Modulation of intracellular signal pathway for preventing liver damage after extended hepatectomy

调节细胞内信号通路预防扩大肝切除术后肝损伤

基本信息

批准号：
18591497
负责人：
UCHINAMI Hiroshi
金额：
$ 2.6万
依托单位：
Akita University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591497/
关键词：
Liver Sureer Stress Response

项目摘要

Ischemia-reperfusion (I/R) injury of the liver is one of major problems after extended hepatectomy or liver transplantation. To perform operation much safer, some strategies to prevent I/R injury has been required.Nrf2 is a transcription factor that protects cell and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. It is likely that preoperative activation of Nrf2 in liver-consisting cells results in prevention of I/R injury of the liver. In this protocol, we evaluated whether Nrf2 activation confer the tolerance for I/R injury of the liver.Oltipraz, 15-deoxy-Δ 12, 14-prostagrandine J2 (PGJ2), and diallyl sulfide (DAS) were used to confirm whether these drugs activate Nrf2 in liver-consisting cells. Liver epithelial cells and liver stellate cells were isolated from rat and mouse liver and cultured. Immunofluorescent assay revealed that Nrf-2 translocated into the nucleus immediately after stimulating by these drugs in both types of cells. The expression of HO-1 was also induced by PGJ2 in a dose dependent manner.It has been reported that activation of stellate cells has detrimental effect during hepatic I/R. To evaluate the effect of PGJ2 on stellate cell activation, the mRNA expression of alpha smooth muscle actin and type I collagen was examined by real time PCR. PGJ2 significantly inhibited the expression of both genes, suggesting that PGJ2 effectively suppressed the activation of stellate cells.Finally, the effect of PGJ2 on I/R injury was examined. C57/B16 mouse was used. We applied 70% ischemia model (60 min). PGJ2 was administrated intravenously via tail vein 3 hours before ischemia.The increasing of AST/ALT level 3 and 6 hours after reperfusion was significantly suppressed by PGJ2. In addition, TUNEL assay revealed that apoptosis after I/R was also suppressed.These data suggested that Nrf2 activation by PGJ2 may bring the beneficial effect in the field of liver surgery.

肝脏的缺血 - 再灌注（I/R）损伤是肝切开术或肝移植后的主要问题之一。为了更安全，需要进行一些防止I/R损伤的策略。NRF2是一种转录因子，可通过激活保护性抗氧化剂和排毒酶来保护细胞和组织免受氧化应激。 NRF2在肝概致细胞中的术前激活可能会导致该协议中的I/R预防，我们评估了NRF2激活会议是否对肝脏I/R损伤的耐受性。TOLLIPRAZ.OLTIPRAZ，15-DEOXY-δ12、12-二氧化和14-促甲甘油的J2（PGJ2）和DAS毒品（PGJ2），以及激活的NRENR usivation（PGJ2），是否是激活的（DAS）。活细胞。从大鼠和小鼠肝脏中分离出肝上皮细胞和肝星状细胞并培养。免疫荧光测定法表明，在两种细胞中这些药物刺激后，NRF-2立即易位到核us中。 HO-1的表达也通过剂量依赖性诱导。据报道，在肝I/R期间，星状细胞的激活具有有害作用。为了评估PGJ2对星状细胞活化的影响，通过实时PCR检查了α平滑肌肌动蛋白和I型胶原蛋白的mRNA表达。 PGJ2显着抑制了这两个基因的表达，这表明PGJ2有效地抑制了星状细胞的激活。在本文中，检查了PGJ2对I/R损伤的影响。使用C57/B16鼠标。我们应用了70％的缺血模型（60分钟）。 PGJ2在缺血前3小时通过尾静脉静脉内给药。在再灌注后AST/ALT级别3和6小时的增加被PGJ2显着抑制。此外，TUNEL分析表明，I/R后的凋亡也被抑制。这些数据表明，PGJ2激活NRF2可能会在肝手术领域带来有益的作用。