Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis.
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.
Wang
Xiao Mei
XM
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Zhang
Yingze
Y
Kim
Hong Pyo
HP
Zhou
Zhihong
Z
Feghali-Bostwick
Carol A
CA
Liu
Fang
F
Ifedigbo
Emeka
E
Xu
Xiaohui
X
Oury
Tim D
TD
Kaminski
Naftali
N
Choi
Augustine M K
AM
D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
D000199:Actins; D051242:Caveolin 1; D024042:Collagen Type I; D005353:Fibronectins; D034741:RNA, Small Interfering; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D006909:Hydroxyproline