Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis

TLDR

Idiopathic pulmonary fibrosis is a progressive chronic disease marked by fibroblast activation and excess extracellular matrix production, and caveolin‑1, a key caveolae component, has been implicated in regulating multiple signaling pathways. The study found that caveolin‑1 expression is markedly reduced in IPF lungs and fibroblasts, and that restoring cav‑1 suppresses bleomycin‑induced fibrosis and TGF‑β1–driven extracellular matrix production through inhibition of the JNK pathway, highlighting cav‑1 as a potential therapeutic target for pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor β1 (TGF-β1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-β1–induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad–cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.