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

在失代偿肝硬化中，小肠细菌过度生长，肠道通透性和抗菌能力紊乱导致细菌和细菌产物进入腹腔的易位增加。胃肠道屏障构成第一道防线，腹膜免疫功能是防止自发性细菌性腹膜炎的关键第二道防线。常驻巨噬细胞是先天免疫细胞的重要组成部分，在识别和吞噬微生物病原体、抗原呈递、炎症的诱导和解决以及募集和激活其他免疫细胞等方面发挥着特殊的功能。本研究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、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、腹膜炎和全身炎症加重。确定失代偿肝硬化中腹膜巨噬细胞的病理分化将确定分子机制，允许在腹膜水平上对细菌易位并发症进行非抗生素靶向预防。

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.