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This Article Full Text Full Text (PDF) All Versions of this Article: 285/2/L334    most recent 00417.2002v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Bogatkevich, G. S. Articles by Ludwicka-Bradley, A. Search for Related Content PubMed PubMed Citation Articles by Bogatkevich, G. S. Articles by Ludwicka-Bradley, A.

Contractile activity and smooth muscle -actin organization in thrombin-induced human lung myofibroblasts

¹Division of Rheumatology and Immunology, Department of Medicine, and ³Department of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425; and ²Department of Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104

Submitted 6 December 2002 ; accepted in final form 24 March 2003

Activated fibroblasts, or myofibroblasts, are crucial players in tissue remodeling, wound healing, and various fibrotic disorders, including interstitial lung fibrosis associated with scleroderma. Here we characterize the signaling pathways in normal lung fibroblasts exposed to thrombin as they acquire two of the main features of myofibroblasts: smooth muscle (SM) -actin organization and collagen gel contraction. Our results show that the small G protein Rho is involved in lung myofibroblast differentiation. Thrombin induces Rho-³⁵S-labeled guanosine 5'-O-(3-thiotriphosphate) binding in a dose-dependent manner. It potently stimulates Rho activity in vivo and initiates protein kinase C (PKC)--Rho complex formation. Toxin B, which inactivates Rho by ADP ribosylation, inhibits thrombin-induced SM -actin organization, collagen gel contraction, and PKC--SM -actin and PKC--RhoA coimmunoprecipitation. However, it has no effect on PKC- activation or translocation of PKC- to the membrane. Overexpression of constitutively active PKC- and constitutively active RhoA induces collagen gel contraction or SM -actin organization, whereas, individually, they do not perform these functions. We therefore conclude that the contractile activity of myofibroblasts induced by thrombin is mediated via PKC-- and RhoA-dependent pathways and that activation of both of these molecules is required. We postulate that PKC--RhoA complex formation is an early event in thrombin activation of lung fibroblasts, followed by PKC--SM -actin coimmunoprecipitation, which leads to the PKC--RhoA-SM -actin ternary complex formation.

fibroblast differentiation; protein kinase C-; RhoA

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