Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion
Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion
复制标题
DOI：
10.1097/01.tp.0000287597.87571.17
复制
发表时间：
2007-11-27
期刊：
影响因子：
6.2
通讯作者：
Billiar, Timothy R.
中科院分区：
文献类型：
--
作者：
Kaczorowski, David J.;Nakao, Atsunori;Billiar, Timothy R.
背景缺血/再灌注（I/R）损伤导致移植物功能障碍，并可能促进移植后的同种免疫反应。冷I/R损伤的分子机制仅得到部分表征，但可能涉及内源性配体对Toll样受体（TLR）-4的激活。我们在小鼠心脏移植模型中检测了TLR 4介导冷I/R环境中早期炎症反应的假设。在TLR 4信号传导缺陷的突变小鼠（C3 H/HeJ）和野生型小鼠（C3 H/HeOuJ）中进行同基因心脏移植。还在品系之间进行了移植（突变心脏移植到野生型受体中，匡威亦然）。供体心脏进行2小时的冷缺血。在再灌注后3和24小时取出移植物。收集血清样品用于细胞因子分析。逆转录聚合酶链反应和组织学分析用于评估移植物内炎症。移植后，血清肿瘤坏死因子（TNF）、白细胞介素（IL）-6、JE/单核细胞趋化蛋白（MCP）-1、IL- 1 β和肌钙蛋白I水平，以及移植物内TNF、IL- 1 β、IL-6、早期生长反应（EGR）-1、细胞间粘附分子（ICAM）-1和诱导型一氧化氮合酶（iNOS）mRNA水平，突变型组与野生型->野生型组相比显著降低（P野生型和野生型->突变型组。免疫组化显示，与野生型->野生型组相比，突变型->突变型组心肌核因子-κ B核转位和中性粒细胞浸润较少。这些发现表明，TLR 4信号传导是器官移植背景下冷I/R后发生的全身和移植物内炎症反应的核心，供体和受体细胞上的TLR 4信号传导有助于这种反应。
Background. Ischemia/reperfusion (I/R) injury leads to graft dysfunction and may contribute to alloimmune responses posttransplantation. The molecular mechanisms of cold I/R injury are only partially characterized but may involve toll-like receptor (TLR)-4 activation by endogenous ligands. We tested the hypothesis that TLR4 mediates the early inflammatory response in the setting of cold I/R in a murine cardiac transplant model.Methods. Syngeneic heart transplants were performed in mutant mice deficient in TLR4 signaling (C3H/HeJ) and wild-type mice (C3H/HeOuJ). Transplants were also performed between the strains (mutant hearts into wild-type recipients and the converse). Donor hearts were subjected to 2 hr of cold ischemia. The grafts were retrieved at 3 and 24 hr after reperfusion. Serum samples were collected for cytokine analysis. Reverse-transcription polymerase chain reaction and histologic analysis were used to assess intra-graft inflammation.Results. After transplant, serum tumor necrosis factor (TNF), interleukin (IL)-6, JE/monocyte chemotractant protein (MCP)- 1, IL- 1 beta, and troponin I levels, as well as intragraft TNF, IL- 1 beta, IL-6, early growth response (EGR) - 1, intercellular adhesion molecule (ICAM) - 1, and inducible nitric oxide synthase (iNOS) mRNA levels, were significantly lower in the mutant-mutant group compared to the wild- type -> wild-type group (P wild-type and wild -type -> mutant groups. Immunohistochemistry revealed less myocardial nuclear factor-kappa B nuclear translocation at and less neutrophil infiltration in the mutant -> mutant group compared to the wild-type -> wild- type group.Conclusions. These findings demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation and that TLR4 signaling on both donor and recipient cells contributes to this response.