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-κB and its roles in an experimental model of cold immobilization stress-induced gastric mucosal lesions.
Design: Prospective, controlled, and randomized animal study.
Setting: University research laboratory.
Subjects: Male Sprague-Dawley rats.
Interventions: The rats were subjected to cold immobilization stress for a total of 6 hrs. The temporal profiles of nuclear factor-κB activation and expression of tumor necrosis factor-α, interleukin-1β, 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-κB activation, rats received an intravenous bolus of a specific nuclear factor-κB 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.
Measurements and Main Results: Exposure of rats to 6 hrs of stress led to a rapid and persistent activation of nuclear factor-κB, which was associated with transient degradation of inhibitory protein IκBα and slower but sustained degradation of IκBβ. Nuclear factor-κB activation preceded the induction of tumor necrosis factor-α, interleukin-1β, 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-κB activation and up-regulation of tumor necrosis factor-α, interleukin-1β, 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-κB 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-κB by reactive oxygen species is an important in vivo mechanism mediating stress-induced gastric inflammatory damage in rats.