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* Burn Institute of Chinese People’s Liberation Army and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China;
Department of Burn Surgery, the No.150 Hospital of Chinese People’s Liberation Army, Luoyang, Henan Province, China; and
Department of Burn Surgery, Second Affiliated Hospital of Kunming Medical College, Kunming, China
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-
, IL-1β, 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.
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1 This work was supported by National Nature Science Foundation of China Grant No. 30571921 and Ministry of Science and Technology of China Grant No. 2005CB522603.
2 Y.-T.J., W.W., and B.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Zhao-Fan Xia, Burn Institute of Chinese People’s Liberation Army and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China. E-mail address: xiazhaofan{at}hotmail.com
4 Abbreviations used in this paper: ROS, reactive oxygen species; CINC, cytokine-induced neutrophil chemoattractant; GSH, reduced glutathione; MAPKAPK-2, MAPK-activated protein kinase 2; MDA, malondialdehyde; MKP, MAPK phosphatase; NAC, N-acetyl-L-cysteine; tempol, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl; MPO, myeloperoxidase.
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