DUODENAL MUCOSAL DEFENSE MECHANISM

十二指肠粘膜防御机制

• 批准号: 6177886
• 负责人: Jonathan D. Kaunitz
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177886
• 关键词: Helicobacter; acid base balance; active immunization; afferent nerve; bicarbonates; disease /disorder model; duodenal ulcer; duodenum; duodenum disorder; enteric bacteria; gastric acid; gastrointestinal epithelium; gastrointestinal infection; histamine; histamine release; inflammation; intestinal mucosa; intravital microscopy; laboratory rat; mast cell; metaplasia; model design /development; mucosal immunity; secretion

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.

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。在过去的十年里，随着人们重新发现并逐渐认识到消化性溃疡疾病很可能是幽门螺杆菌（Hp）感染的结果，溃疡研究的方向发生了根本性的变化。尽管在Hp感染的基础和临床方面花费了大量的努力，但由这种微生物引起的溃疡的发病机制在很大程度上仍不明确。许多关键问题，例如为什么只有一小部分Hp感染宿主会发展成溃疡疾病，大部分都没有答案。尽管存在这些不确定性，关于十二指肠溃疡与Hp的发病机制已形成共识。这个理论，用最简单的术语来说，就是胃Hp定植破坏了正常的调节酸分泌的内分泌/神经反馈机制，导致神经和内分泌分泌刺激下的高分泌反应。这种轻微但慢性的胃酸分泌升高导致十二指肠胃化生，随后Hp从胃迁移而来。这些十二指肠Hp引起十二指肠炎，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的原因，肥大细胞组胺释放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黏膜对酸损伤的易感性。在本提案中，我们提出了一项研究计划，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，从而复制hp感染，溃疡易发患者的十二指肠炎症状态。为了实现这些目的，我们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黏膜防御机制。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Hp感染对十二指肠宿主防御因子的影响的理解。