Activation of p38 MAPK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury
Activation of p38 MAPK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury
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DOI：
10.4049/jimmunol.179.11.7808
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Xia, Zhao-Fan
中科院分区：
文献类型：
--
作者：
Jia, Yi-Tao;Wei, Wei;Xia, Zhao-Fan
应激性溃疡是危重患者的常见并发症，可导致显著的上消化道出血，并伴有高发病率和死亡率。目前，很少有人知道这种类型的胃损伤的发病率的分子机制。在本研究中，我们研究了氧化还原敏感性p38信号转导级联的时间激活及其在冷制动应激诱导胃溃疡的明确实验模型中的作用。暴露的Sprague-Dawley大鼠6小时的冷制动应激导致p38在胃粘膜中的快速激活早在15分钟后的应力，这种激活是最大的应力后1.5小时，并仍然持续到应力结束。SB 239063是一种有效的选择性p38抑制剂，通过预处理选择性阻断p38，抑制了应激促进的TNF-α、IL-1 β和CINC-1的产生，然后防止了随后的中性粒细胞浸润、胃粘膜上皮坏死和凋亡以及溃疡性病变的形成。预先给予自由基清除剂tempol和N-乙酰-L-半胱氨酸，可消除p38激活的应激诱导以及由此产生的粘膜炎症和胃损伤。这些结果表明，活性氧介导的p38激活在冷制动应激大鼠模型应激诱导的胃炎症损伤的发病机制中起着至关重要的作用。我们的研究结果表明，抑制p38激活可能是一个潜在的战略，为预防和治疗应激性溃疡。
Stress ulceration is a common complication in critically ill patients and can result in significant upper gastrointestinal bleeding associated with a high morbidity and mortality. At present, little is known of the molecular mechanisms underlying the incidence of this type of gastric damage. In the present study, we investigated the temporal activation of the redox-sensitive p38 signaling transduction cascade and its roles in a well-defined experimental model of cold immobilization stress-induced gastric ulceration. Exposure of Sprague-Dawley rats to 6 h of cold immobilization stress led to a rapid activation of p38 in the gastric mucosa at as early as 15 min after stress, and this activation was maximal after 1.5 h of stress and still persisted until the end of stress. Selectively blocking p38 by pretreatment with SB 239063, a potent and selective p38 inhibitor, suppressed the stress-promoted TNF-alpha, IL-1 beta, and CINC-1 production and then prevented the subsequent neutrophil infiltration, gastric mucosal epithelial necrosis and apoptosis, and the ulcerative lesions formation. Prior administration of the free radical scavengers, tempol and N-acetyl-L-cysteine, abolished the stress induction of p38 activation and the resulting mucosal inflammation and gastric injury. These results demonstrate that reactive oxygen species-mediated p38 activation plays an essential role in the pathogenesis of stress-induced gastric inflammatory damage in the rat model of cold immobilization stress. Our findings suggested that inhibition of p38 activation might be a potential strategy for the prophylaxis and treatment of stress ulceration.