Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis
Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis
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熊去氧胆酰溶血磷脂酰乙醇酰胺可预防 CD95/FAS 诱导的暴发性肝炎
DOI：
10.1097/shk.0000000000000831
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发表时间：
2017
期刊：
影响因子：
3.1
通讯作者：
Chamulitrat W
中科院分区：
文献类型：
--
作者：
Utaipan T;Otto AC;Gan-Schreier H;Chunglok W;Pathil A;Stremmel W;Chamulitrat W
在病毒性肝炎和自身免疫中，Fas配体激活CD95/Fas的增加参与了暴发性肝炎和肝衰竭的发病机制。我们设计了一种胆汁酸磷脂偶联物熊脱氧胆酰溶血磷脂酰乙醇酰胺（UDCA-LPE， LPE在sn-1处含有油酸）作为肝保护剂，显示出对内毒素诱导的暴发性肝炎的保护作用。我们进一步评估了UDCA-LPE预防死亡受体CD95/ fas诱导的暴发性肝炎的能力。C57BL/6小鼠静脉注射CD95/Fas激动性单克隆抗体（Jo-2），加或不加50 mg/kg UDCA-LPE预处理1 h。从组织学上看，Jo-2给药引起了大量的肝细胞损伤，这与肝磷脂酰胆碱（PC）、溶血卵磷脂和溶血磷脂酰乙醇胺水平的显著降低有关。从组织学上看，UDCA-LPE预处理改善了肝细胞损伤，部分恢复了这些磷脂的损失，其机制涉及抑制细胞质磷脂酶a2的表达。因此，Jo-2处理增加了肝脏裂解型caspase 8、caspase 3和聚（adp -核糖）聚合酶1的表达，另一方面降低了抗凋亡细胞flice抑制蛋白的表达。UDCA-LPE预处理能够逆转所有这些变化。此外，UDCA-LPE通过降低肝脏和血清中jo -2诱导的促炎细胞因子TNF-α、IL-6和IL-1β的水平来减轻炎症反应。UDCA-LPE还能降低jo -2引物分离脾细胞中受刺激的Th1/Th17细胞因子的水平。综上所述，UDCA-LPE对CD95/ fas诱导的暴发性肝炎具有有效的抗炎作用。
Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.
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熊去氧胆酰溶血磷脂酰乙醇酰胺通过上调抗凋亡蛋白抑制胆汁淤积和缺氧诱导的细胞凋亡
影响因子：
3.2
作者：
Sellinger M;Pathil A;Stremmel W;Chamulitrat W
通讯作者：
Chamulitrat W
影响因子：
6.5
作者：
Noga, AA;Vance, DE
通讯作者：
Vance, DE
影响因子：
25.7
作者：
Lazic M;Eguchi A;Berk MP;Povero D;Papouchado B;Mulya A;Johnson CD;Feldstein AE
通讯作者：
Feldstein AE
fas系统参与肝移植后丙型肝炎病毒复发
影响因子：
4.6
作者：
J. Crespo;Monteserrat Rivero;M. Mayorga;E. Fábrega;F. Casafont;M. Gómez‐Fleitas;F. Pons‐Romero
通讯作者：
F. Pons‐Romero
影响因子：
5.8
作者：
M. Sugano;S. Cho;K. Imaizumi;M. Wada
通讯作者：
M. Wada