Duodenal Muscosal Defense Mechanisms

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。 尽管在溃疡发病机制方面取得了重大进展，但消化性溃疡的并发症仍然是一个重要的 高危人群中的问题，特别是在老年人和有严重并存疾病的人中。胃酸 溃疡表现为攻击性因素(酸性和胃蛋白酶)和防御性因素之间的平衡失调。 因素(粘膜碳酸氢盐分泌、血流和粘液分泌)。其中，碳酸氢盐分泌物是 被认为是主要的防御机制，主要是因为研究表明碳酸氢盐分泌与 防止损伤，因为一般而言，增加的碳酸氢盐分泌保护粘膜免受酸诱导的损伤。 然而，像十二指肠这样本质上漏水的上皮细胞可以抵抗的确切方式 强酸性胃液造成的损害仍未解决。 在过去的几年里，我的实验室进行了新颖的观察，为我们提供了独特的见解 十二指肠绒毛上皮细胞是胃酸的主要靶点，能抵抗损伤。我们制定了“细胞内” HCO3~‘-细胞内而非细胞外碳酸氢盐是十二指肠粘膜的主要成分的假说 防御机制。为了验证这一假设，我们设计了一系列实验，旨在“分离”。 碳酸氢盐分泌和粘膜保护。患有囊性纤维症的受试者，尽管有大量的胃 十二指肠分泌酸和低pH值，只有极少数出现十二指肠溃疡。我们认为，这是由于 小苏打被困在十二指肠上皮细胞中。我们计划在有缺陷的小鼠身上直接测试这一假设。 用于CFTR或囊性纤维化基因产品。通过进行这些研究，我们希望获得进一步的 深入了解消化性溃疡的发病机制，希望找到预防溃疡的新疗法 此外，我们还希望进一步了解我们老龄化人口的并发症，并进一步了解囊性纤维化的发病机制。

Peptic ulcer disease is a major cause of morbidity and mortality in elderly and chronically ill populations. Despite major advances made about ulcer pathpgenesis, complications of peptic ulcers still represent a significant problem in at-risk populations, especially in the elderly and those with significant co-morbidities. Peptic ulceration represents a disturbance in the balance between aggressive factors (acid and pepsin) and defensive factors (mucosal bicarbonate secretion, blood flow, and mucus secretion). Of these, bicarbonate secretion is thought to be a primary defense mechanisms, due mainly to studies in which bicarbonate secretion is correlated to injury prevention, since, in general, increased bicarbonate secretion protects the mucosa from acid-induced injury. Nevertheless, the precise means by which an intrinsically leaky epithelium such as the duodenum can resist damage from intensely acid gastric juice remains unresolved. In the past few years, my laboratory has made the novel observation that provides unique insight into how duodenal villus epithelial cells,;the prime targets of gastric acid, can resist injury. We formulated the 'intracellular HCO3~'-hypothesis in which intracellular, not extracellular bicarbonate serves as the principal duodenal mucosal defense mechanism. To test this hypothesis, we have devised a series of experiments designed to 'uncouple' bicarbonate secretion and mucosal protection. Subjects with the disease cystic fibrosis, despite, copious gastric acid secretion and low duodenal pH, only rarely have duodenal ulcers. We believe that this is a result of bicarbonate being trapped in duodenal epithelial cells. We plan to test this hypothesis directly in mice deficient for the CFTR or cystic fibrosis gene product. Through the conduct of these studies, we hope to gain further insight into the mechanism of peptic ulceration, in the hopes of finding new treatments designed to prevent ulcer complications in our aging population, and to also gain additional insight into the pathogenesis of cystic fibrosis.