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

J Exp Med. 2006 Dec 25;203(13):2895-906. doi: 10.1084/jem.20061536. Epub 2006 Dec 18.

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 beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Bleomycin / pharmacology
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Caveolin 1 / physiology
  • Collagen Type I / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Extracellular Matrix / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Gene Expression
  • Humans
  • Hydroxyproline / metabolism
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Phosphorylation
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / physiopathology
  • RNA, Small Interfering / genetics
  • Smad2 Protein / metabolism
  • Transfection
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • Actins
  • Caveolin 1
  • Collagen Type I
  • Fibronectins
  • RNA, Small Interfering
  • Smad2 Protein
  • Smad2 protein, mouse
  • Transforming Growth Factor beta1
  • Bleomycin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8
  • Hydroxyproline