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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/L843    most recent 00295.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Tourkina, E. Articles by Hoffman, S. PubMed PubMed Citation Articles by Tourkina, E. Articles by Hoffman, S.

EDITORIAL FOCUS

Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo

¹Division of Rheumatology and Immunology and ²Division of Pathology, Department of Medicine, Medical University of South Carolina, South Carolina; ³Department of Pharmacology, University of British Columbia, and iCAPTURE Heart and Lung Institute, St. Paul's Hospital, Vancouver, British Columbia, Canada; and ⁴Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut

Submitted 27 July 2007 ; accepted in final form 14 January 2008

Lung fibrosis involves the overexpression of ECM proteins, primarily collagen, by -smooth muscle actin (ASMA)-positive cells. Caveolin-1 is a master regulator of collagen expression by cultured lung fibroblasts and of lung fibrosis in vivo. A peptide equivalent to the caveolin-1 scaffolding domain (CSD peptide) inhibits collagen and tenascin-C expression by normal lung fibroblasts (NLF) and fibroblasts from the fibrotic lungs of scleroderma patients (SLF). CSD peptide inhibits ASMA expression in SLF but not NLF. Similar inhibition of collagen, tenascin-C, and ASMA expression was also observed when caveolin-1 expression was upregulated using adenovirus. These observations suggest that the low caveolin-1 levels in SLF cause their overexpression of collagen, tenascin-C, and ASMA. In mechanistic studies, MEK, ERK, JNK, and Akt were hyperactivated in SLF, and CSD peptide inhibited their activation and altered their subcellular localization. These studies and experiments using kinase inhibitors suggest many differences between NLF and SLF in signaling cascades. To validate these data, we determined that the alterations in signaling molecule activation observed in SLF also occur in fibrotic lung tissue from scleroderma patients and in mice with bleomycin-induced lung fibrosis. Finally, we demonstrated that systemic administration of CSD peptide to bleomycin-treated mice blocks epithelial cell apoptosis, inflammatory cell infiltration, and changes in tissue morphology as well as signaling molecule activation and collagen, tenascin-C, and ASMA expression associated with lung fibrosis. CSD peptide may be a prototype for novel treatments for human lung fibrosis that act, in part, by inhibiting the expression of ASMA and ECM proteins.

scleroderma; collagen; tenascin-C; -smooth muscle actin

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				H. P. Kim and A. M. K. Choi Caveolin-1 stops profibrogenic signaling? Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L841 - L842. [Full Text] [PDF]