fr-167653 and Weight-Gain

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.

Topics: Activating Transcription Factor 2; Animals; Antibiotics, Antineoplastic; Bleomycin; Bronchoalveolar Lavage Fluid; Connective Tissue Growth Factor; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Gene Expression; Growth Inhibitors; Growth Substances; Hydroxyproline; Immediate-Early Proteins; In Situ Nick-End Labeling; Injections, Intravenous; Intercellular Signaling Peptides and Proteins; Lung; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Fibrosis; Pyrazoles; Pyridines; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain