烧伤后淋巴途径中高迁移率族蛋白B1在细胞免疫中的作用及其机制

It has been well demonstrated that host immune dysfunction appears to contribute to the development of sepsis. Previous studies suggested that intestinal lymphatic pathway might be one of the important factors in the pathogenesis of sepsis and subsequent multiple organ dysfunction syndrome (MODS) following major burns and trauma. However, the potential role and underlying mechanism of intestinal lymphatic pathway in immune disorders remains to be elucidated. For further understanding the possible role of high mobility group box-1 protein (HMGB1) in intestinal lymphatic pathway, the present project was conducted to investigate the effect of HMGB1 in mesenteric lymph on host cell-mediated immunity after major burns. In an in vivo study, HMGB1 antagonist was administered into mesenteric lymph duct of rats to investigate the potential role of HMGB1 in lymphatic pathway secondary to thermal injury. In an in vitro study, the effect of mesenteric lymph on immune response of dendritic cells (DCs) was analyzed dynamically, and the relationship between HMGB1 release and DC-mediated immune dysfunction was determined. In addition, the regulation of HMGB1-induced autophagy in DCs was assessed to further clarify the pathophysiological significance of intestinal lymphatic pathway in immunosuppression in the setting of acute insults. The current study will contribute to a deeper understanding on the theory which intestinal lymphatic pathway might serve as one of the early and important routes in the development of sepsis and MODS, and novel strategies on prevention and treatment of postburn sepsis will be provided.

免疫功能障碍是脓毒症发生与发展的重要基础，有研究提示肠淋巴途径是烧伤诱发脓毒症、多器官功能障碍综合征(MODS)的重要途径之一，然而有关肠淋巴途径在免疫紊乱中的潜在作用与可能机制迄今尚不清楚。本项目以严重烧伤后肠淋巴液中高迁移率族蛋白B1(HMGB1)改变为切入点，观察它对细胞免疫的影响及其分子机制。在体内实验中，经肠淋巴管给予HMGB1拮抗剂，明确HMGB1在烧伤后淋巴途径中的作用；体外实验进一步分析淋巴液对树突状细胞(DC)免疫功能的影响及与HMGB1的本质联系；结合体内、体外实验深入探讨肠淋巴途径中HMGB1介导DC自噬的作用及其免疫调节效应，藉以阐明肠淋巴途径在烧伤诱发机体免疫功能紊乱过程中的病理生理意义。该研究有助于深化对“肠淋巴途径作为严重烧伤并发脓毒症、MODS中早期重要途径之一”这一理论的认识，为预防和治疗烧伤后脓毒症提供新思路、开辟新途径。

免疫功能障碍是脓毒症发生与发展的重要基础，肠淋巴途径是烧伤诱发脓毒症、多器官功能障碍综合征(MODS)的重要途径之一，有关肠淋巴途径在免疫紊乱中的潜在作.用与可能机制迄今尚不清楚。本项目以严重烧伤后肠淋巴液中高迁移率族蛋白B1(HMGB1)改变为切入点，观察它对细胞免疫的影响及其分子机制。在体内实验中，经肠淋巴管给予HMGB1拮抗剂，明确HMGB1在烧伤后淋巴途径中的作用；体外实验进一步分析淋巴液对树突状细胞(DC)免疫功能的影响及与HMGB1的本质联系；并结合体内、体外实验深入探讨肠淋巴途径中HMGB1介导DC自噬的作用及其免疫调节效应，藉以阐明肠淋巴途径在烧伤诱发机体免疫功能紊乱过程中的病理生理意义。结果发现，HMGB1 作为肠系膜淋巴液的关键调节因素之一，通过拮抗肠系膜淋巴途径中HMGB1 的表达，能有效减轻烧伤大鼠组织损伤，并提高脾脏DC 的免疫功能；肠淋巴液对烧伤后DC 免疫功能具有显著影响，两者之间存在时-效与量-效关系；肠系膜淋巴途径可介导 DC 自噬。该研究有助于深化对“肠淋巴途径作为严重烧伤并发脓毒症、MODS中早期重要途径之一”这一理论的认识，为预防和治疗烧伤后脓毒症提供新思路、开辟新途径。