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Receptor Type 1 (TGFRI) Kinase Activity but Not p38 Activation Is Required for TGFRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression
Scios Inc., Fremont, California (A.M.K., N.J.G., Y.W., D.D., Y.-W.L., G.O., D.Q., A.L., K.M., T.-T.T., J.Y.M., A.M., S.D., S.C., A.A.P., L.S.H.); and Nebraska Medical Center, Omaha, Nebraska (F.-Q.W., X.L., S.I.R.)
Transforming growth factor-
(TGF) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGF also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGF-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGF-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.
Address correspondence to: Dr. Ann M. Kapoun, 6500 Paseo Padre Park-way, Fremont, CA 94555. E-mail: ann_kapoun{at}yahoo.com
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