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Originally published In Press as doi:10.1074/jbc.M106441200 on September 28, 2001

J. Biol. Chem., Vol. 276, Issue 48, 45184-45192, November 30, 2001
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Thrombin Differentiates Normal Lung Fibroblasts to a Myofibroblast Phenotype via the Proteolytically Activated Receptor-1 and a Protein Kinase C-dependent Pathway*

Galina S. Bogatkevich, Elena Tourkina, Richard M. Silver, and Anna Ludwicka-BradleyDagger

From the Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425

Myofibroblasts are ultrastructurally and metabolically distinctive fibroblasts that express smooth muscle (SM)-alpha actin and are associated with various fibrotic lesions. The present study was undertaken to investigate the myofibroblast phenotype that appears after activation of normal lung fibroblasts by thrombin. We demonstrate that thrombin induces smooth muscle-alpha actin expression and rapid collagen gel contraction by normal lung fibroblasts via the proteolytically activated receptor-1 and independent of transforming growth factor-beta pathway. Using antisense oligonucleotides we demonstrate that a decreased level of PKCepsilon abolishes SM-alpha actin expression and collagen gel contraction induced by thrombin in normal lung fibroblasts. Inhibition of PKCepsilon translocation also abolishes thrombin-induced collagen gel contraction, SM-alpha actin increase, and its organization by normal lung fibroblasts, suggesting that activation of PKCepsilon is required for these effects. In normal lung fibroblasts PKCepsilon binds to SM-alpha actin after thrombin treatment, but in activated fibroblasts derived from scleroderma lung they associate even in untreated cells. This suggests that SM-alpha actin may serve as a substrate for PKCepsilon in lung fibroblasts when activated by thrombin. We propose that thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via a PKC-dependent pathway. Thrombin-induced differentiation of normal lung fibroblasts to a myofibroblast phenotype resembles the phenotype observed in scleroderma lung fibroblasts. Therefore, we conclude that chronic exposure to thrombin after microvascular injury leads to activation of normal lung fibroblasts and to the appearance of a myofibroblast phenotype in vivo. Our study provides novel, compelling evidence that thrombin is an important mediator of the interstitial lung fibrosis associated with scleroderma.

* This work was supported in part by grants from the Scleroderma Foundation (to E. T. and A. L. B.), the R. G. Kozmetsky Foundation, the United Scleroderma Foundation, the Medical University of South Carolina's Environmental Biosciences Program, and National Institutes of Health Clinical Research Center Grant RR1070-1 (to R. M. S.). The Olympus Merlin Confocal Imaging System was supported by the Department of Veteran Affairs shared equipment grant and the Research Enhancement Award Program from the Department of Veteran Affairs.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Div. of Rheumatology and Immunology, Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., Suite 912, PO Box 250623, Charleston, SC 29425. Tel.: 843-792-8401; Fax: 843-792-7121; E-mail: bradleyh@musc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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