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Am J Physiol Lung Cell Mol Physiol 294: L843-L861, 2008. First published January 18, 2008; doi:10.1152/ajplung.00295.2007
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EDITORIAL FOCUS

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

Elena Tourkina,1 Mathieu Richard,1 Pal Gööz,1 Michael Bonner,1 Jaspreet Pannu,1 Russell Harley,2 Pascal N. Bernatchez,3 William C. Sessa,4 Richard M. Silver,1 and Stanley Hoffman1

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 {alpha}-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; {alpha}-smooth muscle actin


Address for reprint requests and other correspondence: E. Tourkina, Division of Rheumatology and Immunology, Dept. of Medicine, Medical Univ. of South Carolina, 96 Jonathan Lucas St., Suite 912, MSC 637, Charleston, SC 29425 (e-mail: tourkine{at}musc.edu)




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