DUODENAL MUCOSAL DEFENSE MECHANISM

消化性溃疡是老年人和慢性病患者发病和死亡的主要原因。 在过去的十年中，随着对消化性溃疡的重新发现和逐渐认识，消化性溃疡最有可能是由H。幽门螺杆菌（Hp）的出现，从根本上改变了溃疡研究的方向。 尽管在Hp感染的基础和临床方面花费了大量的努力，但由于这种生物体引起的溃疡的发病机制在很大程度上仍然不确定。 许多关键问题，如为什么只有一小部分Hp感染的宿主发展为溃疡病，大多数都没有答案。 尽管存在这些不确定性，但关于十二指肠溃疡与Hp的发病机制已达成共识。 用最简单的话来说，这一理论是胃Hp定植破坏了调节酸分泌的正常内分泌/神经反馈机制，导致对神经和内分泌刺激的分泌过度反应。 这种轻度但慢性的酸分泌升高导致十二指肠的胃化生，然后从胃位置迁移的Hp定植于十二指肠。这些十二指肠幽门螺杆菌产生肠炎，然后以某种方式损害粘膜防御，产生十二指肠溃疡。 我们的假设是，肥大细胞脱颗粒增强是Hp相关性肠炎的部分原因或实际原因，肥大细胞释放组胺升高通过抑制上皮碳酸氢盐分泌和粘膜血流增加了十二指肠粘膜对酸损伤的敏感性。 在这个建议中，我们提出了一个研究计划，旨在研究肥大细胞活化对十二指肠防御机制的影响。 这种十二指肠功能的改变已经在文献中的实验模型中建立;我们的目的是研究其对十二指肠防御机制的影响，以便在Hp感染的溃疡倾向患者中复制十二指肠的炎症状态。 为了实现这些目的，将在标准酸损伤和碳酸氢盐分泌灌注模型中测量十二指肠粘膜防御机制。 此外，我们实验室在过去七年中开发的一种测量胃防御机制的新技术将被修改，以便我们能够测量十二指肠防御机制，包括细胞内pH值和粘膜血流量。 通过实现这些目标，我们希望增加对现在几乎未知的-幽门螺杆菌感染对十二指肠宿主防御因子的影响的理解。

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 is 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.