Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 203, Issue 13, Pages 2895-2906Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061536
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Funding
- NHLBI NIH HHS [P01 HL070807, R01-HL060234, R01-HL079904, R01-HL073745-01, R01 HL060234, R01 HL073745, R01 HL055330, R01 HL063700, P01-HL70807, R01-HL55330, R01 HL079904] Funding Source: Medline
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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 beta 1 (TGF-beta 1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta 1-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.
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