The mechanism of liver dysfunction in endogenous septic shock model mice

脓毒症是一种全身炎症综合征，通常由细菌感染引起，并与多器官衰竭和功能障碍有关。尽管抗生素有效，感染性休克的死亡率仍然很高。我们通过反复给予吲哚美辛(IND)和β-葡聚糖(BG)两种药物，建立了一种小鼠脓毒症的动物模型。BG和IND联合应用可引起大鼠严重致死，各脏器白细胞数量增多，这些细胞被激活。BG/IND处理组小鼠肝脏固定于缓冲福尔马林中，苏木精-伊红染色。脓毒症小鼠肝脏中非实质细胞比例增加。BG/IND小鼠各器官的细菌含量显著高于对照组小鼠。此外，BG/IND组小鼠血清中肿瘤坏死因子-α、单核细胞趋化蛋白-1和IL-6的浓度也明显升高。提示BG/IND2对胃肠道的严重损伤和通透性增加可导致溃疡、多脏器炎症和脓毒症。给予BG/IND的小鼠从腹膜渗出细胞(PEC)培养中产生显著浓度的一氧化氮(NO)。为了观察NO对动物致死率的影响，给予一氧化氮合酶抑制剂L-NAME。L的名字增加了死亡率。L-NAME和BG/IND可促进内皮细胞产生IL-1β、IL-6和肿瘤坏死因子-α。L-NAME与BG/IND合用也能增加小鼠GOT和GPT的释放。提示NO的产生在该模型中具有保护作用。BG/IND组给予抗生素治疗的小鼠存活时间延长。此外，给予抗生素治疗的小鼠血清中内毒素诱导的炎性细胞因子的产生减少。这些事实有力地表明，抗生素治疗保护了小鼠免受内毒素的致敏，从而降低了脓毒症的风险，如微生物易位和白细胞在肠道中的聚集。

Sepsis is a systemic inflammatory syndrome commonly caused by bacterial infection and is associated with multiple organ failure and dysfunction. Despite effective antibiotics, septic shock remains the high mortality. We have developed an animal model of sepsis in mice by repeatedly administering two drugs, indomethacin (IND) and β-glucan (BG). The combination of BG and IND induced severe lethality and increased the number of leukocytes in various organs and these cells were activated.1. The livers of BG/IND treated mice were fixed in buffered formalin and stained with hematoxylin-eosin. The rate of nonparenchymal cell was increased in the livers of septic mice. BG/IND mice contained significantly higher numbers of bacteria than control mice in various organs. Moreover, TNF-α,MCP-1, and IL-6 concentrations of BG/IND administered mice in sera were enhanced. It suggested that severe damage and increased permeability of the gastrointestinal tract led to ulcers, inflammation of multiple organs and sepsis on administration of BG/IND.2. The mice administered BG/IND produced a significant concentration of nitric oxide (NO) from peritoneal exuded cells (PEC) culture. To examine the effect of NO on the lethality, a NOS inhibitor, L-NAME was administered. L-NAME increased the mortality. Treatment with L-NAME and BG/IND enhanced production of IL-1β,IL-6 and TNF-α in PEC was significantly increased. The release of GOT and GPT was also increased in mice treated with the combination of L-NAME and BG/IND. It suggested that the production of NO has a protective effect in this model.3. BG/IND administered mice treated with antibiotics prolonged the survival. Moreover, LPS elicited productions of inflammatory cytokines were decreased in sera of mice treated with antibiotics. These facts strongly suggested that the antibiotics treatment protected mice from the sensitization to LPS and thus reduced risk of sepsis, such as microbial translocation and leukocyte accumulation in the gut.