Abstract
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 -alpha, 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Animals
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Antibiotics, Antineoplastic
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Bleomycin
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Bronchoalveolar Lavage Fluid / cytology
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Connective Tissue Growth Factor
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Cyclic AMP Response Element-Binding Protein / metabolism
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Disease Models, Animal
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Gene Expression / drug effects
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Growth Inhibitors / pharmacology*
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Growth Substances / genetics
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Hydroxyproline / analysis
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Immediate-Early Proteins / genetics
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In Situ Nick-End Labeling
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Injections, Intravenous
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Intercellular Signaling Peptides and Proteins*
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Lung / chemistry
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Lung / enzymology
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Lung / pathology
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Male
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Mice
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Mice, Inbred ICR
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation
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Pulmonary Fibrosis / drug therapy*
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Pulmonary Fibrosis / metabolism*
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Pulmonary Fibrosis / pathology
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Pyrazoles / pharmacology*
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Pyridines / pharmacology*
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RNA, Messenger / analysis
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Transcription Factors / metabolism
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Transforming Growth Factor beta / genetics
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Weight Gain / drug effects
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p38 Mitogen-Activated Protein Kinases
Substances
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Activating Transcription Factor 2
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Antibiotics, Antineoplastic
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Atf2 protein, mouse
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CCN2 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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FR 167653
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Growth Inhibitors
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Growth Substances
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Pyrazoles
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Pyridines
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RNA, Messenger
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Transcription Factors
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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Bleomycin
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Connective Tissue Growth Factor
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Hydroxyproline