Duodenal Mucosal Defense Mechanisms

十二指肠粘膜防御机制

• 批准号: 7356225
• 负责人: Jonathan D. Kaunitz
• 金额: $ 26.33万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356225
• 关键词: 6-carboxyfluorescein; ASIC channel; Abbreviations; Acids; Alkaline Phosphatase; Anions; Anti-Inflammatory Agents; Anti-inflammatory; Apical; Benign; Benzoates; Bicarbonates; Binding; Blood flow; CCL21 gene; Carbon Dioxide; Carbonic Anhydrase II; Carboxylic Acids; Cations; Cell membrane; Cystic Fibrosis Transmembrane Conductance Regulator; Cytomegalovirus; Data; Defense Mechanisms; Disease; Duodenum; Dyspepsia; Epithelial; Epithelial Cells; Epithelium; Esters; Esthesia; Gastric Acid; Generations; Glycosylphosphatidylinositols; Green Fluorescent Proteins; Health; Helicobacter pylori; Hemorrhage; Host Defense; In Situ; Incidence; Injury; Intensive Care; Intestines; Investigation; Knowledge; Laboratories; Length; Ligaments; Location; Macaca mulatta; Measurement; Measures; Membrane; Microclimate; Minerals; Movement; Mucous Membrane; Mucous body substance; Mus; NHE1; Nature; Nausea; Nucleotides; Pathogenesis; Perception; Perforation; Perfusion; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Physiological; Population; Portal vein structure; Primitive foregut structure; Protein Isoforms; Proteins; Purinoceptor; Pylorus; Rattus; Regulation; Risk; Role; Signal Transduction; Sodium-Hydrogen Antiporter; Stilbenes; Stimulus; Stomach; Stress; Submucosa; Surveys; System; Testing; Translating; Ulcer; Vanilloid; Virulence; absorption; apical membrane; basolateral membrane; benzoate; brush border membrane; capsazepine; carbonate dehydratase; design; extracellular; novel; receptor; response; sensor; solute; therapy design

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.

描述（申请人提供）：对十二指肠黏膜的损伤，虽然发病率在下降，但在过去的几十年里毒性有所增加。尽管出现了有效的抗分泌药物，并且发现了幽门螺杆菌在粘膜损伤发病机制中的作用，但粘膜溃疡及其并发症，如穿孔和出血，仍然是重症监护患者和服用非甾体抗炎药的患者的一个问题。此外，功能性恶心和消化不良——一种现有治疗方法有限的疾病——折磨着数百万人。我们提供的数据支持了新的假设，即整个十二指肠酸负荷被吸收为CO2，碳酸酐酶（CA）的可溶性和膜结合异构体促进了H+和CO2之间的多次相互转化。在这种方式下，大量的H+可以很容易地被吸收，而不会有过度酸化上皮细胞或粘膜下间质的风险。根据这一假设，上皮细胞大量分泌HCO3-的主要功能是将腔内的H+转化为更良性、更容易吸收的H+当量CO2。十二指肠也有一个发达的化学感觉系统，它能迅速对腔内酸作出反应，并产生一系列协调一致的保护反应，如增加粘膜血流量和粘液分泌。我们打算进一步验证这一假设，详细研究二氧化碳是如何通过上皮细胞的顶膜吸收的，膜结合磷酸酶如何参与HCO3分泌的调节，以及粘膜下酸传感器如何将腔酸信号转导成输出生理反应，以及恶心等感觉的感知。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防御酸损伤提供新的信息。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，有关十二指肠酸感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。