阻断肠-肝轴对脓毒症大鼠器官功能的保护机制

Sepsis is one of the leading causes of death in critically ill patients. It induces to septic shock and multiple organ dysfunction syndrome(MODS). The gut is considered as the motor organ and pivot organ in the process of multiple organ dysfunction syndrome induced by sepsis. Intestine-derived inflammatory cytokines activate the Kupffer cells in the liver via the portal vein system. The activated Kupffer cells can produce a large amounts of pro-inflammatory. Hepatic-derived cytokines exit the liver and enter the gut to complete the inflammatory loop via bile, resulting in increasing intestinal, hepatic inflammation promoting tissue injury. The vicious circle of cytokine between intestine and liver enlarges the inflammation cascade gradually and eventually lead to MODS. Our previous study had indicated that the TNF-α in the bile was significantly increased in rats with hemorrhagic shock. Biliary tract external drainage could alleviate pathological damage of the intestine, liver, lung. It may be a hit that bile would be a possible factor to exacerbate intestinal injury.However, the machanisum still remains unknown.The aim of this project was to study the effect of blocking the gut-liver axis on the pathological change and organ function in septic rats by supplementing glutamine and bile drainge. Intestinal epithelial cells were co-cultured with the bile drained from the septic rats to observe the intestinal epithelial apoptosis and pro-inflammatory and to explore the mechanism of the intestine injury by bile and exacerbation to organ dysfunction. This project may provide the basis for novel therapeutic approaches to sepsis and MODS by studying the gut-liver axis.

脓毒症可引起脓毒性休克和多器官功能障碍，是导致重症病人死亡的首位病因。脓毒症引发多器官功能衰竭，肠道是启动器官和枢纽器官。肠源性炎症因子经门脉系统激活肝Kupffer细胞产生大量的炎症因子，肝脏产生的炎症因子又可经胆汁排泄到肠道加重肠道损伤。肠-肝之间形成一个炎症因子的恶性循环，炎症反应逐级放大，最终导致MODS。我们前期研究发现失血性休克大鼠胆汁中TNF-α明显升高，胆汁外引流可减轻肠、肝、肺的病理损伤。但脓毒症发生时胆汁是否会加重肠道损伤？如何加重肠道损伤？目前尚无相关研究。本课题通过给脓毒症大鼠补充谷氨酰胺和胆汁外引流等措施阻断肠-肝轴，观察肠、肝、肺病理和功能变化；将引流的胆汁与肠上皮细胞共培养，观察肠上皮细胞凋亡和炎症因子的变化，探讨胆道途径加重脏器功能损害的机制。本项目旨在研究脓毒症肠-肝轴的调节规律，为脓毒症及MODS的防治提供理论依和方向。

脓毒症是由感染引起的全身炎症反应综合征，进一步可发展为严重脓毒症，进而导致感染性休克和多器官功能障碍综合征（MODS）。脓毒症具有“高发病率、高死亡率、高治疗费用”的特点，是目前重症病人发病率和死亡率占第一位的病因。其导致病人死亡的根本原因是脓毒症导致炎症介质释放引起全身炎症反应，各种炎症因子之间的“级联反应”以及各个脏器之间炎症因子相互影响形成一个复杂的炎症因子网络最终导致MODS。肠源性炎症因子经门脉系统激活肝Kupffer细胞产生大量的炎症因子，肝脏产生的炎症因子又可经胆汁排泄到肠道加重肠道损伤。肠-肝之间形成一个炎症因子的恶性循环，炎症反应逐级放大，最终导致MODS. 本课题通过给脓毒症大鼠补充谷氨酰胺和胆汁外引流等措施阻断肠-肝轴，观察肠、肝、肺病理和功能变化；将引流的胆汁与肠上皮细胞共培养，观察肠上皮细胞凋亡和炎症因子的变化，探讨胆道途径加重脏器功能损害的机制。研究内容包括以下两部分：一、谷氨酰胺改善肠屏障对脓毒症大鼠肠、肝、肺功能的影响；二、胆道外引流对脓毒症大鼠肠、肝、肺功能的影响及其机制。研究取得以下结果：1.谷氨酰胺能够保护肠粘膜上皮细胞，改善肠道通透性，减轻肠道炎症因子的合成和易位，部分阻断肠→肝的炎症通路从而保护肝脏和肺脏等其它脏器。2.脓毒症胆汁中炎症细胞因子可加重肠道损伤，其机制是胆汁中的炎症因子可引起肠粘膜上皮细胞非凋亡途径的坏死。胆道外引流部分阻断了肝→肠的炎症通路，减少了肝脏炎症因子对肠道的进一步损伤，打断了肠-肝恶性循环和肠-肝轴，对肠、肝、肺发挥保护作用。本项目揭示了脓毒症肠-肝轴的调节规律，为脓毒症及MODS的防治提供理论依和方向。