SURGICAL STUDIES ON GALLBLADDER INFLAMMATION

急性胆囊炎是一种常见的疾病，造成大量的发病率 与死 目前急性胆囊炎的确定性治疗仍在继续 仅用于稳定患者病情的外科手术和药物治疗 胆囊切除术前 这一长期目标 我们的建议是描绘一系列复杂的机制， 局部胆囊成纤维细胞增加类花生酸的释放， 引发急性胆囊炎。 我们的长期目标是建立 抑制特定类二十烷酸释放的药物治疗方案 通过刺激胆囊成纤维细胞来防止或延缓 引发急性胆囊炎。 兔胆总管结扎（BDL，急性胆囊炎模型）将 用于检查以下具体目标：1）确定 营养因子（胆汁脂质改变，胆囊内 压力）参与调节胆囊类花生酸 2）确定急性炎症过程中的合成; 调节增加合成和释放的分子机制 BDL后胆囊类花生酸; 3）测定细胞内 促进酶“上调”的途径 导致72小时BDL培养物中PGI 2增加。 该提案将利用若干战略来确定 胆囊类二十烷酸在急性胆囊炎发病中的作用 的 第一个策略将检查增加胆囊内 压力和胆汁脂质改变对胆囊粘膜组织学的影响， 类花生酸释放 第二种策略将检查分子 负责增加胆囊类花生酸合成的机制， 在早期胆囊炎开始时释放。 第三个策略 将是研究细胞内第二信使的作用， 负责刺激类花生酸合成的酶的调节 在急性胆囊炎的开始和传播过程中。

Acute cholecystitis is a common disease that causes substantial morbidity and death. Current definitive treatment of acute cholecystitis continues to be surgical with medical treatment utilized only to stabilize patients prior to cholecystectomy. The overall long term objective of this proposal is to delineate the complex series of mechanisms that stimulate local gallbladder fibroblasts to increase eicosanoid release during the initiation of acute cholecystitis. Our long term goal is to establish medical treatment regimens that inhibit the specific eicosanoids released by the stimulated gallbladder fibroblasts to prevent or retard the initiation of acute cholecystitis. Rabbit common bile duct ligation (BDL, model of acute cholecystitis) will be utilized to examine the following specific aims: 1) To determine the trophic factors (altered biliary lipids, increased intra-gallbladder pressure) involved with the regulation of gallbladder eicosanoid synthesis during evolving acute inflammation; 2) To determine the molecular mechanisms regulating the increase synthesis and release of gallbladder eicosanoid following BDL; 3) To determine the intracellular pathways that contribute to the "up regulation" of the enzymes responsible for increased PGI2 in the 72-hour BDL cultures. The proposal will utilize several strategies to determine the role of gallbladder eicosanoids in the initiation of acute cholecystitis. The first strategy will examine the effects of increased intra-gallbladder pressure and altered biliary lipids on gallbladder mucosal histology and eicosanoid release. The second strategy will examine the molecular mechanisms responsible for increased gallbladder eicosanoid synthesis and release during the initiation of early cholecystitis. The third strategy will be to examine the role of intracellular second messengers on the regulation of the enzymes responsible for stimulated eicosanoid synthesis during the initiation and propagation of acute cholecystitis.