Sustained activation of nuclear factor-kappaB by reactive oxygen species is involved in the pathogenesis of stress-induced gastric damage in rats.
OBJECTIVE
Stress ulceration is a common complication in critically ill patients, but the mechanisms involved are poorly understood. In this study we investigated the temporal activation of the redox-sensitive transcription factor nuclear factor-kappaB and its roles in an experimental model of cold immobilization stress-induced gastric mucosal lesions.


METHODS
Prospective, controlled, and randomized animal study.


METHODS
University research laboratory.


METHODS
Male Sprague-Dawley rats.


METHODS
The rats were subjected to cold immobilization stress for a total of 6 hrs. The temporal profiles of nuclear factor-kappaB activation and expression of tumor necrosis factor-alpha, interleukin-1beta, cytokine-induced neutrophil chemoattractant-1 (CINC-1), intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS) were determined in the gastric corpus mucosa of stressed rats. To study the roles of nuclear factor-kappaB activation, rats received an intravenous bolus of a specific nuclear factor-kappaB inhibitor Bay 11-7082 (20 mg/kg) 1 hr before stress. For antioxidant administration, rats were treated with intravenous injection of a free radical scavenger pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg) 1 hr before stress.


RESULTS
Exposure of rats to 6 hrs of stress led to a rapid and persistent activation of nuclear factor-kappaB, which was associated with transient degradation of inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. Nuclear factor-kappaB activation preceded the induction of tumor necrosis factor-alpha, interleukin-1beta, CINC-1, ICAM-1, and iNOS messenger RNAs, all of which were linearly increased with the duration of stress. Bay 11-7082 selectively blocked the stress-induced nuclear factor-kappaB activation and up-regulation of tumor necrosis factor-alpha, interleukin-1beta, CINC-1, ICAM-1, and iNOS messenger RNAs. Inhibition of expression of these proinflammatory genes prevented the increases in myeloperoxidase activity (an indicator of neutrophil infiltration) in gastric mucosa and the development of gastric damage. Pyrrolidine dithiocarbamate dose-dependently inhibited the stress-induced nuclear factor-kappaB pathway activation and consequential proinflammatory gene expression, neutrophil infiltration, and gastric damage, suggesting the involvement of reactive oxygen species in these processes.


CONCLUSIONS
Sustained activation of nuclear factor-kappaB by reactive oxygen species is an important in vivo mechanism mediating stress-induced gastric inflammatory damage in rats.
Jia
Yi-Tao
YT
Chinese PLA Institute of Burn Surgery & Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Ma
Bing
B
Wei
Wei
W
Xu
Yu
Y
Wang
Yu
Y
Tang
Hong-Tai
HT
Xia
Zhao-Fan
ZF
D000818:Animals; D016166:Free Radical Scavengers / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis*; D018384:Oxidative Stress; D011759:Pyrrolidines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013315:Stress, Psychological / Q000150:complications*; D013859:Thiocarbamates / Q000494:pharmacology
D016166:Free Radical Scavengers; D016328:NF-kappa B; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid