The modulation of transcription factor in liver regeneration after hepatic ischemia/reperfusion injury

转录因子在肝缺血/再灌注损伤后肝再生中的调控

• 批准号: 15591381
• 负责人: KATO Atsushi
• 金额: $ 2.24万
• 依托单位: Chiba University
• 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 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591381/
• 关键词: Ischemia; Reperfusion; Liver Regeneration; Transcription Factor; Damaged Liver; Cytokines; Chemokines

1.Liver regeneration after hepatic ischemia/reperfusion injury.Although there is abundant evidence to support the mechanisms of hepatic ischemia/reperfusion, much less is known about the role of regeneration of the liver after ischemia/reperfusion. I used C57BL/6 mice to assess the function of activin-follistatin system in hepatic regeneration after ischemia and reperfusion injury. The expression of mRNA for activin during a time course of liver ischemia/reperfusion was determined by real time PCR methods. Activin expression was increased within 1 hour of reperfusion. Serum levels of activin were also increased after early time point of reperfusion. Follistatin protein levels in serum samples increased just after activin protein levels. These results indicate that activin inhibits initiation of regeneration in hepatocytes at early time point after hepatic ischemia/reperfusion. The activin-follistatin system is one of the important regulatory systems modulating regeneration processes of … More the liver. Endogenous interleukin-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury. Thus, an alternative possibility is that IL-13 directly regulates regeneration of the liver through hepatocytes and endothelial cells function.2.Hepatic ischemia/reperfusion injury alterations in experimental cholestasis.Previous studies from our laboratory have established that obstructive jaundice can increase the neutrophil infiltrates into the liver and significantly elevate hepatoceLLular injury after hepatic ischemia/reperfusion. Male C57BL/6 mice underwent ligation and division of the common bile duct to make obstructive jaundice. Obstructive jaundice mice are far more susceptible to 90 minutes ischemia than 30 minutes ischemia 7 day after surgery. NFκB activation and subsequent production of proinflammatory cytokines such as TNF-α were dramatically increased in obstructive jaundice mice in early time point after hepatic ischemia/reperfusion compared to sham controls. These findings demonstrate that obstructive jaundice develops inflammatory cascade through NFκB activation and renders liver susceptible to hepatic ischemia/reperfusion.3.Clinical examination of hepatic ischemia/reperfusion injuryPostopertive levels of interleukin-6,interleukin-10,macrophage chemoattractant protein-1 and long hepatic ischemia were significantly correlated with postoperative surgical site infection and hepatocellular damage. Hepatic ischemia/reperfusion injury is potentially involved in the pathophysiology of postoperative infection and organ dysfunction. Less

1.肝脏缺血/再灌注损伤后的肝脏再生。虽然有大量证据支持肝脏缺血/再灌注的机制，但对于缺血/再灌注后肝脏再生的作用知之甚少。我使用C57BL/6小鼠进行肝脏再生。评估激活素-卵泡抑素系统在缺血和再灌注损伤后肝再生中的功能。肝脏一段时间内激活素mRNA的表达。通过实时PCR方法测定缺血/再灌注。再灌注后1小时内激活素的血清水平也在再灌注的早期时间点后增加。表明激活素在肝缺血/再灌注后的早期时间点抑制肝细胞再生的启动。激活素-卵泡抑素系统是重要的调节系统之一。调节肝脏的再生过程。内源性白细胞介素 13 在缺血/再灌注损伤期间保护肝细胞和血管内皮细胞。因此，另一种可能性是 IL-13 通过肝细胞和内皮细胞功能直接调节肝脏的再生。实验性胆汁淤积中肝缺血/再灌注损伤的改变。我们实验室之前的研究已经证实，梗阻性黄疸可以增加肝脏缺血/再灌注后，中性粒细胞渗入肝脏，显着加重肝细胞损伤。对雄性 C57BL/6 小鼠进行胆总管结扎和分割，使梗阻性黄疸小鼠更容易受到 90 分钟缺血的影响。术后 7 天，NFκB 激活并随后产生促炎细胞因子，例如 TNF-α。与假手术对照组相比，梗阻性黄疸小鼠在肝缺血/再灌注后的早期时间点显着增加。这些发现表明，梗阻性黄疸通过 NFκB 激活产生炎症级联反应，并使肝脏对肝缺血/再灌注敏感。3.肝缺血/再灌注的临床检查。再灌注损伤术后白细胞介素 6、白细胞介素 10、巨噬细胞趋化因子水平Protein-1和长期肝缺血与术后手术部位感染和肝细胞损伤显着相关，肝缺血/再灌注损伤可能参与术后感染和器官功能障碍的病理生理学。

项目成果

Interleukin 18 causes hepatic ischemia/repefusion injury by suppressing anti-inflammatory cytokine expression in mice

白细胞介素18通过抑制小鼠抗炎细胞因子表达引起肝缺血/再灌注损伤

• 发表时间: 2004
• 期刊: Hepatology 39
• 作者: Takeuchi D;Kato A;et al.
• 通讯作者: et al.

Circulating heat-shock protein 70 is associated with postoperative infection and organ dysfunction after liver resection

• DOI: 10.1016/j.amjsurg.2003.08.029
• 发表时间: 2004-06-01
• 期刊: AMERICAN JOURNAL OF SURGERY
• 影响因子: 3
• 作者: Kimura, F;Itoh, H;Miyazaki, M
• 通讯作者: Miyazaki, M

Yoshidome H, Kato A, Miyazaki M.et al.: "Surgical treatment for extrahepatic recurrence after hepatectomy for colorectal metastases."Hepatogastroenterology. (in press).

Yoshidome H、Kato A、Miyazaki M.等：“结直肠转移肝切除术后肝外复发的手术治疗。”肝胃肠病学。

Kato A, et al.: "Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury"Hepatology. .37. 304-312 (2003)

Kato A 等人：“内源性 IL-13 在缺血/再灌注损伤期间保护肝细胞和血管内皮细胞”肝病学。

Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury

• DOI: 10.1053/jhep.2003.50075
• 发表时间: 2003-02-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kato, A;Maya, T;Lentsch, AB
• 通讯作者: Lentsch, AB