ACID NEUTRALIZATION AND DISPOSAL IN GASTRIC EPITHELIUM

胃上皮中的酸中和和处理

• 批准号: 2143886
• 负责人: DAVID I SOYBEL
• 金额: $ 11.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2143886
• 关键词: Urodela; acid base balance; alternatives to animals in research; aquatic organism; aspirin; basolateral membrane; chlorine; cholanate compound; cyclic AMP; electrophysiology; gastric mucosa; gastrointestinal epithelium; gastrointestinal pharmacology; hydrogen; ion transport; membrane transport proteins; microelectrodes; potassium; prostaglandins; tissue /cell culture; ulcer

Previous studies have indicated that the gastric mucosa normally is protected from the damaging effects of luminal acid by preventing diffusion of acid from the lumen into the mucosa and neutralizing or disposing of H+ ions entering the tissue. Impairment of these protective properties, rather than hypersecretion of acid is generally held to be the cause of acute mucosal erosions elicited by topical agents of injury or systemic sepsis or stress. Recent work in isolated gastric epithelial systems, however, has suggested: 1) that transport and permeability processes located in the basolateral (i.e. serosal-side) cell membrane regulate intracellular ion composition and pH; 2) that processes leading to basolateral uptake of HCO3- or extrusion of H+ may depend substantially on cotransport or exchange mechanisms with Na+, K+ or C1-; and 3) that topical agents of injury such as aspirin or bile salts may not only reduce the resistance of the epithelium to back-diffusion of acid, but they may directly impair these cellular mechanisms of H+ neutralization or disposal. To further define these protective mechanisms at the cellular level, the proposed studies are designed: 1) to identify basolateral mechanisms which regulate intracellular levels of Na+, K+ and C1-; 2) to examine the basolateral co-transport mechanisms by which the cell uses these ions to take up HCO3- or extrude H+ in order to preserve cell pH; 3) to evaluate the effects of topical agents of injury on the cell's ability to handle experimental acid loads, independent of their effects on permeability to luminal acid. These three sets of specific aims will be pursued using intracellular microelectrode techniques in an in vitro model of surface epithelium from the gastric antrum of the amphibian, Necturus maculosus. The first set will be addressed by defining the contributions of the different permeability and transport properties which regulate intracellular levels of Na+, K+ and C1-. These studies will also examine the influence of changes in luminal acidity and nutrient composition on the processes which regulate intracellular levels of these ions. The second set of studies will be directed at identifying specific processes such as Na+/H+ or C1-/HCO3- exchange in the cell's ability to buffer an acid load and evaluating the dependence of these processes on intracellular ion composition. Further studies will evaluate the influence of cellular regulatory agents such as prostaglandin or cAMP on the cell's ability to maintain ion composition and pH during experimental acid loading. The final set of studies will evaluate the effects of two well known ulcerogens, aspirin and bile salt, on processes which regulate cell ion composition and whether alterations in these processes would impair the cell's ability to neutralize or dispose of influxing H+ ions. The proposed studies should provide, at the cellular level, a more detailed understanding of the protective functions of the gastric surface epithelium and of the disturbances of cell transport and permeability properties which occur in different ulcerogenic conditions.

先前的研究表明，胃粘膜通常是 通过防止扩散来保护腔酸的破坏作用 从管腔进入粘膜的酸，并中和或处置H+ 离子进入组织。 这些保护特性的损害， 通常认为酸的不是过度分泌是 受伤或全身性局部药物引起的急性粘膜侵蚀 败血症或压力。 在孤立的胃上皮系统中的最新工作， 但是，已经建议：1）运输和渗透率的过程 位于基底外侧（即浆膜侧）细胞膜调节 细胞内离子组成和pH； 2）处理导致 HCO3-或H+挤出的基底外侧摄取可能取决于 具有Na+，K+或C1-的共转运或交换机制； 3）这个话题 阿司匹林或胆汁盐等受伤的药物不仅可以减少 上皮对酸的反向扩散的抗性，但它们可能 直接损害了H+中和或处置的这些细胞机制。 为了在细胞水平上进一步定义这些保护机制 拟议的研究设计为：1）确定基底外侧机制 调节Na+，K+和C1-的细胞内水平； 2）检查 基底外侧的共同传输机制，细胞使用这些离子来 占用HCO3或挤出H+以保留细胞pH； 3）评估 局部受伤药物对细胞处理能力的影响 实验酸负荷，与它们对渗透性的影响无关 腔酸。 将使用这三组特定目标 在表面体外模型中的细胞内微电极技术 来自两栖动物的胃鼻毛的上皮。 第一组将通过定义 调节的不同渗透性和运输特性 Na+，K+和C1-的细胞内水平。 这些研究还将检查 腔内酸度和养分组成的变化对 调节这些离子的细胞内水平的过程。 第二个 一组研究将致力于确定特定过程，例如 Na+/H+或C1-/HCO3-在细胞缓冲酸负荷的能力中交换 并评估这些过程对细胞内离子的依赖性 作品。 进一步的研究将评估细胞的影响 监管剂，例如前列腺素或牢房的营地 在实验酸负荷过程中保持离子组成和pH。 这 最终研究将评估两个知名的效果 在调节细胞离子的过程上，溃疡性，阿司匹林和胆汁盐 组成以及这些过程中的改变是否会损害 细胞中和或处置流入H+离子的能力。 提议 研究应在细胞级别提供更详细的 了解胃表上皮的保护功能 以及细胞运输和渗透率的干扰 发生在不同的溃疡性条件下。