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

• Published in: The American journal of pathology Vol. 188; no. 10; pp. 2207 - 2222
• Main Authors: Nagaraja, M.R., Tiwari, Nivedita, Shetty, Shwetha K., Marudamuthu, Amarnath S., Fan, Liang, Ostrom, Rennolds S., Fu, Jian, Gopu, Venkadesaperumal, Radhakrishnan, Vijay, Idell, Steven, Shetty, Sreerama
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018; American Society for Investigative Pathology
• Subjects: Airway Remodeling - physiology; Animals; Antibiotics, Antineoplastic - toxicity; Bleomycin - toxicity; Caveolin 1 - deficiency; Caveolin 1 - metabolism; Caveolin 1 - pharmacology; Fibroblasts - metabolism; Humans; Idiopathic Pulmonary Fibrosis - physiopathology; Mice, Inbred C57BL; Peptide Fragments - pharmacology; Transduction, Genetic; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2018.07.005

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.