Duodenal Mucosal Defense Mechanisms

描述(申请人提供)：十二指肠粘膜损伤，虽然发生率下降，但在过去几十年中毒性增加。尽管出现了有效的抗分泌药物，并发现了幽门螺杆菌在粘膜损伤发病机制中的作用，但粘膜溃疡及其导致的并发症，如穿孔和出血，仍然是重症监护患者和服用非类固醇抗炎药的患者面临的一个问题。此外，功能性恶心和消化不良是一种可用疗法有限的疾病，困扰着数百万受试者。我们提供的数据支持这一新的假设，即整个十二指肠酸负荷以CO2的形式被吸收，H+和CO2之间的多次相互转换是由可溶的和膜结合的碳酸酐酶(CA)亚型促进的。在这种方式下，大量的H+可以容易地被吸收，而不会有过度酸化上皮细胞或粘膜下间质的风险。根据这一假说，大量的上皮HCO3-分泌的主要功能是将管腔内的H+转化为更良性和更容易吸收的H+当量二氧化碳。十二指肠也有一个发达的化学感觉系统，对鲁米那酸迅速做出反应，做出一系列协调的保护反应，如增加粘膜血流量和粘液分泌。我们打算通过详细研究二氧化碳是如何被上皮细胞的顶膜吸收的，膜结合的磷酸酶如何参与HCO3分泌的调节，粘膜下酸传感器如何将腔酸信号转化为传出的生理反应，以及对恶心等感觉的感知，来进一步检验这一假设。由于十二指肠保护机制与十二指肠酸吸收机制直接相关，这一性质的研究将为十二指肠宿主抵御酸损伤提供新的信息。然后，这些知识可以用来帮助设计新的疗法，旨在加强十二指肠抵抗酸损伤的能力。此外，有关十二指肠酸感应机制的知识可用于设计有效治疗功能性恶心和消化不良的治疗方法。

DESCRIPTION (provided by applicant): Injury to the duodenal mucosa, though decreasing in incidence, has increased in virulence over the past several decades. Despite the advent of potent antisecretory medications and the discovery of the role of Helicobacter pylori in the pathogenesis of mucosal injury, mucosal ulceration with resultant complications such as perforation and bleeding remains a problem for subjects in intensive care and those taking non-steroidal anti-inflammatory drugs. Furthermore, functional nausea and dyspepsia, a disease for which available therapies are limited, afflicts millions of subjects. We have provided data to support the novel hypothesis that the entire duodenal acid load is absorbed as CO2, with multiple interconversions between H+ and CO2 facilitated by soluble and membrane-bound isoforms of carbonic anhydrase (CA). In this fashion, large quantities of H+ can be readily absorbed without the risk of overly acidifying the epithelial cells or the submucosal interstitium. According to this hypothesis, the primary function of the large amount of epithelial HCO3- secretion is to convert luminal H+ into the more benign and readily absorbable H+ equivalent CO2. The duodenum also has a well- developed chemosensory system that promptly responds to luminal acid with a coordinated set of protective responses, such as an increase in mucosal blood flow and mucus secretion. We intend to further test this hypothesis by examining in detail how CO2 is absorbed across the apical membrane of the epithelial cells, how membrane- bound phosphatases participate in the regulation of HCO3- secretion, and how submucosal acid sensors transduce the luminal acid signal into efferent physiological responses, as well as the perception of sensations such as nausea. Since duodenal protective mechanisms are directly related to the mechanism of duodenal acid absorption, investigations of this nature will provide new information regarding duodenal host defenses from acid injury. This knowledge can then be used to help design new therapies designed at strengthening the ability of the duodenum to resist acid injury. Furthermore, the knowledge regarding the mechanism of duodenal acid sensing can be used to design therapies to effectively treat functional nausea and dyspepsia.