The mechanism of liver dysfunction in endogenous septic shock model mice

内源性感染性休克模型小鼠肝功能障碍的机制

• 批准号: 15590402
• 负责人: OHNO Naohito
• 金额: $ 2.3万
• 依托单位: Tokyo University of Pharmacy and Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590402/
• 关键词: sepsis; NSAIDs; beta-glucan; liver injury; nitric oxide; intestinal bacteria; antibiotics; βグルカン; 酸化窒素; 敗血症性ショック

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.

脓毒症是一种全身性炎症综合征，常由细菌感染引起，并与多器官功能衰竭和功能障碍有关。尽管使用了有效的抗生素，感染性休克仍然是高死亡率的疾病。我们通过反复给予吲哚美辛（IND）和β-葡聚糖（BG）两种药物，在小鼠中建立了脓毒症动物模型。BG和IND联合应用可诱导严重的致死性，并使各器官中白细胞数量增加，这些细胞被激活.将BG/IND处理小鼠的肝脏固定在福尔马林缓冲液中，并用苏木精-伊红染色。脓毒症小鼠肝脏非实质细胞比例增加。BG/IND小鼠在各个器官中含有比对照小鼠显著更高数量的细菌。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给药时胃肠道严重损伤和通透性增加导致溃疡、多器官炎症和脓毒症。给予BG/IND的小鼠从腹膜渗出细胞（PEC）培养物中产生显著浓度的一氧化氮（NO）。为了检查NO对致死率的影响，施用NOS抑制剂L-NAME。L-NAME增加死亡率。L-NAME和BG/IND可显著增加PEC产生IL-1β、IL-6和TNF-α的能力。L-NAME和BG/IND联合治疗组小鼠的GOT和GPT的释放也增加，提示NO的产生在该模型中具有保护作用. BG/IND给药的小鼠用抗生素治疗延长了生存期。此外，LPS引起的炎症细胞因子的产生在用抗生素处理的小鼠血清中减少。这些事实有力地表明，抗生素治疗保护小鼠免于对LPS致敏，从而降低脓毒症的风险，例如肠道中的微生物易位和白细胞积聚。

项目成果

Particulate and soluble β-glucans from Candida albicans modulate cytokine release from human leukocytes

来自白色念珠菌的颗粒状和可溶性 β-葡聚糖调节人类白细胞的细胞因子释放

• 发表时间: 2005
• 期刊: Toxicology of 1→3-Beta-Glucans
• 作者: Ken-ichi Ishibashi;Yukari Nakagawa;Naohito Ohno;Toshimi Murai
• 通讯作者: Toshimi Murai

Structure and immunomodulating activity of fungal β-1,3-glucan

真菌β-1,3-葡聚糖的结构和免疫调节活性

• 发表时间: 2005
• 期刊: Dojin News 114
• 作者: Sachiko Nameda;Maki Saito;Noriko N.Miura;Yoshiyuki Adachi;Naohito Ohno;Naohito Ohno
• 通讯作者: Naohito Ohno

Fate of β-glucans in vivo : organ distribution and degradation mechanisms of fungal β-glucans in the body

β-葡聚糖在体内的命运：真菌β-葡聚糖在体内的器官分布和降解机制

• 发表时间: 2005
• 期刊: Toxicology of 1→3-Beta-Glucans
• 作者: Sachiko Nameda;Maki Saito;Noriko N.Miura;Yoshiyuki Adachi;Naohito Ohno;Naohito Ohno;Yoshiyuki Adachi;Noriko N.Miura
• 通讯作者: Noriko N.Miura

Effect of nitric oxide on β-glucan/indomethacin-induced septic shock

一氧化氮对β-葡聚糖/吲哚美辛诱导的感染性休克的影响

• 发表时间: 2005
• 期刊: Biol. Pharm. Bull 28
• 作者: Sachiko Nameda;Maki Saito;Noriko N.Miura;Yoshiyuki Adachi;Naohito Ohno
• 通讯作者: Naohito Ohno

β-glucan receptor (s) and their signal transduction

β-葡聚糖受体及其信号转导

• 发表时间: 2005
• 期刊: Toxicology of 1→3-Beta-Glucans
• 作者: Sachiko Nameda;Maki Saito;Noriko N.Miura;Yoshiyuki Adachi;Naohito Ohno;Naohito Ohno;Yoshiyuki Adachi
• 通讯作者: Yoshiyuki Adachi