title: Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system.
abstract: Alveolar type II (ATII) cell apoptosis and depressed fibrinolysis that promotes alveolar fibrin deposition are associated with acute lung injury (ALI) and the development of pulmonary fibrosis (PF). We therefore sought to determine whether p53-mediated inhibition of urokinase-type plasminogen activator (uPA) and induction of plasminogen activator inhibitor-1 (PAI-1) contribute to ATII cell apoptosis that precedes the development of PF. We also sought to determine whether caveolin-1 scaffolding domain peptide (CSP) reverses these changes to protect against ALI and PF. Tissues as well as isolated ATII cells from the lungs of wild-type (WT) mice with BLM injury show increased apoptosis, p53, and PAI-1, and reciprocal suppression of uPA and uPA receptor (uPAR) protein expression. Treatment of WT mice with CSP reverses these effects and protects ATII cells against bleomycin (BLM)-induced apoptosis whereas CSP fails to attenuate ATII cell apoptosis or decrease p53 or PAI-1 in uPA-deficient mice. These mice demonstrate more severe PF. Thus p53 is increased and inhibits expression of uPA and uPAR while increasing PAI-1, changes that promote ATII cell apoptosis in mice with BLM-induced ALI. We show that CSP, an intervention targeting this pathway, protects the lung epithelium from apoptosis and prevents PF in BLM-induced lung injury via uPA-mediated inhibition of p53 and PAI-1.
authors.affiliation: Texas Lung Injury Institute, Department of Medicine, The University of Texas Health Science Center, Tyler, Texas 75708, USA.
authors.forename: Yashodhar P
authors.initials: YP
authors.lastname: Bhandary
authors.forename: Shwetha K
authors.initials: SK
authors.lastname: Shetty
authors.forename: Amarnath S
authors.initials: AS
authors.lastname: Marudamuthu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Gyetko
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Gharaee-Kermani
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Shetty
authors.forename: Barry C
authors.initials: BC
authors.lastname: Starcher
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001761:Bleomycin; D051242:Caveolin 1 / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C571371:caveolin-1 (82-101); D001761:Bleomycin; D003094:Collagen; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D014568:Urokinase-Type Plasminogen Activator