title: Caveolin-1: a critical regulator of lung fibrosis in idiopathic 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 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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Xiao Mei
authors.initials: XM
authors.lastname: Wang
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhou
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Emeka
authors.initials: E
authors.lastname: Ifedigbo
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: 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
chemical_list: 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