Inhibition of the MAP kinase ERK protects from lipopolysaccharide-induced lung injury
Inhibition of the MAP kinase ERK protects from lipopolysaccharide-induced lung injury
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DOI：
10.1016/j.bcp.2009.03.012
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发表时间：
2009-06-15
影响因子：
5.8
通讯作者：
Pahl, Andreas
中科院分区：
文献类型：
--
作者：
Schuh, Katrin;Pahl, Andreas
慢性阻塞性肺疾病（COPD）的发病机制的特征在于与肺嗜酸性粒细胞相关的肺部炎症以及患者的支气管肺泡灌洗液或痰液中促炎介质水平升高。近年来研究发现丝裂原活化蛋白激酶（MAPK）信号通路参与了肺损伤的炎症反应。本研究利用ERK上游激酶MEK 1/2的特异性抑制剂U 0126，探讨细胞外信号相关MAPK在LPS诱导的小鼠急性肺损伤模型中的作用。U 0126在体内和体外均能抑制ERK的磷酸化。在新鲜分离的人外周血单核细胞中，U 0126剂量依赖性地阻断IL-2和TNF-α的释放。对于体内研究，将小鼠暴露于雾化LPS以诱导模拟COPD的某些方面的急性肺损伤。这导致中性粒细胞向肺的募集和促炎细胞因子向支气管肺泡灌洗液的释放。用U 0126预处理小鼠显著降低了肺嗜中性粒细胞增多症，并降低了支气管肺泡液中TNF-α和趋化性MIP-2和KC的水平。U 0126还降低了BAL液中的白蛋白水平。血管渗漏的标志肺组织的组织学检查显示使用U 0126的ERK MAPK抑制有效地减弱LPS诱导的肺部炎症反应。这些数据表明，ERK信号传导在急性肺损伤中发挥着重要作用，对ERK的药物抑制为肺部炎症性疾病，特别是COPD提供了一种有前途的新治疗策略。(c)2009 Elsevier Inc. All rights reserved.
The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation associated with lung neutrophilia and elevated levels of pro-inflammatory mediators in the bronchoalveolar lavage fluid or sputum of patients. Recent findings revealed that mitogen-activated protein kinase (MAPK) signaling cascade is involved in the inflammatory response of lung injury. In the present study we could elucidate the role of extracellular signal-related MAPK in the murine model of LPS-induced acute lung injury by using U0126, a specific inhibitor of MEK1/2, upstream kinases of ERK. Phosphorylation of ERK was inhibited by U0126 in vivo as well as in vitro. In freshly isolated human peripheral blood mononuclear cells U0126 dose-dependently blocked the release of IL-2 and TNF-alpha. For in vivo studies mice were exposed to aerosolized LPS to induce an acute lung injury mimicking some aspects of COPD. This led to a recruitment of neutrophils to the lung and to the release of pro-inflammatory cytokines into bronchoalveolar lavage. Pretreatment of mice with U0126 significantly reduced lung neutrophilia and diminished levels of TNF-alpha and chemotactic MIP-2 and KC in bronchoalveolar fluid. U0126 also decreased albumin levels in BAL fluid. a marker of vascular leakage. Histological examination of lung tissues revealed that ERK MAPK inhibition using U0126 efficiently attenuated LPS-induced pulmonary inflammatory responses. These data suggest that ERK signaling plays an important role in acute lung injury and pharmacologic inhibition of ERK provides a promising new therapeutic strategy for lung inflammatory diseases and in particular COPD. (c) 2009 Elsevier Inc. All rights reserved.