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1 Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871; and 2 National Kinki Chuou Hospital for Chest Disease, Sakai, Osaka 591-8555, Japan
To elucidate the pathophysiology of
pulmonary fibrosis, we investigated the involvement of p38
mitogen-activated protein kinase (MAPK), which is one of the major
signal transduction pathways of proinflammatory cytokines, in a murine
model of bleomycin-induced lung fibrosis. p38 MAPK and its substrate,
activating transcription factor (ATF)-2, in bronchoalveolar lavage
fluid cells were phosphorylated by intratracheal exposure of bleomycin,
and the phosphorylation of ATF-2 was inhibited by subcutaneous
administration of a specific inhibitor of p38 MAPK, FR-167653.
FR-167653 also inhibited augmented expression of tumor necrosis factor
-
, connective tissue growth factor, and apoptosis of lung
cells induced by bleomycin administration. Moreover, daily subcutaneous
administration of FR-167653 (from 1 day before to 14 days after
bleomycin administration) ameliorated pulmonary fibrosis and pulmonary
cachexia induced by bleomycin. These findings demonstrated that p38
MAPK is involved in bleomycin-induced pulmonary fibrosis, and its
inhibitor, FR-167653, may be a feasible therapeutic agent.
phosphorylation of p38 mitogen-activated protein kinase; tumor
necrosis factor-; connective tissue growth factor; antiapoptotic
effect
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