A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis
A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis
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DOI：
10.1152/ajplung.00187.2001
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发表时间：
2002-07-01
影响因子：
4.9
通讯作者：
Hayashi, S
中科院分区：
文献类型：
--
作者：
Matsuoka, H;Arai, T;Hayashi, S
为了阐明肺纤维化的病理生理机制，我们研究了促炎症细胞因子的主要信号转导通路之一p38丝裂原活化蛋白激酶(MAPK)在博莱霉素诱导的小鼠肺纤维化模型中的作用。支气管肺泡灌洗液细胞中p38MAPK及其底物激活转录因子-2(ATF-2)经气管内染毒后被磷酸化，而p38MAPK的特异性抑制剂FR-167653可抑制ATF-2的磷酸化。FR-167653还可抑制博莱霉素诱导的肺细胞肿瘤坏死因子-α、结缔组织生长因子表达增强和细胞凋亡。此外，每日皮下注射FR-167653(给药前1天至给药后14天)可减轻博莱霉素所致的肺纤维化和肺恶病质。这些结果表明，p38MAPK参与了博莱霉素诱导的肺纤维化，其抑制剂FR167653可能是一种可行的治疗药物。
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, FR167653, may be a feasible therapeutic agent.