Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll‐like receptor 4/nuclear factor‐kappa B pathway
Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll‐like receptor 4/nuclear factor‐kappa B pathway
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DOI：
10.1097/00029330-200703020-00015
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发表时间：
2007-03
影响因子：
6.1
通讯作者：
Hui Wang;Zhuo Li;Heshui Wu;Yang Wang;Chun-fang Jiang;Qi-chang Zheng;Jinxiang Zhang
中科院分区：
文献类型：
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作者：
Hui Wang;Zhuo Li;Heshui Wu;Yang Wang;Chun-fang Jiang;Qi-chang Zheng;Jinxiang Zhang
研究背景肝缺血再灌注损伤（IRI）是指缺血肝叶血流恢复后，肝组织损伤加重的一种病理过程。Toll样受体4（TLR 4）在几种肝细胞类型上表达，核因子-κ B（NF-B）信号通路对介导肝脏炎症反应至关重要。由于IRI本质上是一种由多种危险信号诱发的深度急性炎症反应，因此我们在部分肝IRI小鼠模型中研究了TLR 4/NF-B信号通路的激活。方法野生型小鼠（WT，C3 H/HeN）和TLR 4突变型小鼠（C3 H/HeJ）分别行肝脏部分缺血45 min，再灌注1 h和3 h。假手术组采用相同的手术方法，不阻断血供。再灌注结束时，检测肝功能损害程度和肝组织切片病理学改变，作为肝损伤程度的指标。用鲎试剂法测定门静脉内毒素水平。NF-B活化通过电泳迁移率变动分析（EMSA）测定。通过酶联免疫吸附试验（ELISA）评估肝IRI后全身血液中肿瘤坏死因子（TNF-）和白细胞介素-1（IL-1）的水平。结果部分肝IRI后，突变型小鼠肝功能损害和肝组织形态学损伤较野生型小鼠明显减轻。野生型小鼠NF-B活化强于TLR 4突变型小鼠，且均强于假手术小鼠（P<0.01）。各组内毒素均未检出。全身血液中TNF-α和IL-1的水平在两种菌株中均升高，但在假手术组中较低。TLR 4基因突变小鼠的上述介导因子水平明显低于野生型小鼠（P<0.01）。结论TLR 4/NF-B信号通路可能介导内源性危险信号触发的肝脏IRI。TLR 4/NF-B通路的抑制可能是在某些临床环境中减轻缺血/再灌注诱导的组织损伤的潜在治疗靶点。
Background Restoration of blood flow to the ischemic liver lobes may paradoxically exacerbate tissue injury, which is called hepatic ischemia/reperfusion injury (IRI). Toll‐like receptor 4 (TLR4), expressed on several liver cell types, and the nuclear factor‐kappa B (NF‐B) signaling pathway are crucial to mediating hepatic inflammatory response. Because IRI is essentially a kind of profound acute inflammatory reaction evoked by many kinds of danger signals, we investigated TLR4/NF‐B signaling pathway activation in a murine model of partial hepatic IRI. Methods Wild‐type mice (WT, C3H/HeN) or TLR4 mutant mice (C3H/HeJ) were subjected to 45 minutes of partial hepatic ischemia followed by 1 hour, 3 hours of reperfusion. Sham group accepted the same procedure without the obstruction of blood supply. At the end of reperfusion, the compromise of liver function and the histological change of liver sections were measured as the severity of liver injury. The level of endotoxin in the portal vein was measured by limulus assay. NF‐B activation was determined by electrophoretic mobility shift assay (EMSA). The levels of tumor necrosis factor‐ (TNF‐) and interleukin‐1 (IL‐1) in systemic blood after hepatic IRI were assessed by enzyme‐linked immunosorbent assay (ELISA). Results The compromise of liver function and the morphological injuries in mutant mice were relieved more markedly than those in WT mice after partial hepatic IRI. NF‐B activation in WT mice was stronger than that in TLR4 mutant mice, and both were stronger than those in the sham operated mice (P<0.01). Endotoxin in each group was undetectable. The levels of TNF‐ and IL‐1 in systemic blood were elevated in both strains, but lower in the sham operated group. These mediators were significantly decreased in TLR4 mutant mice compared with those in WT mice (P<0.01). Conclusions The TLR4/NF‐B signaling pathway may mediate hepatic IRI triggered by endogenous danger signals. Inhibition of the TLR4/NF‐B pathway may be a potential therapeutic target for attenuating ischemia/reperfusion‐induced tissue damage in some clinical settings.