Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis.
Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis.
复制标题
TLR4/NF-κB激活诱导细胞凋亡介导肝移植后肠损伤
DOI：
10.3892/mmr.2015.4719
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发表时间：
2016-02
影响因子：
3.4
通讯作者：
Hei ZQ
中科院分区：
文献类型：
--
作者：
Yuan DD;Chi XJ;Jin Y;Li X;Ge M;Gao WL;Guan JQ;Zhang AL;Hei ZQ
在肝移植过程中，由于肠道充血，肠道动力和屏障常常受损。肠道细菌和肠源性内毒素进入血流或淋巴系统并移位至其他器官，可导致术后多器官功能障碍（MODF）和全身炎症反应综合征（SIRS），严重影响患者生存。然而，肝移植引起的肠道损伤的机制尚不清楚，缺乏有效的治疗方法。因此，本研究调查这些影响是否与内毒素介导的细胞凋亡。建立大鼠自体原位肝移植（AOLT）模型，观察再灌注后不同时间点的动态肠损伤。测定了内毒素和主要受体toll样受体4（TLR 4）及其下游信号分子核因子-κB（NF-κB）水平的变化。最后采用免疫组化和末端脱氧核苷酸转移酶dUTP缺口末端标记法检测caspase-3表达和肠细胞凋亡。AOLT导致了显著的病理性肠损伤，在再灌注后4或8小时出现最严重的肠损伤。此外，内毒素和炎性细胞因子（如肿瘤坏死因子-α和白细胞介素-6）的水平在此期间达到峰值，并逐渐降至正常水平。TLR 4及其下游NF-κB B的表达、NF-κ B介导的caspase-3的激活和肠细胞凋亡与肠组织病理损伤相一致。因此，肝移植后肠损伤的可能机制与NF-κB激活诱导的细胞凋亡有关。
Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell aapoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.