Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury.
Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury.
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内质网应力调节肝缺血发病机理和再灌注损伤中的肝脏炎症免疫反应。
DOI：
10.1097/tp.0b013e318259d38e
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发表时间：
2012-08-15
期刊：
影响因子：
6.2
通讯作者：
Zhai Y
中科院分区：
文献类型：
--
作者：
Liu J;Ren F;Cheng Q;Bai L;Shen X;Gao F;Busuttil RW;Kupiec-Weglinski JW;Zhai Y
虽然内质网（ER）应激与器官缺血和再灌注损伤（IRI）的病理生理学有关，但其潜在机制尚未完全阐明。特别是，由于组织促炎免疫应答是局部IRI的关键介质，因此ER应激如何影响肝脏免疫细胞激活级联仍有待确定。在体外，巨噬细胞和肝细胞中的ER应激由药理学试剂诱导。研究了巨噬细胞TLR 4和肝细胞TNF-α的反应。在体内，在小鼠部分肝热缺血模型中，研究了IR诱导的ER应激和小分子伴侣4-苯基丁酸（PBA）改善ER应激对肝脏免疫应答的影响。ER应激的巨噬细胞对TLR 4刺激产生显著增强的促炎免疫应答;而ER应激的肝细胞对TNF-α诱导的细胞死亡变得更敏感。IR导致受影响肝脏中sXBP-1和ATF 6水平上调。与减少的局部促炎基因诱导程序平行，用PBA预处理的小鼠免受肝脏IRI。我们的研究记录了ER应激在肝脏IRI机制中的潜在免疫调节作用，并为靶向应激反应作为改善器官移植受者组织炎症的新治疗手段提供了理论基础。
Although endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of organ ischemia and reperfusion injury (IRI), the underlying mechanisms have yet to be fully elucidated. In particular, as tissue pro-inflammatory immune response is the key mediator of local IRI, how ER stress impacts liver immune cell activation cascade remains to be determined. In vitro, ER stress in macrophages and hepatocytes were induced by pharmacological agents. Macrophage TLR4 and hepatocyte TNF-α responses were studied. In vivo, the induction of ER stress by IR and the impact of ER stress amelioration by a small molecule chaperon 4-phenyl butyric acid (PBA) on liver immune response were studied in a murine partial liver warm ischemia model. ER stressed macrophages generated a significantly enhanced pro-inflammatory immune response against TLR4 stimulation; while ER stressed hepatocyte became more susceptible to TNF-α induced cell death. IR resulted in upregulations of sXBP-1 and ATF6 levels in affected livers. Mice pre-treated with PBA were protected from liver IRI, in parallel with diminished local pro-inflammatory gene induction program. Our study documents a potential immune regulatory role of ER stress in the mechanism of liver IRI, and provides a rationale for targeting stress response as a new therapeutic means to ameliorate tissue inflammation in organ transplant recipients.