungs and from mice with bleomycin-induced pulmonary fibrosis showed an increased rate of proliferation compared with normal lung fibroblasts (NL-fibroblasts) derived from histologically "normal" lung. Basal expression of plasminogen activator inhibitor-1 (PAI-1) in human and murine FL-fibroblasts was reduced, whereas collagen-I and α-smooth muscle actin were markedly elevated. Conversely, alveolar type II epithelial cells surrounding the fibrotic foci in situ, as well as those isolated from IPF lungs, showed increased activation of caspase-3 and PAI-1 with a parallel reduction in uPA expression. Transduction of an adenovirus PAI-1 cDNA construct (Ad-PAI-1) suppressed expression of uPA and collagen-I and attenuated proliferation in FL-fibroblasts. On the contrary, inhibition of basal PAI-1 in NL-fibroblasts increased collagen-I and α-smooth muscle actin. Fibroblasts isolated from PAI-1-deficient mice without lung injury also showed increased collagen-I and uPA. These changes were associated with increased Akt/phosphatase and tensin homolog proliferation/survival signals in FL-fibroblasts, which were reversed by transduction with Ad-PAI-1. This study defines a new role of PAI-1 in the control of fibroblast activation and expansion and its role in the pathogenesis of fibrosing lung disease and, in particular, IPF.
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Amarnath S
authors: AS
authors: Marudamuthu
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Shwetha K
authors: SK
authors: Shetty
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Yashodhar P
authors: YP
authors: Bhandary
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Sophia
authors: S
authors: Karandashova
authors: the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors: Michael
authors: M
authors: Thompson
authors: the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors: Venkatachalem
authors: V
authors: Sathish
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Galina
authors: G
authors: Florova
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Taryn B
authors: TB
authors: Hogan
authors: the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors: Christina M
authors: CM
authors: Pabelick
authors: the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors: Y S
authors: YS
authors: Prakash
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Yoshikazu
authors: Y
authors: Tsukasaki
authors: the Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536.
authors: Jian
authors: J
authors: Fu
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Mitsuo
authors: M
authors: Ikebe
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708.
authors: Steven
authors: S
authors: Idell
authors: From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, sreerama.shetty@uthct.edu.
authors: Sreerama
authors: S
authors: Shetty
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001761:Bleomycin; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009130:Muscle, Smooth / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D055293:Receptors, Urokinase Plasminogen Activator; D001761:Bleomycin; D014568:Urokinase-Type Plasminogen Activator
keywords: Animal Model; Fibroblast; Fibrosis; Lung; PAI-1; Pulmonary Fibrosis
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