Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
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DOI：
10.1172/jci97912
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发表时间：
2018-11-01
影响因子：
15.9
通讯作者：
Seufferlein, Thomas
中科院分区：
文献类型：
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作者：
Armacki, Milena;Trugenberger, Anna Katharina;Seufferlein, Thomas
肠上皮细胞凋亡失调会引发肠道损伤，改变肠道屏障，并可能促进细菌易位，导致全身炎症反应综合征（SIRS）和/或多器官功能障碍综合征（MODS）。多种胃肠道疾病，包括炎症性肠病，与肠细胞凋亡有关。同样，重症患者也会出现肠道通透性过高和肠道衰竭，从而使肠道成为 SIRS 病理学的中心。细胞凋亡和免疫调节功能的调节归因于三十八阴性激酶 1 (TNK1)，其活性仅通过表达来调节。我们研究了 TNK1 对肠道完整性的影响及其在 MODS 中的作用。 TNK1 表达诱导隐窝特异性细胞凋亡，导致细菌易位、随后的感染性休克和早期死亡。从机制上讲，TNK1 体内表达导致 STAT3 磷酸化、p65 核转位以及 IL-6 和 TNF-α 的释放。 TNF-α 中和抗体部分阻止了肠道损伤的发展。相反，肠道特异性删除 TNK1 可保护肠粘膜免受实验性结肠炎的影响，并阻止肠道中细胞因子的释放。最后，在小鼠和猪创伤模型以及人类炎症性肠病中，发现 TNK1 在肠道中失调。因此，TNK1 可能是 MODS 期间预防多个器官（尤其是肠道）损伤的靶标。
Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-alpha. A TNF-alpha neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.