Critical role of p38 mitogen-activated protein kinase signaling in septic lung injury
Critical role of p38 mitogen-activated protein kinase signaling in septic lung injury
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DOI：
10.1097/01.ccm.0b013e31816204fa
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发表时间：
2008-02-01
影响因子：
8.8
通讯作者：
Thorlacius, Henrik
中科院分区：
文献类型：
--
作者：
Asaduzzaman, Muhammad;Wang, Yusheng;Thorlacius, Henrik
目的：白细胞介导的组织损伤是脓毒性肺损伤的一个关键特征，尽管肺募集白细胞的信号传导机制仍然难以捉摸。本研究的目的是确定p38丝裂原活化蛋白激酶（MAPK）信号转导在脓毒性肺损伤中的作用。设计：前瞻性实验研究。设置：大学医院研究单位。受试者：雄性C57 BL/6小鼠。干预措施：盲肠结扎穿孔（CLP）后6和24小时，肺水肿，支气管肺泡浸润的白细胞，髓过氧化物酶，和CXC趋化因子的水平进行了测定。在CLP诱导前立即给予特异性p38 MAPK抑制剂SB 239063和SKF 86002。p38 MAPK的磷酸化和活性测定免疫沉淀和Western blot. Measures和主要结果：CLP诱导明确的肺损伤的特点是水肿形成，白细胞浸润，并增加CXC趋化因子在肺中的水平。此外，CLP增加肺中p38 MAPK的磷酸化和活性，SB 239063显著抑制。有趣的是，抑制p38 MAPK信号传导可防止CLP诱导的肺损伤和水肿。事实上，SB 239063和SKF 86002都减少了CLP诱导的白细胞募集在支气管肺泡空间和形成CXC趋化因子在lung.Conclusions：我们的数据表明，p38 MAPK信号转导构成了一个关键的作用，在调节CXC趋化因子的生产在脓毒性肺损伤和抑制p38 MAPK活性废除肺浸润的白细胞以及肺水肿。这些新的发现表明，靶向p38 MAPK信号通路可能为多微生物脓毒症肺损伤的新治疗策略铺平道路。
Objective: Leukocyte-mediated tissue damage is a key feature in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of leukocytes remain elusive. The aim of the present study was to define the role of p38 mitogen-activated protein kinase (MAPK) signaling in septic lung injury.Design: Prospective experimental study.Setting: University hospital research unit.Subjects: Male C57BL/6 mice.Interventions: Pulmonary edema, bronchoalveolar infiltration of leukocytes, levels of myeloperoxidase, and CXC chemokines were determined 6 and 24 hrs after cecal ligation and puncture (CLP). The specific p38 MAPK inhibitors SB 239063 and SKF 86002 were given immediately before CLP induction. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot.Measurements and Main Results: CLP induced clear-cut pulmonary damage characterized by edema formation, leukocyte infiltration, and increased levels of CXC chemokines in the lung. Moreover, CLP increased phosphorylation and activity of p38 MAPK in the lung, which was markedly inhibited by SB 239063. Interestingly, inhibition of p38 MAPK signaling protected against CLP-induced lung damage and edema. Indeed, both SB 239063 and SKF 86002 decreased CLP-induced leukocyte recruitment in the bronchoalveolar space and formation of CXC chemokines in the lung.Conclusions: Our data demonstrate that p38 MAPK signaling constitutes a key role in regulating CXC chemokine production in septic lung injury and that inhibition of p38 MAPK activity abolishes pulmonary infiltration of leukocytes as well as lung edema. These novel findings suggest that targeting the p38 MAPK signaling pathway may pave the way for a new therapeutic strategy against lung injury in polymicrobial sepsis.