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Am J Physiol Lung Cell Mol Physiol (March 28, 2003). doi:10.1152/ajplung.00417.2002
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Submitted on December 6, 2002
Accepted on March 24, 2003

Contractile Activity and Smooth Muscle-{alpha} Actin Organization in Thrombin-induced Human Lung Myofibroblasts

Galina S. Bogatkevich1*, Elena Tourkina1, Charles S. Abrams2, Russell A. Harley3, Richard M. Silver1, and Anna Ludwicka-Bradley1

1 Department of Medicine, Medical University of South Carolina, Division of Rheumatology, Charleston, SC, USA
2 Department of Medicine, University of Pennsylvania Medical School, Philadelphia, PA, USA
3 Department of Pathology, Medical University of South Carolina, Division of Rheumatology, Charleston, SC, USA

* To whom correspondence should be addressed. E-mail: bogatkev{at}musc.edu.

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-{alpha} (SM-{alpha}) actin organization and collagen gel contraction. Our results show that small G-protein Rho is involved in lung myofibroblast differentiation. Thrombin induces Rho-[35S]GTP{gamma}S binding in a dose-dependent manner. It potently stimulates Rho activity in vivo and initiates Protein Kinase C (PKC){epsilon}-Rho complex formation. Toxin B, which inactivates Rho by ADP ribosylation inhibits thrombin-induced SM-{alpha} actin organization, collagen gel contraction, PKC{epsilon}/SM-{alpha} actin, and PKC{epsilon}/RhoÁ co-immunoprecipitation. However, it has no effect on PKC{epsilon} activation or translocation of PKC{epsilon} to the membrane. Overexpression of both constitutively active PKC{epsilon} and constitutively active RhoA induce collagen gel contraction or SM-{alpha} 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{epsilon}- and RhoA-dependent pathways and that activation of both of these molecules is required. We postulate that PKC{epsilon}/RhoA-complex formation is an early event in thrombin-activation of lung fibroblasts followed by PKC{epsilon}/SM-{alpha} actin co-immunoprecipitation, which leads to the PKC{epsilon}/RhoA/SM-{alpha} actin ternary complex formation.




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