Duodenal Mucosal Defense Mechanisms

描述（由申请方提供）：十二指肠粘膜损伤的发生率虽然有所下降，但在过去几十年中毒力有所增加。尽管强效抗分泌药物的出现以及幽门螺杆菌在粘膜损伤发病机制中的作用的发现，但粘膜溃疡以及由此产生的穿孔和出血等并发症仍然是重症监护受试者和服用非甾体抗炎药的受试者面临的一个问题。此外，功能性恶心和消化不良，一种可用疗法有限的疾病，折磨着数百万受试者。我们提供的数据支持新的假设，即整个十二指肠酸负荷被吸收为CO2，与H+和CO2之间的多重相互转化促进可溶性和膜结合的碳酸酐酶（CA）的亚型。以这种方式，大量的H+可以很容易地被吸收，而不会导致上皮细胞或粘膜下层间质过度酸化的风险。根据这一假设，大量上皮HCO 3-分泌的主要功能是将管腔H+转化为更良性和更容易吸收的H+等效CO2。十二指肠也有一个发育良好的化学感受系统，它能迅速对管腔酸作出反应，并产生一系列协调的保护性反应，如粘膜血流量和粘液分泌增加。我们打算通过详细研究CO2如何穿过上皮细胞的顶膜吸收、膜结合磷酸酶如何参与HCO 3分泌的调节、粘膜下酸传感器如何将管腔酸信号转化为传出生理反应以及感觉（如恶心）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，因此这种性质的研究将提供有关十二指肠宿主防御酸损伤的新信息。这些知识可以用来帮助设计新的治疗方法，旨在加强十二指肠抵抗酸损伤的能力。此外，关于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疗法。

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.