title: Activation of p38 MAPK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury.
abstract: 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-1beta, 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.
authors.affiliation: Burn Institute of Chinese People's Liberation Army and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Jia
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Kai-Yang
authors.initials: KY
authors.lastname: Lv
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Tang
authors.forename: Duo
authors.initials: D
authors.lastname: Wei
authors.forename: Zhao-Fan
authors.initials: ZF
authors.lastname: Xia
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003080:Cold Temperature / Q000009:adverse effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects; D005753:Gastric Mucosa / Q000276:immunology / Q000293:injuries* / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000276:immunology*; D013113:Spin Labels; D013315:Stress, Psychological / Q000276:immunology / Q000503:physiopathology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D003497:Cyclic N-Oxides; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013113:Spin Labels; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; C001803:tempol; D000111:Acetylcysteine