Modulation of cholera toxin-induced fluid accumulation in a murine model of experimental cholera.

摘要

Diarrheal disease is a significant contributor to morbidity and mortality, especially in developing nations. At increased risk are children, who are especially susceptible to dehydration. One cause of diarrheal disease is intestinal infection with Vibrio cholerae. Epidemic cholera results from bacterial secretion of cholera toxin (CT), with subsequent increases in intestinal levels of 3′,5′-adenosine monophosphate (cAMP), eicosanoids (PGE₂), and 5-hydroxytryptamine (5-HT), which evoke the hypersecretion of water and electrolytes from the small intestinal mucosa. We hypothesized that alteration in the formation or activity of CT-induced PGE₂ results in physiological effects (e.g., intestinal ion transport) in experimental cholera. We identified a protective role for the cyclooxygenase enzyme (COX) metabolite, PGE₂ , in intestinal tissue protection from CT-insult, established the mechanism of action of novel inhibitors of experimental cholera, and described the influence of these inhibitors on CT-induced cytokines.; Non-steroidal anti-inflammatory drugs, which inhibit COX activity, reduce CT-induced fluid accumulation. It had not been conclusively determined which COX isoform is involved in CT's action. We evaluated the role of the COX enzymes and their arachidonic acid (AA) metabolites in experimental cholera by utilizing selective chemical inhibitors of the COX enzymes and cox gene-deficient mice. The effects of CT on fluid accumulation, PGE₂ production, and mucosal tissue injury were measured. COX-2 specific inhibitors inhibited CT-induced fluid accumulation, but there was no significant difference amongst cox-1−/− and cox-2−/− gene-deficient mice. CT elicited small intestinal tissue injury in cox gene-deficient mice, which was attributed to increased levels of oxidative stress. These results suggest a tissue protective role for AA metabolites in the small intestine against oxidative stress.; The fluid secretory response to CT is also inhibited by L-histidine. We identified and characterized a novel covalent adduct formed by a chemical reaction between PGE₂ and L-histidine (PGE₂-L-histidine), which abrogated the intestinal secretory response to CT. (Abstract shortened by UMI.)