Low-dose TNF-α protects against hepatic ischemia-reperfusion injury in mice:: Implications for preconditioning
Low-dose TNF-α protects against hepatic ischemia-reperfusion injury in mice:: Implications for preconditioning
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DOI：
10.1053/jhep.2003.50009
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发表时间：
2003-01-01
期刊：
影响因子：
13.5
通讯作者：
Farrell, G
中科院分区：
文献类型：
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作者：
Teoh, N;Leclercq, I;Farrell, G
肿瘤坏死因子α (tnf - α)与肝缺血再灌注损伤的发病机制有关，但也可使肝细胞进入细胞周期。缺血预处理可以预防缺血再灌注（IR）肝损伤，并与核因子κ b （nf - κ b）的激活和细胞周期进入有关。我们研究了在存在或不存在缺血预处理的情况下，肝脏IR期间TNF- α释放的模式，并测试了单次低剂量注射TNF是否可以模拟缺血预处理的生物学效应。在未成熟小鼠中，肝缺血期间肝脏和血浆中tnf - α水平升高，90分钟后达到高水平；再灌注44小时后，数值仍保持升高。缺血预处理刺激后，肝脏和血清tnf - α水平早期升高，但在第二个延长的缺血间期高峰期间，tnf - α值低于幼稚小鼠，并在2小时再灌注时降至可忽略不计的水平。肝脏IR前30分钟注射1杯或5杯/kg体重的tnf - α，根据肝脏组织学和血清谷丙转氨酶（ALT）水平测定，可显著减轻肝损伤。与缺血预处理一样，tnf - α预处理激活了NF-kappaB DNA结合、STAT3、细胞周期蛋白D1、细胞周期蛋白依赖性激酶4 （c4k4）的表达，并通过肝细胞核增殖细胞核抗原（PCNA）染色确定细胞周期进入。总之，“预处理”的肝保护作用可以通过注射tnf - α来模拟，其对细胞周期进入具有相同的下游作用。我们认为，tnf - α水平的短暂升高可能替代或介导缺血预处理对肝IR损伤的肝保护作用。
Tumor necrosis factor alpha (TNF-alpha) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor kappaB (NF-kappaB) and cell cycle entry. We examined the pattern of TNF-alpha release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naive mice, hepatic and plasma levels of TNF-alpha rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-alpha levels, but, during a second prolonged ischemic interval peak, TNF-alpha values were lower than in naive mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 mug or 5 mug/kg body weight TNF-alpha 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-alpha pretreatment activated NF-kappaB DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (c4k4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of "preconditioning" can be simulated by TNF-alpha injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-alpha levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury.