IL-1β通过容积调节氯通道LRRC8A介导急性肺损伤肺水清除障碍

Volume-regulated chloride channel (VRCC) plays an important role in the maintenance of constant cell volume and regulation of ion transport. It is recently found that LRRC8A is the molecular basis of VRCC. No studies have been reported for the role of VRCC in the pulmonary edema induced by acute lung injury. IL-1β is one of the most biologically active proinflammatory cytokines and it could increase microvascular lung epithelial permeability which leads to the pulmonary edema. However, the effect of IL-1β in lung epithelial ion transport remains unclear. Our preliminary work showed that LRRC8A channel existed in the human alveolar type II cells and IL-1β could inhibit LRRC8A current. Based on these findings, we hypothesize that LRRC8A channel plays a key role in alveolar fluid clearance (AFC) and IL-1β-induced AFC damage was mediated by LRRC8A. This proposal will focus on the regulation of LRRC8A channel by IL-1β and the mechanism, and discuss the effect of LRRC8A channel regulation on the rat AFC. This study will help to clarify the significance of LRRC8A channel in the IL-1β-induced pulmonary edema in acute lung injury, and provide new possible targets for clinical treatment of pulmonary edema induced by acute lung injury.

容积调节氯通道（VRCC）在维持细胞容积稳定、调节离子转运等方面发挥重要作用，最近发现VRCC的分子基础是LRRC8A。有关VRCC在急性肺损伤所致肺水肿中的作用尚未有研究。IL-1β是生物活性最强的一种促炎症因子，它可以通过增加肺部毛细血管上皮细胞通透性而导致水肿的发生，但是其对肺上皮细胞离子转运的影响仍不完全清楚。我们的前期工作发现人肺泡Ⅱ型上皮细胞存在LRRC8A通道，且IL-1β对此通道电流有抑制作用。据此我们提出假设：LRRC8A通道在肺水清除中起关键作用且IL-1β通过LRRC8A介导急性肺损伤所致肺水清除障碍。本申请拟在此基础之上深入研究IL-1β对LRRC8A通道的调节作用及其分子机制，并探讨LRRC8A通道功能调节对大鼠肺水清除的影响。此研究对深入认识LRRC8A在IL-1β诱发急性肺损伤肺水肿中的作用及机制具有重要意义，同时为临床治疗急性肺损伤所致肺水肿提供新的靶点。

最近研究发现LRRC8A是容积调节氯通道的分子基础，其在维持细胞体积稳定方面发挥重要作用。本研究的目的是探讨LRRC8A在肺水清除中的作用以及炎症因子对LRRC8A的影响及机制。我们利用脂多糖来进行急性肺损伤模型的建立。结果显示，脂多糖处理后，大鼠肺水清除率降低，肺泡灌洗液中炎症因子IL-1β、TNF-α及IL-6的水平显著升高，但肺组织中LRRC8A的表达水平显著降低。此外，LRRC8A的特异性阻断剂DCPIB也可以显著降低肺水清除率。然而将LRRC8A特异性过表达于肺组织中后，肺水清除率显著增加。我们在肺泡II型上皮细胞上也观察了LPS以及炎症因子IL-1β, TNF-α和IL-6对LRRC8A通道电流的影响，结果表明LPS对LRRC8A电流无影响，IL-1β对电流抑制最大，且与p38/ERK的磷酸化抑制有关。总之，研究结果表明LRRC8A在LPS诱导的急性肺损伤肺水清除障碍中发挥了重要作用，且IL-1β通过p38/ERK抑制LRRC8A的功能。本研究结果提示LRRC8A可以作为临床治疗急性肺损伤的潜在靶点。