Propofol attenuated liver transplantation-induced acute lung injury via connexin43 gap junction inhibition.
Propofol attenuated liver transplantation-induced acute lung injury via connexin43 gap junction inhibition.
复制标题
异丙酚通过抑制 connexin43 间隙连接来减轻肝移植引起的急性肺损伤。
DOI：
10.1186/s12967-016-0954-1
复制
发表时间：
2016-06-30
影响因子：
7.4
通讯作者：
Hei Z
中科院分区：
文献类型：
--
作者：
Yuan D;Su G;Liu Y;Chi X;Feng J;Zhu Q;Cai J;Luo G;Hei Z
肝移植术后急性肺损伤（acutelunginjury，ALI）是肝移植术后严重的并发症，严重影响患者的生存率。然而，其机制尚不清楚，有效的治疗方法仍然缺乏。本研究旨在探讨异丙酚对肝移植后急性肺损伤的影响及其机制是否与连接蛋白43（Cx43）的改变有关。作者推测，内毒素诱导的Cx43间隙连接（GJ）增强在介导肝移植后ALI中起关键作用，并且已知抑制间隙连接的麻醉剂丙泊酚预处理可以提供有效的保护。雄性Sprague-Dawley大鼠在不存在或存在选择性Cx43抑制剂庚醇（0.1 mg/kg）和丙泊酚（50 mg/kg）（临床麻醉中常用的麻醉剂）治疗的情况下进行自体原位肝移植（AOLT）。在体外研究中，BEAS-2B细胞，一种表达Cx43的肺上皮细胞系，暴露于脂多糖（LPS），这是导致ALI的主要原因。Cx43 GJ的功能受Cx43特异性抑制剂gap 26（300 μM）或增强剂、视黄酸（10 μM）和两种特异性siRNA的调控。与假手术组相比，AOLT可导致大鼠急性肺损伤，血浆内毒素水平明显升高。Cx43抑制通过减少炎症反应降低ALI。在体外研究中，LPS诱导的BEAS-2B细胞损伤通过Cx43功能抑制而减弱，但通过增强而放大。另一个重要发现是丙泊酚降低Cx43功能，保护LPS介导的BEAS-2B细胞损伤或AOLT诱导的ALI，其机制也与炎症反应减少有关。Cx43在肝移植后急性肺损伤中起重要作用。异丙酚降低Cx43的功能，并在体内和体外对ALI的保护。这一发现为肝移植术后器官保护的靶向干预提供了新的依据。
Postoperative acute lung injury (ALI) is a severe complication after liver transplantation, which influences patient survival rate obviously. However, its mechanisms are unclear and effective therapies are still lacking. The current study focused on effects of propofol on liver transplantation-induced ALI and whether its underlying mechanism was relative with connexin43 (Cx43) alternation. The authors postulated that endotoxin induced enhancement of Cx43 gap junction (GJ) plays a critical role in mediating post liver transplantation ALI and that pretreatment with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. Male Sprague–Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx43 inhibitor, enanthol (0.1 mg/kg) and propofol (50 mg/kg), a commonly used anesthetic in clinical anesthesia. In vitro study, BEAS-2B cells, a kind of lung epithelial cell line expressing Cx43, exposed to lipopolysaccharide (LPS), which mainly contributed to ALI. Function of Cx43 GJ was regulated by Cx43 specific inhibitors, gap26 (300 μM) or enhancer, retinoic acid (10 μM) and two specific siRNAs. Compared with the sham group, AOLT results in ALI obviously with plasma endotoxin increase. Cx43 inhibition decreased ALI through inflammatory reaction reduction. In vitro studies, LPS-induced BEAS-2B cells damage was attenuated by Cx43 function inhibition, but amplified by enhancement. Another important finding was propofol reduced Cx43 function and protected against LPS-mediated BEAS-2B cells damage or AOLT-induced ALI, mechanisms of which were also associated with inflammatory reaction decrease. Cx43 plays a vital role in liver transplantation-induced ALI. Propofol decreased Cx43 function and protected against ALI in vivo and in vitro. This finding provide a new basis for targeted intervention of organ protection in liver transplantation, even in other kinds of operations.