MYOGENIC DISORDERS OF THE GALLBLADDER

急性胆囊炎(AC)在18年期间影响88%的症状性胆囊炎(GB)结石患者，在老年患者中发病率和死亡率很高。尽管其发病率很高，但其发病机制尚不清楚。我们的初步研究表明，假设人类AC是在允许的GB环境中发展起来的，其特征是GB停滞和肌肉细胞保护受损，从而允许胆汁侵袭性因子启动炎症过程。因此，这项建议将研究造成这种GB环境的肌源性异常，并检查疏水性胆盐和活性氧物种(ROS)作为可能的侵袭性因素。具体地说，它将研究：1)致石性胆汁和肌肉细胞过度掺入胆固醇(CH)导致的胆汁淤积在炎症过程中似乎恶化的作用；2)GB肌肉细胞利用的细胞保护机制。它将集中在PGE2在上调自由基清除剂中的作用，以及其受体和途径在暴露于可溶的炎症介质后是否仍具有功能。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PGE2受体介导的细胞保护功能的不利影响。PGE2受体缺陷可能使这些细胞更容易受到低浓度侵袭性因子的损伤；3)疏水性胆盐和ROS是否启动了炎症过程，并导致了在人和实验性AC中证实的肌肉缺陷。它将研究胆汁淤积是否增强了胆盐通过胆囊壁的扩散。它还将通过检测它们是否由ROS介导以及它们是否在正常和有缺陷的肌肉细胞中诱导细胞保护反应来研究它们影响肌肉细胞的机制；以及，4)疏水性胆盐是否在体外防止疏水性胆盐的有害作用，以及它们是否有效地预防正常胆汁和致结石胆汁对GB的实验性AC的治疗。这些研究将在分离的肌细胞中进行，这些肌细胞来自伴有或不伴有胆汁结石的人胆结石，以及结扎胆总管诱发的实验性胆汁结石。这些研究的结果可能为使用疏水性胆汁酸预防治疗这一并发症提供证据和理论基础。

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.