Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia
Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia
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DOI：
10.4049/jimmunol.1502287
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发表时间：
2017-01-15
影响因子：
4.4
通讯作者：
Tsokos, George C.
中科院分区：
文献类型：
--
作者：
Satyam, Abhigyan;Kannan, Lakshmi;Tsokos, George C.
肠缺血再灌流导致局部和远隔器官损伤，归因于再灌注期的炎症反应。缺血在多大程度上促进了缺血/再灌注损伤的研究还不够深入。在仔细评估缺血30分钟后的肠道组织后，我们注意到野生型小鼠的局部粘膜损伤。这种损伤在C3缺乏的小鼠中显著减轻，这表明C3参与了这一过程。如预期的那样，用眼镜蛇蛇毒因子耗尽循环补体可消除再灌注期结束时记录的损伤，但未能消除缺血期发生的损伤。免疫组织化学研究显示，缺血时的组织损伤与C3/C3片段的表达增加有关，主要是在肠上皮细胞，提示局部补体参与。用Caco 2肠上皮细胞进行的体外研究表明，在存在内毒素或暴露于低氧条件下，细胞产生更高的C3mRNA和C3a片段。CACO2细胞还能产生组织蛋白B和L，抑制组织蛋白抑制C3a的释放。最后，我们发现，接受组织蛋白酶抑制剂治疗的小鼠和组织蛋白酶B缺陷小鼠在缺血期遭受有限的肠道损伤。据我们所知，我们的发现首次表明，在再灌注前的缺血过程中，会发生显著的肠道损伤，这是由于组织蛋白酶依赖的方式激活了肠上皮细胞内的C3。组织蛋白酶活性的调节可能会防止暴露在缺血中的器官损伤。
Intestinal ischemia followed by reperfusion leads to local and remote organ injury attributed to inflammatory response during the reperfusion phase. The extent to which ischemia contributes to ischemia/reperfusion injury has not been thoroughly studied. After careful evaluation of intestinal tissue following 30 min of ischemia, we noticed significant local mucosal injury in wild-type mice. This injury was drastically reduced in C3-deficient mice, suggesting C3 involvement. Depletion of circulating complement with cobra venom factor eliminated, as expected, injury recorded at the end of the reperfusion phase but failed to eliminate injury that occurred during the ischemic phase. Immunohistochemical studies showed that tissue damage during ischemia was associated with increased expression of C3/C3 fragments primarily in the intestinal epithelial cells, suggesting local involvement of complement. In vitro studies using Caco2 intestinal epithelial cells showed that in the presence of LPS or exposure to hypoxic conditions the cells produce higher C3 mRNA as well as C3a fragment. Caco2 cells were also noted to produce cathepsins B and L, and inhibition of cathepsins suppressed the release of C3a. Finally, we found that mice treated with a cathepsin inhibitor and cathepsin B-deficient mice suffer limited intestinal injury during the ischemic phase. To our knowledge, our findings demonstrate for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. Modulation of cathepsin activity may prevent injury of organs exposed to ischemia.