Department of Hepatobiliary Surgery, Weifang Traditional Chinese Hospital, 261001 Shandong, China.
Department of hepatobiliary surgery, Tianjin First Center hospital, No. 24, Fukang road, Nankai district, 300192 Tianjin, China.
Clin Res Hepatol Gastroenterol. 2019 Apr;43(2):161-170. doi: 10.1016/j.clinre.2017.04.009. Epub 2019 Feb 1.
The study is aimed to investigate the protective effects and possible mechanism of tacrolimus (FK506) pre-treatment in hepatic ischemia-reperfusion injury in rats.
The rats were randomly assigned into four groups, which were S, IR, L and H group, and then all groups were subjected to 60min of 70% partial warm liver ischemia, except S group. Rats in the L and H group were pre-treated with two different doses FK506 at 60min before ischemia. The rats of the IR group received an identical volume of normal saline. All animals were sacrificed after 6h of reperfusion. Transaminases were measured by biochemistry analyzer. Elisa kit was used to detect TNF-α, IL-6 and IL-1β levels in serum. Liver specimens were stained with hematoxylin and eosin (HE) to assess the pathologic changes. The expressions of heme oxygenase-1 (HO-1), hypoxia-inducible factor-1α (HIF-1α), nuclear factor of activated T cells (NFAT3) were measured by real-time quantitative PCR and western blotting and the Bcl-2 and the Bax protein were tested by western blotting.
In rats pre-treated with FK506, the levels of transaminases, TNF-α and IL-1β were reduced significantly and also liver damage was dramatically mitigated compared to those without FK506 pre-treatment. Moreover, the expression of HO-1 at the level of both transcription and translation increased clearly and the activation of the HIF-1α was found in FK506 pre-treated livers. Moreover, NFAT3 protein transportation to the nucleus was reduced and Bax protein expression was decreased, but the expression of Bcl-2 protein was markedly increased after FK506 pre-treatment.
FK506 pre-treatment could lessen hepatic ischemia-reperfusion injury through up-regulating the expression of HIF-1α and HO-1, and inhibiting nuclear translocation of NFAT3 in liver tissues.
本研究旨在探讨他克莫司（FK506）预处理对大鼠肝缺血再灌注损伤的保护作用及可能机制。
将大鼠随机分为 S、IR、L 和 H 四组，除 S 组外，其余各组均进行 70%部分热肝缺血 60min。L 和 H 组在缺血前 60min 给予两种不同剂量 FK506 预处理，IR 组给予等量生理盐水。所有动物在再灌注 6h 后处死。采用生化分析仪检测转氨酶。采用 ELISA 试剂盒检测血清 TNF-α、IL-6 和 IL-1β水平。苏木精-伊红（HE）染色评估肝组织病理变化。采用实时定量 PCR 和 Western blot 检测血红素加氧酶-1（HO-1）、缺氧诱导因子-1α（HIF-1α）、激活 T 细胞核因子（NFAT3）的表达，Western blot 检测 Bcl-2 和 Bax 蛋白。
FK506 预处理组大鼠转氨酶、TNF-α和 IL-1β水平明显降低，肝损伤明显减轻。此外，FK506 预处理组肝脏 HO-1 的转录和翻译水平明显增加，HIF-1α 激活。NFAT3 蛋白向核内转移减少，Bax 蛋白表达减少，Bcl-2 蛋白表达明显增加。
FK506 预处理可通过上调 HIF-1α和 HO-1 的表达，抑制 NFAT3 向核内转移，减轻肝脏缺血再灌注损伤。
