Peptic ulcer disease is a major cause of morbidity and mortality in elderly and chronically ill populations. The past decade, with the re-discovery and emerging realization that peptic ulcer disease is most likely the result of infection with the organism H. pylori (Hp), has radically changed the direction of ulcer research. Despite the enormous amount of effort spent of basic and clinical aspects of Hp infection, the pathogenesis of ulcers due to this organism remains largely undefined. Many key questions, such as why only a small fraction of Hp infected hosts develop ulcer disease, are mostly unanswered. Despite these uncertainties, a consensus regarding the pathogenesis of duodenal ulcers to Hp has evolved. This theory, stated in the simplest terms, is that gastric Hp colonization disrupts the normal endocrine/neural feedback mechanisms regulating acid secretion, leading to a hypersecretory response to neural and endocrine secretory stimuli. This mild but chronic elevation of acid secretion produces gastric metaplasia of the duodenum, which then becomes colonized with Hp migrating from their gastric location. These duodenal Hp produce duodenitis, which then in some fashion impair mucosal defense, producing duodenal ulcers. Our hypothesis is that enhanced mast cell degranulation is part or actually a cause of Hp-related duodenitis, and that elevated histamine release from mast cells increases the susceptibility of the duodenal mucosa to acid injury by suppressing epithelial bicarbonate secretion and mucosal blood flow. In this proposal, we present a research plan designed to study the effects of mast cell activation on duodenal defense mechanisms. This alteration of duodenal function has been established in experimental models in the literature;
our aim i s to study its effect on duodenal defense mechanisms so as to replicate the inflamed state of the duodenum in Hp-infected, ulcer prone patients. To accomplish these ends, duodenal mucosal defense mechanisms will be measured in a standard acid injury and bicarbonate secretion perfusion model. Furthermore, a novel technique developed in our laboratory over the past seven year to measure gastric defensive mechanisms will be modified so that we will be able to measure duodenal defense mechanisms, including intracellular pH and mucosal blood flow. By accomplishing these aims, we hope to increase understanding of what is now virtually unknown---the impact of Hp infection in duodenal host defense factors.
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