Mechanism of vulnerability to endotoxin of regenerating liver and its treatment

再生肝易受内毒素影响的机制及治疗

• 批准号: 10671170
• 负责人: NAKAMURA Satoshi
• 金额: $ 1.98万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671170/
• 关键词: Hepatic resection; Endotoxin; Platelet-activating factor; PAF-receptor; TNF-a; NF-kB; hepatic regeneration; PAF; CINC; NF-κB; LPS; TNF2; TNFα

Background. Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver ijury in regenerating rat livers. Both LPS and PPAF activate nuclear factor-kappa B (NF-kB), a key transcription factor for tumor necrosis factor-a (TNF-a) and cytokine-induced neutrophil attractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kB-mediated regulation of TNF-a and CINCin regenerating rat livers.Methods. LPS (1.5 mg/kg) was intravenously administered into 70 % hepatectomized rats and sham-operated rats 46 hours postoperatively.Results. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-kB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Heptectomized rats showed NF-kB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells.Conclusions. Based on these results, we propose that PAD contributes to continuous CINC up-regulation and NF-kB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat liver.

背景。血小板激活因子（PAF）已被证明是脂多糖（LPS）诱导的再生大鼠肝脏损伤发病机制中的重要介质。 LPS 和 PPAF 均可激活核因子 kappa B (NF-kB)，这是肿瘤坏死因子 -a (TNF-a) 和细胞因子诱导的中性粒细胞吸引剂 (CINC) 的关键转录因子。本研究的目的是探讨PAF如何参与LPS诱导和NF-kB介导的TNF-a和CINC在大鼠肝脏再生中的调节。方法。术后46小时，70%肝切除大鼠和假手术大鼠静脉注射LPS（1.5 mg/kg）。 结果。仅在肝切除大鼠中，LPS 给药导致高死亡率、肝脏分散性坏死、CINC 阳性中性粒细胞浸润，以及肝脏中 CINC 信使 RNA 持续上调和 NF-kB 激活。 PAF受体拮抗剂TCV-309的预处理和后处理均有效防止了这些现象。注射LPS后4小时，七肢切除大鼠的肝细胞、库普弗细胞和坏死周围的中性粒细胞中出现NF-kB染色，表明这些细胞中该因子被激活。结论。基于这些结果，我们提出，PAD 通过中性粒细胞的积累和激活，促进 CINC 的持续上调和 NF-kB 的激活，从而参与 LPS 诱导的大鼠肝脏再生过程中的肝损伤。

项目成果

Shohachi Suzuki, Satoshi Nakamura, et al.: "The roles of platelet-activating factor and endothelin-1 in renal damage after total hepatic ischemia and reperfusion."Transplantation. 69. 2267-2273 (2000)

Shohachi Suzuki、Satoshi Nakamura 等人：“血小板活化因子和内皮素-1 在全肝缺血和再灌注后肾损伤中的作用。”移植。

坂口孝宣: "Acute portal hypertension increases ileal Vulnerability to platelet-activating factor in rats"Journal of Surgical Research. 86. 116-122 (1999)

Takanobu Sakaguchi：“急性门静脉高压增加大鼠回肠对血小板活化因子的脆弱性”《外科研究杂志》86. 116-122 (1999)。

Takanori Sakaguchi, Satoshi Nakamura, et al.: "Participation of platelet-activating factor in the lipopolysaccharide-induced injury in partially hepatectomized rats."Hepatology. 30. 959-967 (1999)

Takanori Sakaguchi、Satoshi Nakamura 等人：“血小板激活因子参与部分肝切除大鼠脂多糖诱导的损伤。”肝病学。

坂口孝宣: "Participation of platelet-Activating Factor in the Lipoplysacharide-Induced liver injury in partially hepatectomized rats"Hepatology. 30. 959-967 (1999)

Takanobu Sakaguchi：“血小板激活因子参与部分肝切除大鼠脂多糖诱导的肝损伤”《肝病学》30. 959-967 (1999)。

Suzuki S. et al.: "The roles of platelet-activating factor and endothelin-1 in renal damage after total hepatic inchemia and reperfusion"Transplantation. 69. 2267-2273 (2000)

Suzuki S.等人：“血小板活化因子和内皮素-1在全肝缺血和再灌注后肾损伤中的作用”移植。