Transglutaminase type II is involved in the pathogenesis of endotoxic shock
Transglutaminase type II is involved in the pathogenesis of endotoxic shock
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DOI：
10.4049/jimmunol.180.4.2616
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Piacentini, Mauro
中科院分区：
文献类型：
--
作者：
Falasca, Laura;Farrace, Maria Grazia;Piacentini, Mauro
脓毒症的发病机制以宿主不能调节炎症反应为特征，其结果是炎症过程的失调导致器官功能障碍和死亡。转谷氨酰胺酶II型(TG2)的表达改变与许多炎症性疾病的发生有关。因此，在本研究中，我们质疑TG2是否也参与了感染性休克体内发生的病理性炎症失调。为此，我们以TG2基因敲除小鼠为实验模型，用脂多糖诱导感染性休克过程。有趣的是，我们的结果表明，TG2消融导致了对实验性脓毒症的部分抵抗。TG2(-/-)小鼠存活率的提高反映在器官损伤的急剧减少，突出表现为中性粒细胞在肾脏和腹膜中的有限渗透，以及促炎介质和线粒体功能的更好的动态平衡。我们还发现，在野生型小鼠中，内毒素血症时TG2的表达增加，并直接参与了核因子-kappaB的激活机制，可能导致炎症过程中持续的激活循环，从而促进败血症发病机制的发展。我们认为，抑制TG2可能是治疗脓毒症相关炎症过程的一种新方法。
The pathogenesis of sepsis is characterized by the inability of the host to regulate the inflammatory response, and as a consequence, dysregulated inflammatory processes induce organ dysfunctions and death. Altered transglutaminase type II (TG2) expression is associated with the development of many inflammatory diseases. Therefore, in this study, we questioned whether TG2 could also contribute to the pathological inflammatory dysregulation occurring in septic shock in vivo. To this aim, we used as an experimental model the TG2 knockout mice, in which the process of septic shock was elicited by treatment with LPS. Interestingly, our results demonstrated that TG2 ablation leads to partial resistance to experimental sepsis. The increased survival of TG2(-/-) mice was reflected in a drastic reduction of organ injury, highlighted by a limited infiltration of neutrophils in kidney and peritoneum and by a better homeostasis of the proinflammatory mediators as well as mitochondrial function. We also showed that in wild-type mice, the TG2 expression is increased during endotoxemia and, being directly involved in the mechanisms of NF-kappa B activation, it may cause a continuous activation cycle in the inflammatory process, thus contributing to development of sepsis pathogenesis. We propose that the inhibition of TG2 could represent a novel approach in the treatment of inflammatory processes associated with sepsis.