Background

Mycophenolate mofetil (MMF), an immunosuppressive drug, exerts anti-inflammatory effects on organs during ischemia/reperfusion (I/R) injury. However, the exact function of MMF in hepatic I/R injury remains largely unknown. The purpose of this study was to explore the role and potential mechanism of MMF protection in hepatic I/R injury.

Methods

Male wild type (WT) and TLR4 knockout (KO) mice were injected intraperitoneally with MMF or normal saline. Animals underwent 90 min of partial hepatic ischemia, followed by 1, 6, or 24 h of reperfusion. Hepatic histology, serum amiotransferase, inflammatory cytokines, hepatocyte apoptosis, and hepatocyte autophagy were examined to assess liver injury.

Results

Treatment with MMF significantly decreased hepatic I/R injury as indicated by a reduction in serum aminotransferase levels, Suzuki scores, and the overall degree of necrosis. MMF treatment inhibited TLR4 activation dramatically. MMF administration also significantly inhibited the activation of the NF-κB pathway and the expression of pro-inflammatory cytokines. In TLR4 KO mice, MMF still exerted protection from hepatic I/R injury. MMF treatment inhibited hepatocyte apoptosis, as indicated by reduced TUNEL staining, and reduced the accumulation of cleaved caspase-3. In addition, MMF may induce autophagy and increase autophagic flux before and after hepatic reperfusion by augmenting the expression of LC3-II, P62, and Beclin-1. The induction of autophagy by MMF treatment may be related to TLR4 activation.

Conclusions

Our results indicate that MMF treatment ameliorates hepatic I/R injury. The mechanism of action likely involves the ability of MMF to decrease apoptosis and the inflammatory response while inducing autophagy.

中文翻译：

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吗替麦考酚酯预处理保护小鼠肝脏免受野生型和 toll 样受体 4 敲除小鼠的缺血/再灌注损伤

背景

吗替麦考酚酯 (MMF) 是一种免疫抑制药物，在缺血/再灌注 (I/R) 损伤期间对器官发挥抗炎作用。然而，MMF 在肝 I/R 损伤中的确切作用仍然很大程度上未知。本研究旨在探讨MMF在肝脏I/R损伤中的保护作用及潜在机制。

方法

用 MMF 或生理盐水腹膜内注射雄性野生型 (WT) 和 TLR4 敲除 (KO) 小鼠。动物经历 90 分钟的部分肝缺血，然后再灌注 1、6 或 24 小时。检查肝组织学、血清氨基转移酶、炎性细胞因子、肝细胞凋亡和肝细胞自噬以评估肝损伤。

结果

MMF 治疗显着降低了肝脏 I/R 损伤，这表现为血清转氨酶水平、Suzuki 评分和总体坏死程度的降低。MMF 治疗显着抑制 TLR4 活化。MMF 给药还显着抑制 NF-κB 通路的激活和促炎细胞因子的表达。在 TLR4 KO 小鼠中，MMF 仍然对肝脏 I/R 损伤发挥保护作用。MMF 处理抑制肝细胞凋亡，如减少的 TUNEL 染色所示，并减少切割的 caspase-3 的积累。此外，MMF 可能通过增加 LC3-II、P62 和 Beclin-1 的表达来诱导自噬并增加肝再灌注前后的自噬通量。MMF处理诱导自噬可能与TLR4活化有关。

结论

我们的结果表明，MMF 治疗可改善肝脏 I/R 损伤。作用机制可能涉及 MMF 在诱导自噬的同时减少细胞凋亡和炎症反应的能力。