p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis

Shwetha K. Shetty, Nivedita Tiwari, Amarnath S. Marudamuthu, Bijesh Puthusseri, Yashodhar P. Bhandary, Jian Fu, Jeffrey Levin, Steven Idell, Sreerama Shetty

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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.

Original languageEnglish
Pages (from-to)1016-1034
Number of pages19
JournalAmerican Journal of Pathology
Issue number5
StatePublished - May 2017

Bibliographical note

Funding Information:
Supported in part by Flight Attendant Medical Research Institute Clinical Innovator Awards 150063 and 082380 (S.S.), American Heart Association grant GRNT19020001 (S.S.), and NIH grants R01HL133067-01 and R21ES025815 (S.S.).

Publisher Copyright:
© 2017 American Society for Investigative Pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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