MYOGENIC DISORDERS OF THE GALLBLADDER

急性胆囊炎（AC）在18年内影响88%的症状性胆囊结石患者，在老年患者中具有显著的发病率和死亡率。尽管发病率很高，但其发病机制尚未阐明。我们的初步研究提出了一种假设，即人类AC是在以GB停滞和肌肉细胞保护受损为特征的宽松GB环境中发展的，这使得胆道侵袭性因子能够启动炎症过程。因此，本提案将研究造成这种GB环境的肌原性异常，并检查疏水胆盐和活性氧（ROS）作为可能的侵袭性因素。具体来说，它将研究：1)由结石胆汁和过量胆固醇（Ch）掺入肌肉细胞引起的胆汁淤积的作用，在炎症过程中似乎会恶化；2) GB肌细胞的细胞保护机制。它将重点关注PGE2在自由基清除剂上调中的作用，以及它的受体和途径在暴露于可溶性炎症介质后是否保持功能。本研究将探讨受体保护和抗激动剂诱导脱敏的机制，以及过量的膜Ch对PGE2受体介导的细胞保护功能的有害影响。有缺陷的PGE2受体可能使这些细胞更容易受到低浓度侵袭性因子的损伤；3)疏水胆盐和ROS是否启动了炎症过程并导致了人体和实验AC中的肌肉缺陷。我们将研究胆汁淤积是否增强了胆盐通过GB壁的扩散。它还将通过检查它们是否由活性氧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；4)疏水胆汁盐是否能在体外预防疏水胆汁盐的有害作用，对正常胆汁和结石性胆汁GB的实验性AC是否有效。这些研究将在分离的肌肉细胞中进行，这些肌肉细胞来自有或没有AC的人胆结石的GB，以及正常胆汁和产石胆汁的动物胆总管结扎引起的实验性AC。这些研究的结果可能为支持使用疏水胆汁酸预防治疗这种并发症提供证据和理论依据。

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.