ESOPHAGEAL CYTOPROTECTION--AGENTS AND MECHANISMS

食管细胞保护——代理和机制

• 批准号: 3234322
• 负责人: Roy Charles Orlando
• 金额: $ 23.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3234322
• 关键词: acidity /alkalinity; acids; antibody formation; cellular pathology; chromium; cryoprotective agents; cytology; cytolysis; disease /disorder proneness /risk; divalent cations; divalent metal; esophagus; gastrointestinal absorption /transport; gastrointestinal epithelium; gel electrophoresis; histochemistry /cytochemistry; hydrogen transport; immunofluorescence technique; laboratory rabbit; molybdenum; nonelectrolyte transport; nuclear magnetic resonance spectroscopy; radiotracer; reflux esophagitis; secretion; selenium; sucrose; sulfates; tungsten

Reflux esophagitis is a common clinical disorder with the potential to lead to serious complications such as stricture and Barrett's (columnar-lined) esophagus, the latter a premalignant condition. Since contact of the esophageal epithelium with gastric acid is primarily responsible for the injury, therapy has been directed toward prevention of reflux, neutralization of acid and inhibition of acid secretion. These therapies however have had only limited success so that esophagitis continues to be a significant clinical problem. An alternative approach to the treatment of this disorder is by augmentation of epithelial defense mechanisms against acid (H+), and agents which enhance these mechanisms are designated as "cytoprotective." The specific aims of this proposal are: 1) to identify agents with cytoprotective properties against H+ injury to esophageal epithelium and 2) once identified, to explore the mechanisms behind their actions. Based on our prior research elucidating the mechanisms by which H+ injures the epithelium, two in vitro methods using the Ussing chamber have been developed for identifying agents with cytoprotective properties. Agents identified to have cytoprotective properties in vitro will be re-evaluated in vivo to confirm by morphological and functional (transport) criteria their protective effects against injury in the acid-perfused rabbit esophagus. Confirmation in vivo will be followed by investigations to define their mechanism(s) of action. As a starting point, the existing mechanisms for protection against H+-injury that are present in healthy esophageal epithelia will be investigated in vitro using Ussing chamber transport studies, electron microscopy with tracers, and pH microelectrode techniques. These investigations will seek to establish for rabbit and human esophagi: a) the locations and nature of the permeability barriers, b) the route(s) of H+ entry into the epithelium, c) the intracellular mechanisms for H+ removal, d) the rate of epithelial reconstitution after injury and e) the existence of a pH gradient across the mucus-unstirred water layer. Subsequently cytoprotective agents will be tested to determine if their protective effects against H+ injury are mediated through one or more of the established mechanisms. These studies ultimately may provide a fresh approach to the development of agents for the prevention and treatment of reflux esophagitis.

反流食管炎是一种常见的临床疾病，有可能导致 严重的并发症，例如狭窄和巴雷特（柱状衬里） 食道，后者是预先态度的。 由于接触 食管上皮胃酸上皮主要是造成 受伤，治疗已针对预防反流， 中和酸和酸分泌的抑制作用。 这些疗法 但是，成功的成功只有有限的，因此食管炎继续是 重大的临床问题。 治疗的另一种方法 这种疾病是通过增强上皮防御机制 酸（H+）和增强这些机制的药物被指定为 “细胞保护性。” 该提案的具体目的是：1）确定 具有细胞保护特性的药物对食管的H+损伤的药物 上皮和2）一旦确定，探索其背后的机制 动作。 基于我们先前的研究，阐明了该机制 H+损伤上皮，两种体外方法使用USSING室 已开发用于识别具有细胞保护特性的药物。 被确定在体外具有细胞保护特性的药物将是 在体内重新评估以通过形态和功能确认（传输） 标准其防止酸性损伤的保护作用 兔食管。 在体内确认将进行调查 定义其作用机制。 作为起点，现有 保护健康中存在的H+-Injoury的机制 食管上皮将在体外使用USSING室进行研究 传输研究，带有示踪剂的电子显微镜和pH微电极 技术。 这些调查将寻求为兔子建立 人类食管：a）渗透性障碍的位置和性质， b）H+进入上皮的路线，c）细胞内 H+去除的机制，d）上皮重建的速率 损伤和e）跨粘液未抑制的pH梯度存在 水层。 随后将测试细胞保护剂 确定其针对H+损伤的保护作用是否介导 通过一种或多种已建立的机制。 这些研究 最终可以为代理的开发提供一种新的方法 反流食管炎的预防和治疗。