Hyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway.
Hyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway.
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DOI：
10.1111/ajt.13360
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发表时间：
2015-11
影响因子：
8.8
通讯作者：
Zhai, Y.
中科院分区：
文献类型：
--
作者：
Yue, S.;Zhou, H. M.;Zhu, J. J.;Rao, J. H.;Busuttil, R. W.;Kupiec-Weglinski, J. W.;Lu, L.;Zhai, Y.
虽然移植前糖尿病是肝移植后死亡的危险因素，但其潜在机制尚未完全明确。在小鼠肝脏局部热缺血模型中，我们研究了糖尿病/高血糖如何影响组织炎症损伤对抗缺血再灌注（IR），重点研究了晚期糖基化终产物（AGE）及其受体（RAGE）途径。我们的研究结果表明，链脲佐菌素诱导的糖尿病小鼠的肝细胞损伤加重，与肝脏的高炎症免疫激活有关。糖尿病小鼠血清中AGEs水平升高，而HMGB1水平不升高。RAGE拮抗剂肽和小干扰RNA均能减轻糖尿病小鼠的肝损伤，抑制炎症免疫激活。糖尿病小鼠的库普弗细胞(KCs)/巨噬细胞，而不是肝细胞，表达了显著更高水平的RAGE，导致它们对TLR配体和AGEs的高炎症反应。在体外，高血糖增加巨噬细胞RAGE表达，增强其TLR反应。我们的研究结果表明，KCs中AGE-RAGE信号通路的激活是导致糖尿病/高血糖宿主对肝脏IR的高炎症免疫反应和加重肝细胞损伤的原因。
Although pre-transplant diabetes is a risk factor for mortality post-liver transplant, the underlying mechanism has not been fully defined. In a murine liver partial warm ischemia model, we addressed the question of how diabetes/hyperglycemia impacted tissue inflammatory injuries against ischemia reperfusion (IR), focusing on the Advanced Glycation End-product (AGE) and its receptor (RAGE) pathway. Our results showed that hepatocellular injury was exacerbated in Streptozotocin-induced diabetic mice against IR, in association with hyper-inflammatory immune activation in livers. Serum levels of AGEs, but not HMGB1, were increased in diabetic mice in response to liver IR. Both RAGE antagonist peptides and small interfering RNA alleviated liver injuries and inhibited inflammatory immune activation against IR in diabetic, but not normal, mice. Kupffer cells (KCs)/macrophages, but not hepatocytes, from diabetic mice expressed significantly higher levels of RAGE, leading to their hyper-inflammatory responsiveness to both TLR ligands and AGEs. In vitro, hyperglycemia increased macrophage RAGE expressions and enhanced their TLR responses. Our results demonstrated that the activation of the AGE-RAGE signaling pathway in KCs was responsible for hyper-inflammatory immune responses and exacerbated hepatocellular injuries in diabetic/hyperglycemic hosts against liver IR.
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影响因子：
7.7
作者：
Parathath S;Grauer L;Huang LS;Sanson M;Distel E;Goldberg IJ;Fisher EA
通讯作者：
Fisher EA
影响因子：
7.7
作者：
Bucciarelli LG;Ananthakrishnan R;Hwang YC;Kaneko M;Song F;Sell DR;Strauch C;Monnier VM;Yan SF;Schmidt AM;Ramasamy R
通讯作者：
Ramasamy R
DOI：
10.4049/jimmunol.1400280
发表时间：
2014-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Yue S;Rao J;Zhu J;Busuttil RW;Kupiec-Weglinski JW;Lu L;Wang X;Zhai Y
通讯作者：
Zhai Y
影响因子：
7.4
作者：
Gill, Roop;Tsung, Allan;Billiar, Timothy
通讯作者：
Billiar, Timothy
影响因子：
7.7
作者：
Juranek JK;Geddis MS;Song F;Zhang J;Garcia J;Rosario R;Yan SF;Brannagan TH;Schmidt AM
通讯作者：
Schmidt AM