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Exogenous melatonin protects small‐for‐size liver grafts by promoting monocyte infiltration and releases interleukin‐6
Journal of Pineal Research ( IF 10.3 ) Pub Date : 2018-04-21 , DOI: 10.1111/jpi.12486
Zhuolun Song 1 , Bostjan Humar 1 , Anurag Gupta 1 , Eleonora Maurizio 1 , Nathalie Borgeaud 1 , Rolf Graf 1 , Pierre-Alain Clavien 1 , Yinghua Tian 1
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Defective regeneration of small‐for‐size (SFS) liver remnants and partial grafts remains a key limiting factor in the application of liver surgery and transplantation. Exogenous melatonin (MLT) has protective effects on hepatic ischemia‐reperfusion injury (IRI), but its influence on graft regeneration is unknown. The aim of the study is to investigate the role of MLT in IRI and graft regeneration in settings of partial liver transplantation. We established three mouse models to study hepatic IRI and regeneration associated with partial liver transplantation: (I) IR+PH group: 60 minutes liver ischemia (IR) plus 2/3 hepatectomy (PH); (II) IR+exPH group: 60 minutes liver IR plus extended hepatectomy (exPH) associated with the SFS syndrome; (III) SFS‐LT group: Arterialized 30% SFS liver transplant. Each group was divided into MLT or vehicle‐treated subgroups. Hepatic injury, inflammatory signatures, liver regeneration, and animal survival rates were assessed. MLT reduced liver injury, enhanced liver regeneration, and promoted interleukin (IL) 6, IL10, and tumor necrosis factor‐α release by infiltrating, inflammatory Ly6C+ F4/80+ monocytes in the IR+PH group. MLT‐induced IL6 significantly improved hepatic microcirculation and survival in the IR+exPH model. In the SFS‐LT group, MLT promoted graft regeneration and increased recipient survival along with increased IL6/GP130‐STAT3 signaling. In IL6−/− mice, MLT failed to promote liver recovery, which could be restored through recombinant IL6. In the IR+exPH and SFS‐LT groups, inhibition of the IL6 co‐receptor GP130 through SC144 abolished the beneficial effects of MLT. MLT ameliorates SFS liver graft IRI and restores regeneration through monocyte‐released IL6 and downstream IL6/GP130‐STAT3 signaling.

中文翻译:

外源性褪黑激素通过促进单核细胞浸润并释放白介素-6,从而保护小型肝移植物

小尺寸(SFS)肝残留物和部分移植物的再生不良仍然是肝脏手术和移植应用中的关键限制因素。外源性褪黑激素(MLT)对肝缺血再灌注损伤(IRI)具有保护作用,但其对移植物再生的影响尚不清楚。该研究的目的是研究MLT在IRI和移植物再生在部分肝移植中的作用。我们建立了三种小鼠模型来研究肝脏IRI和部分肝移植相关的再生:(I)IR + PH组:60分钟肝缺血(IR)加2/3肝切除术(PH);(II)IR + exPH组:60分钟肝脏IR加SFS综合征相关的肝切除术(exPH);(III)SFS-LT组:动脉化30%SFS肝移植。每个小组分为MLT小组或媒介治疗小组。评估肝损伤,炎症信号,肝再生和动物存活率。MLT通过浸润IR + PH组中炎性的Ly6C + F4 / 80 +单核细胞,减少了肝损伤,增强了肝的再生,并促进了白介素(IL)6,IL10和肿瘤坏死因子-α的释放。MLT诱导的IL6在IR + exPH模型中显着改善了肝微循环和存活率。在SFS-LT组中,MLT促进了移植物的再生并增加了受体的存活率,同时还增加了IL6 / GP130-STAT3信号传导。在 IR + PH组炎症性Ly6C + F4 / 80 +单核细胞。MLT诱导的IL6在IR + exPH模型中显着改善了肝微循环和存活率。在SFS-LT组中,MLT促进了移植物的再生并增加了受体的存活率,同时还增加了IL6 / GP130-STAT3信号传导。在 IR + PH组炎症性Ly6C + F4 / 80 +单核细胞。MLT诱导的IL6在IR + exPH模型中显着改善了肝微循环和存活率。在SFS-LT组中,MLT促进了移植物的再生并增加了受体的存活率,同时还增加了IL6 / GP130-STAT3信号传导。在IL6 -/-小鼠,MLT不能促进肝脏恢复,这可以通过重组IL6来恢复。在IR + exPH和SFS-LT组中,通过SC144对IL6受体GP130的抑制作用消除了MLT的有益作用。MLT改善SFS肝移植IRI,并通过单核细胞释放的IL6和下游IL6 / GP130-STAT3信号传导恢复再生。
更新日期:2018-04-21
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