RT Journal Article SR Electronic T1 Transforming Growth Factor-β Receptor Type 1 (TGFβRI) Kinase Activity but Not p38 Activation Is Required for TGFβRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 518 OP 531 DO 10.1124/mol.105.021600 VO 70 IS 2 A1 Ann M. Kapoun A1 Nicholas J. Gaspar A1 Ying Wang A1 Debby Damm A1 Yu-Wang Liu A1 Gilbert O'Young A1 Diana Quon A1 Andrew Lam A1 Kimberly Munson A1 Thomas-Toan Tran A1 Jing Ying Ma A1 Alison Murphy A1 Sundeep Dugar A1 Sarvajit Chakravarty A1 Andrew A. Protter A1 Fu-Qiang Wen A1 Xiangde Liu A1 Stephen I. Rennard A1 Linda Slanec Higgins YR 2006 UL http://molpharm.aspetjournals.org/content/70/2/518.abstract AB Transforming growth factor-β (TGFβ) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFβ also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFβRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFβRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFβ-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 TGFβ-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.