The mechanism of liver dysfunction in endogenous septic shock model mice

脓毒症是一种全身性炎症综合征，通常由细菌感染引起，并与多器官功能衰竭和功能障碍有关。尽管有有效的抗生素，感染性休克的死亡率仍然很高。我们通过反复给药吲哚美辛（IND）和β-葡聚糖（BG）建立了小鼠脓毒症的动物模型。BG和IND联合用药可致大鼠严重死亡，使各脏器白细胞数量增加，白细胞活化1。BG/IND处理小鼠的肝脏用缓冲福尔马林固定，苏木精-伊红染色。脓毒症小鼠肝脏非实质细胞率升高。BG/IND小鼠各脏器细菌数量明显高于对照小鼠。此外，BG/IND给药小鼠血清中TNF-α、MCP-1和IL-6浓度升高。提示BG/ ind给药后，胃肠道严重损伤和通透性增加，导致溃疡、多脏器炎症和脓毒症。给予BG/IND的小鼠从腹腔渗出细胞（PEC）培养中产生显著浓度的一氧化氮（NO）。为观察NO对大鼠致死性的影响，采用NOS抑制剂L-NAME。L-NAME增加死亡率。L-NAME和BG/IND处理可显著提高PEC中IL-1β、IL-6和TNF-α的产生。在L-NAME和BG/IND联合治疗的小鼠中，GOT和GPT的释放也增加。提示在该模型中NO的产生具有保护作用。抗生素治疗的BG/IND小鼠存活时间延长。此外，LPS诱导的炎症细胞因子的产生在抗生素处理的小鼠血清中减少。这些事实强烈表明，抗生素治疗可以保护小鼠免受LPS的致敏，从而降低败血症的风险，如肠道微生物易位和白细胞积聚。

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.