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Received for publication December 12, 2005.
Revised March 27, 2006.
Accepted for publication April 4, 2006.
R1 kinase activity, but not p38 activation is
required for TGFR1-induced myofibroblast
differentiation and pro-fibrotic gene expression
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. Here, we examined the
underlying processes of TGFR1 kinase activity in
myofibroblast conversion of human lung fibroblasts using
specific inhibitors of TGFR1 (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 SD-208, but not
SD-282 treated animals. 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 while 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.
Key words:
P38 MAP Kinase, Regulation of gene expression
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