title: p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53-miR-34a feedback as a potential therapeutic target in PF.
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Shwetha K
authors.initials: SK
authors.lastname: Shetty
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Amarnath S
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: Bijesh
authors.initials: B
authors.lastname: Puthusseri
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Yashodhar P
authors.initials: YP
authors.lastname: Bhandary
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: Division of Occupational Medicine, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Levin
authors.affiliation: Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
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: D056809:Alveolar Epithelial Cells / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051242:Caveolin 1 / Q000494:pharmacology; D002478:Cells, Cultured; D005246:Feedback; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology*; D055370:Lung Injury / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D020545:Respiratory Mucosa / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D051242:Caveolin 1; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53