Modulation of Peritoneal Macrophage Differentiation and Function for Prophylaxis of Complications in Decompensated Cirrhosis

失代偿性肝硬变患者的小肠细菌过度生长、肠道通透性和抗菌能力受损导致细菌和细菌产物向腹膜腔内移位增加。胃肠道屏障是预防自发性细菌性腹膜炎的第一道防线，而腹膜免疫功能则是预防自发性细菌性腹膜炎的关键第二道防线。常驻巨噬细胞是天然免疫细胞的重要组成部分，在识别和吞噬微生物病原体、抗原提呈、诱导和消解炎症以及募集和激活其他免疫细胞等方面发挥着特殊的功能。这项建议旨在研究细菌易位在多大程度上与腹膜巨噬细胞群体的特定表型相关，其特征是促炎细胞因子产生增加、内毒素耐受性、吞噬能力降低和未成熟、新近招募的单核细胞数量增加，从而导致腹膜免疫缺陷、腹膜炎和加重全身炎症。明确失代偿期肝硬变患者腹膜巨噬细胞的病理分化将确定允许非抗生素靶向预防腹膜水平细菌移位并发症的分子机制。

In decompensated cirrhosis small intestinal bacterial overgrowth, intestinal permeability and disturbed antimicrobial capacity contribute to increased translocation of bacteria and bacterial products into the peritoneal cavity. Whereas the gastrointestinal barrier constitutes the first line of defense, peritoneal immune function is the crucial second line of defense to prevent spontaneous bacterial peritonitis. Resident macrophages comprise a key population of innate immune cells and fulfill specialized functions regarding recognition and phagocytosis of microbial pathogens, antigen presentation, induction and resolution of inflammation as well as recruitment and activation of other immune cells. This proposal aims at investigating to which extent bacterial translocation is associated with a specific phenotype of the peritoneal macrophage population characterized by increased pro-inflammatory cytokine production, endotoxin tolerance, reduced phagocytic capability and increased numbers of immature, recently recruited monocytes, and therefore contributes to peritoneal immune deficiency, peritonitis, and aggravated systemic inflammation. Defining pathological differentiation of peritoneal macrophages in decompensated cirrhosis will identify molecular mechanisms allowing non-antibiotic targeted prophylaxis of complications of bacterial translocation at the peritoneal level.