DUODENAL MUCOSAL DEFENSE MECHANISM

消化性溃疡是老年人和慢性病人群发病率和死亡率的主要原因。在过去的十年里，随着消化性溃疡疾病的重新发现和逐渐认识到很可能是幽门螺杆菌(Hp)感染的结果，从根本上改变了溃疡的研究方向。尽管在幽门螺杆菌感染的基础和临床方面花费了大量的精力，但这种微生物引起的溃疡的发病机制在很大程度上仍然不清楚。许多关键问题，比如为什么只有一小部分受HP感染的宿主会患上溃疡病，大多没有答案。尽管有这些不确定性，但关于十二指肠溃疡致幽门螺杆菌的发病机制已形成共识。简而言之，胃幽门螺杆菌定植破坏了正常的内分泌/神经反馈机制，调节胃酸分泌，导致对神经和内分泌刺激的高分泌反应。这种轻微但慢性的胃酸分泌升高会导致十二指肠胃化生，然后随着幽门螺杆菌从胃部位迁徙，十二指肠胃化生成为定植。这些十二指肠幽门螺杆菌会产生十二指肠炎，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相关性十二指肠炎的部分或实际上原因，肥大细胞释放的组胺增加通过抑制上皮重碳酸盐分泌和粘膜血流增加十二指肠黏膜对酸损伤的易感性。在这个提案中，我们提出了一个研究计划，旨在研究肥大细胞激活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建立了实验模型；我们的目的是研究其对十二指肠防御机制的影响，以复制幽门螺杆菌感染、易溃疡患者的十二指肠炎症状态。为了达到这些目的，将在标准的酸损伤和碳酸氢盐分泌灌流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项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和粘膜血流量。通过实现这些目标，我们希望增加对目前几乎未知的东西的理解-幽门螺杆菌感染对十二指肠宿主防御因素的影响。

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.