器官移植2017，Vol.8Issue(5)：349-354,6.DOI:10.3969/j.issn.1674-7445.2017.05.003
高剂量西罗莫司可能通过促进细胞自噬对老年小鼠肝脏缺血-再灌注损伤起保护作用
High-dose sirolimus protects hepatic ischemia-reperfusion injury probably through promoting cellular autophagy in aged mice
摘要
Abstract
Objective To investigate the effect and mechanism of high-dose sirolimus (rapamycin) upon protecting the hepatic ischemia-reperfusion injury (HIRI) in aged mice. Methods Twenty C57BL/6 aged mice were randomly and evenly divided into the ischemia-reperfusion injury group (IRI group), low-dose rapamycin pretreatment group (rpm group), high-dose rapamycin pretreatment group (RPM group) and control group (Sham group) using the random number table method (5 mice in each group). In the Sham group, abdominal cavity was incised and sutured alone. In the other three groups, aged mouse 70% HIRI models were established. The ischemia time was 60 min. At preoperative 1 h, rapamycin at a dose of 1 mg/kg and 5 mg/kg was administered via intraperitoneal injection in the rpm and RPM groups. At 12 h post-reperfusion, hematoxylin-eosin (HE) staining was performed to observe the histological changes in the mouse liver. Suzuki grading method was adopted to evaluate the pathological score. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), tumor necrosis factor (TNF)-α and interleukin (IL)-10 and the LC3B-Ⅱ protein level in the liver tissues were quantitatively measured and statistically compared among different groups. Results HE staining of the liver tissues revealed normal liver tissues in the Sham group, severe liver cellular injury accompanied with a large quantity of inflammatory cellular infiltration in the IRI and rpm groups. Mild sinusoidal congestion and slight inflammatory cellular infiltration were observed in the RPM group. The pathological score was 5 (4-6) in the RPM group, significantly lower than 7 (5-8) and 8 (7-10) in the rpm and IRI groups (Z=-2.554 and -2.731, both P<0.05). In terms of postoperative liver function parameters, the AST level was (691±207) U/L in the RPM group, significantly lower compared with (2032±575) U/L and (1817±777) U/L in the IRI and rpm groups (t=4.90 and 3.13, both P<0.05). In the RPM group, the ALT level was measured as (996±584) U/L, considerably lower than (2992±992) U/L and (2373±687) U/L in the IRI and rpm groups (t=3.86 and 3.41, both P<0.05). The AST and ALT levels did not significantly differ between the IRI and rpm groups (both P>0.05). No statistical significance was identified in the TNF-α and IL-10 levels among different groups (all P>0.05). Western blot analysis revealed that the relative expression level of LC3B-Ⅱ protein in the liver tissue of the RPM group was significantly higher than those in the Sham, IRI and rpm groups (all P<0.05). Conclusions Administration of high-dose rapamycin exerts a protective effect upon HIRI probably through promoting cellular autophagy in aged mice.关键词
缺血-再灌注损伤/肝移植/小鼠,老年/西罗莫司(雷帕霉素)/细胞自噬/丙氨酸转氨酶/天冬氨酸转氨酶/肿瘤坏死因子/白细胞介素/LC3B-Ⅱ蛋白Key words
Ischemia-reperfusion injury/Liver transplantation/Mouse/elderly,Sirolimus (rapamycin)/Cellular autophagy/Alanine aminotransferase/Aspartate aminotransferase/Tumor necrosis factor/Interleukin/LC3B-Ⅱ protein分类
医药卫生引用本文复制引用
滕旭,丁凡,陈文捷,许赤..高剂量西罗莫司可能通过促进细胞自噬对老年小鼠肝脏缺血-再灌注损伤起保护作用[J].器官移植,2017,8(5):349-354,6.基金项目
深圳市科技计划项目(JCYJ20150402112934552) （JCYJ20150402112934552）
