Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch
Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch
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DOI：
10.1165/ajrcmb.27.1.4766
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发表时间：
2002-07-01
影响因子：
6.4
通讯作者：
Pugin, M
中科院分区：
文献类型：
--
作者：
Oudin, S;Pugin, M
正压机械通气时呼吸道过度伸展或急性重症哮喘发作与重要的生物学反应有关。白细胞介素8(IL-8)依赖的中性粒细胞募集似乎在机械应激诱导的气道炎症过程中起关键作用。在此，我们证明了体外循环拉伸的人支气管上皮BEAS-2B细胞在mRNA和蛋白质水平上都能产生IL-8。这种细胞压力“启动”了激活蛋白(AP)-1和环磷酸腺苷(CAMP)反应元件。有丝分裂原激活蛋白(MAP)激酶(MAPK)p44/42、SAPK/INK和p38在循环应变开始后(5-10分钟)都被迅速激活(磷酸化)。药物抑制剂SB203580阻断p38可抑制细胞伸展产生IL-8，而p44/42途径的抑制剂PD98059可部分抑制IL-8的反应。非特异性酪氨酸激酶抑制剂金雀异黄素也阻断了拉伸诱导的IL-8的产生。这表明，MAPK，尤其是p38，是介导细胞在周期性拉伸反应中激活的近端和关键的细胞内信号分子，周期性拉伸是一种类似于机械通气期间施加于肺上皮细胞的机械应变。药物抑制p38通路有望成为呼吸机患者的一种新的治疗途径。
Overstretching the airways during positive pressure mechanical ventilation or attacks of acute severe asthma is associated with important biologic responses. Interleukin ((IL)-8-dependent neutrophil recruitment seems to play a critical role in the process of mechanical stress-induced airway inflammation. Herein, we show that human bronchial epithelial BEAS-2B cells submitted to cyclic stretch in vitro produce IL-8, at both the mRNA and protein levels. This cellular stress "turns on" activator protein (AP)-1 and cyclic AMP (cAMP)-responding elements. The mitogen-activated protein (MAP) kinases (MAPK) p44/42, SAPK/INK, and p38 were all rapidly activated (phosphorylated) after the initiation of the cyclic strain (5-10 min). The blockade of p38 with the pharmacologic inhibitor SB203580 abrogated IL-8 production by cell stretching, and an inhibitor of the p44/42 pathway, PD98059, partially inhibited the IL-8 response. A nonspecific tyrosine kinase inhibitor, genistein, also blocked the stretch-induced IL-8 production. This suggests that MAPK, and p38 in particular, are proximal and key intracellular signaling molecules mediating cell activation in response to cyclic stretch, a mechanical strain similar to that applied to lung epithelial cells during mechanical ventilation. Pharmacologic inhibition of the p38 pathway holds promise as a new therapeutic avenue in ventilated patients.