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-α, 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.

The protective of hydrogen on stress-induced gastric ulceration

“…Previous studies have showed that treatment with p38 MAPK and JNK kinases inhibitors could lessen cold constraint stress-induced tissue injury [2,19]. Our studies exhibited that pre-treatment with Hs also inhibited the excessive P-p38 MAPK and P-JNK activity, but not total JNk and p38 MAPK (Fig.…”

“…In the present study, we observed that pretreatment with hydrogen resulted in significantly decreased TNF-α, IL-1β and CINC-1 production and then prevented the subsequent neutrophils infiltration. This is a number of recent reports that showed that ROS-mediated p38 MAPK, JNK and NF-κB activation played an essential role in the pathogenesis of cold constraint stress-induced gastric damage [1,2,19]. To explore the downstream signaling mechanisms responsible for the roles of hydrogen to suppress proinflammatory cytokine production, we assessed how they affected the activation of P-p38 MAPK, P-JNK and NF-κB.…”

“…Under the hypoxic-ischemic condition, reactive oxygen species (ROS) such as superoxide anions (O 2 − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (⋅OH) are rapidly and continuously produced, and the resulting oxidative stress is crucially responsible for the development and progression of epithelial necrosis and mucosal ulceration. A growing body of experimental and clinical evidence proved that stress-induced gastric mucosal damage is mediated through the ROS [1][2][3]. Scientists have demonstrated that ⋅OH was one of the major causative factors for stressinduced gastric ulceration [3].…”

Effects of caffeic acid phenethyl ester in the prevention of stress ulcer in rats

“…As a result, it was found that NF-kB activation played an important role in stress ulcer by increasing proinflammatory gene over expression in the gastric mucosa. In another study, it was indicated that there might be a pathway through which NF-kB and AP-1 activation is triggered by SOR and this was defined as the SOR/NF-kB pathway (43). In the same study, SOR/NF-kB pathway was shown to increase TNF-α, IL-1 and CINC-1and that AP-1, allowed for the transcription of genes such as C/EBP or Stat3 genes.…”

Evaluation of a poly-herbal preparation for the treatment of peptic ulcer

“…Histamine released during stress results an increase in gastric acid secretion and a decrease in mucous production, is known to be responsible for stress-induced ulcer (Jia et al, 2007). However, a significant reversal of ulcer score and ulcer index by ulcerene (50 and 100 mg/kg), suggests its ulcer curative potential, that can be related to the blockade of H2 receptors similar to ranitidine (50 mg/kg).…”