MYOGENIC DISORDERS OF THE GALLBLADDER

胆囊肌源性疾病

• 批准号: 6634870
• 负责人: JOSE BEHAR
• 金额: $ 27.83万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634870
• 关键词: G protein; biliary tract disorder chemotherapy; chemoprevention; cholanate compound; cholecystitis; cholelithiasis; cytoprotection; disease /disorder etiology; free radical oxygen; free radical scavengers; guinea pigs; human tissue; inflammation; molecular pathology; muscle contraction; muscle relaxation; nonhuman therapy evaluation; prostaglandin E; prostaglandin receptor; smooth muscle; squirrel

Acute cholecystitis (AC) affects 88% of patients with symptomatic gallbladder (GB) stones over a 18 year period and has a significant morbidity and mortality in elderly patients. in spite of its high prevalence, its pathogenesis has yet to be elucidated. Our preliminary studies suggest the hypothesis that human AC develops in a permissive GB environment characterized by GB stasis and impaired muscle cytoprotection that allows biliary aggressive factors to initiate the inflammatory process. This proposal therefore will study the myogenic abnormalities responsible for creating this GB environment and examine hydrophobic bile salts and reactive oxygen species (ROS) as possible aggressive factors. Specifically, it will investigate: 1) the role of bile stasis induced by lithogenic bile and excessive cholesterol (Ch) incorporation by muscle cells that seems to worsen during the inflammatory process; 2) the mechanisms of cytoprotection utilized by GB muscle cells. It will focus on the role of PGE2 in the upregulation of scavengers of free radicals and whether its receptors and pathways remain functional after exposure to soluble mediators of inflammation. It will examine the mechanisms of receptor protection and resistance to agonist induced desensitization a well as the detrimental influence of excessive membrane Ch on cytoprotective functions mediated by PGE2 receptors. Defective PGE2 receptors could make these cells more susceptible to damage by lower concentrations o aggressive factors; 3) whether hydrophobic bile salts and ROS initiate the inflammatory process and cause the muscle defects demonstrated in human and experimental AC. It will examine whether bile stasis enhances the diffusion of bile salts through the GB wall. It will also investigate the mechanisms whereby they affect muscle cells by examining whether they are mediated by ROS and whether they induce cytoprotective responses in normal and defective muscle cells; and, 4) whether hydrophobic bile salts prevent the deleterious effects of hydrophobic bile salts in vitro and whether they are effective in the prophylactic treatment of experimental AC in GB's with normal and lithogenic bile. These studies will be conducted in dissociated muscle cells from human GB's with gallstones with or without AC and from experimental AC induced by ligation of the common bile duct in animals with normal and lithogenic bile. The results of these studies may provide evidence and a rationale in support for using hydrophobic bile acids in the prophylactic treatment of this complication.

急性胆囊炎（AC）影响88%的有症状的胆囊（GB）结石患者超过18年的时间，并有显着的发病率和死亡率在老年患者。尽管其发病率很高，但其发病机制尚未阐明。我们的初步研究表明，假设人类AC的发展在一个宽松的GB环境，其特征是GB停滞和受损的肌肉细胞保护，使胆道侵略性因素启动炎症过程。因此，该提案将研究负责创建这种GB环境的肌源性异常，并检查疏水性胆汁盐和活性氧（ROS）作为可能的侵袭性因素。具体而言，它将研究：1）致石性胆汁和过度胆固醇（Ch）掺入的肌肉细胞，似乎在炎症过程中恶化诱导胆汁淤积的作用; 2）GB肌细胞利用的细胞保护机制。它将集中在前列腺素E2的作用，在自由基的清除剂的上调，以及其受体和途径是否保持功能后，暴露于可溶性介质的炎症。它将研究受体保护和抵抗激动剂诱导的脱敏的机制，以及过量的膜Ch对PGE 2受体介导的细胞保护功能的不利影响。PGE 2受体缺陷可能使这些细胞更容易受到较低浓度的侵袭性因子的损伤; 3）疏水性胆盐和ROS是否启动炎症过程并导致人类和实验AC中证实的肌肉缺陷。它将检查胆汁淤积是否会增强胆盐通过GB壁的扩散。还将通过检查它们是否由ROS介导以及它们是否在正常和有缺陷的肌细胞中诱导细胞保护反应来研究它们影响肌细胞的机制;以及，4）疏水性胆汁盐是否在体外防止疏水性胆汁盐的有害作用以及它们是否有效地预防性治疗具有正常和致石胆汁的GB中的实验AC。这些研究将在患有或不患有AC的胆结石的人GB的解离肌细胞中进行，以及在具有正常和致石性胆汁的动物中通过结扎胆总管诱导的实验AC中进行。这些研究的结果可以提供证据和理由，支持使用疏水性胆汁酸预防性治疗这种并发症。