A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis.
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.
Matsuoka
Hiroto
H
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Arai
Toru
T
Mori
Masahide
M
Goya
Sho
S
Kida
Hiroshi
H
Morishita
Hiroshi
H
Fujiwara
Hiroshi
H
Tachibana
Isao
I
Osaki
Tadashi
T
Hayashi
Seiji
S
D051698:Activating Transcription Factor 2; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D055513:Connective Tissue Growth Factor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000235:genetics; D006909:Hydroxyproline / Q000032:analysis; D017874:Immediate-Early Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D000903:Antibiotics, Antineoplastic; C497106:Atf2 protein, mouse; C526318:CCN2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C104334:FR 167653; D006131:Growth Inhibitors; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006909:Hydroxyproline