p53 Expression in Lung Fibroblasts Is Linked to Mitigation of Fibrotic Lung Remodeling

M. R. Nagaraja, Nivedita Tiwari, Shwetha K. Shetty, Amarnath S. Marudamuthu, Liang Fan, Rennolds S. Ostrom, Jian Fu, Venkadesaperumal Gopu, Vijay Radhakrishnan, Steven Idell, Sreerama Shetty

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease. A cardinal feature of the pathogenesis of IPF is excessive extracellular matrix deposition attributable to proliferation of activated fibrotic lung fibroblasts (fLfs). To assess the underlying mechanism, we analyzed the status of the tumor suppressor protein p53 in fLfs from the lungs of IPF patients or mice with bleomycin-induced established PF. We report that basal expression of p53 is markedly reduced in fLfs. Forced expression of caveolin-1 in fLfs increased basal p53 and reduced profibrogenic proteins, including collagen-1. Transduction of fLfs with adenovirus expressing p53 reduced expression of these proteins. Conversely, inhibition of baseline p53 in control lung fibroblasts from lung tissues increased profibrogenic protein expression. Lung transduction of adenovirus expressing p53 reduced bleomycin-induced PF in wild-type or caveolin-1–deficient mice. Furthermore, treatment of fLfs or fibrotic lung tissues with caveolin-1 scaffolding domain peptide (CSP) or its fragment, CSP7, restored p53 and reduced profibrogenic proteins. Treatment of wild-type mice with i.p. CSP or CSP7 resolved bleomycin-induced PF. These peptides failed to resolve PF in inducible conditional knockout mice lacking p53 in fLfs, indicating the induction of baseline fLf p53 as the basis of the antifibrotic effects.

Original languageEnglish
Pages (from-to)2207-2222
Number of pages16
JournalAmerican Journal of Pathology
Volume188
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding Information:
Supported in part by NIH grants R01HL133067-01 (S.S.) and R21ES025815 (S.S.) and Flight Attendant Medical Research Institute, Clinical Investigator Award 150063 (S.S.).

Publisher Copyright:
© 2018 American Society for Investigative Pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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