Mesenteric ischemia-reperfusion injury up-regulates certain CC, CXC, and XC chemokines and results in multi-organ injury in a time-dependent manner
Mesenteric ischemia-reperfusion injury up-regulates certain CC, CXC, and XC chemokines and results in multi-organ injury in a time-dependent manner
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DOI：
10.1684/ecn.2014.0345
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发表时间：
2013-10-01
影响因子：
2.8
通讯作者：
Mercer, David W.
中科院分区：
文献类型：
--
作者：
Jawa, Randeep S.;Quist, Erin;Mercer, David W.
前言：发生多器官功能障碍的创伤患者全身趋化细胞因子水平升高。肠缺血再灌注(IR)损伤可能起一定作用。本研究的目的是检测肠系膜IR损伤的小鼠模型中趋化因子的产生。鉴于中性粒细胞的重要作用，对CXC趋化因子的研究很多，但对CC和XC趋化因子的研究很少。我们假设肠IR损伤会导致远隔器官损伤，并使血清CC和XC趋化因子水平升高。方法：空腹雌性C57BL6小鼠麻醉后行剖腹手术。IR组结扎肠系膜上动脉(SMA)30、45或75min，对照组行假剖腹手术，每组5~7只。在指定的时间点后，关闭伤口，让小鼠恢复6小时。安乐死后，测定血清中15种趋化因子(10种CC、4种CXC和1种XC)的水平，并进行组织病理学分析。结果：SMA阻断75min是血清细胞因子水平显著上调、肠道和远隔器官损伤、中性粒细胞流入组织的关键时间段。肠缺血75分钟后，与假手术组相比，7种CC趋化因子水平显著升高：MCP-1、MCP-3、MIP-1β、MIP-3β、嗜酸性粒细胞趋化因子、MDC和RANTES。XC趋化因子淋巴粘连蛋白水平也升高。MIP-2、IP-10和KC/GRO(CXC趋化因子)水平显著升高。MIP-1α仅在再灌流45min时显著升高。在任何缺血时间段，我们没有发现IR损伤引起的MCP-5、MIP-1伽马或GCP-2水平的任何显著变化。随着缺血时间的延长，血清IL-6水平相应升高。结论：这项研究的新发现是，随着组织损伤，CC趋化因子嗜酸性粒细胞趋化因子、MCP-3、MDC、MIP-3β以时间依赖的方式显著增加。这些数据表明，对IR损伤的反应是复杂的，在各种白细胞上活跃的趋化因子可能在诱导局部和远程组织损伤中发挥作用。
Introduction: Trauma patients who develop multi-organ dysfunction have increased systemic levels of chemotactic cytokines. Ischemia-reperfusion (IR) injury to the gut may play a role. The purpose of this study was to examine chemokine production in a mouse model of mesenteric IR injury. Given the pre-eminent role of the neutrophil, there has been much investigation of the CXC chemokines, but very limited research on the CC and XC chemokines. We hypothesized that intestinal IR injury would induce remote organ injury and enhance serum CC and XC chemokine levels. Methods: Fasted female C57BL6 mice were anesthetized prior to laparotomy. In IR animals, the superior mesenteric artery (SMA) was occluded for 30, 45, or 75 min, while controls underwent sham laparotomy, n = 5-7 per group. After the indicated time point, the incision was closed and the mouse was allowed to recover for six hours. Following euthanasia, serum levels of 15 chemokines (10 CC, 4 CXC, and 1 XC) were assessed and histopathologic analyses performed. Results: Seventy-five minutes of SMA occlusion was the key time frame for significant serum cytokine level up-regulation, intestinal and remote organ injury, and neutrophil influx into tissues. With 75 min of intestinal ischemia, significantly elevated serum levels, as compared to shams, were noted for seven CC chemokines: MCP-1, MCP-3, MIP-1 beta, MIP-3 beta, eotaxin, MDC, and RANTES. Levels of the XC chemokine lymphotactin also increased. Levels of MIP-2, IP-10, and KC/GRO (CXC chemokines) rose significantly. MIP-1 alpha levels were only significantly increased at 45 min IR. We did not find any significant IR injury-induced changes in levels of MCP-5, MIP-1 gamma, or GCP-2, at any ischemia time frame. Serum levels of IL-6 correspondingly increased significantly with longer ischemia times. Conclusions: The novel finding of this study is the demonstration of significant systemic increases in the CC chemokines eotaxin, MCP-3, MDC, MIP-3 beta in a time-dependent manner, along with tissue injury. The data suggest a complex response to IR injury whereby chemokines that are active on a variety of leukocytes may play a role in inducing local and remote tissue injury.