Rosiglitazone promotes ENaC-mediated alveolar fluid clearance in acute lung injury through the PPAR/SGK1 signaling pathway
Rosiglitazone promotes ENaC-mediated alveolar fluid clearance in acute lung injury through the PPAR/SGK1 signaling pathway
复制标题
罗格列酮通过 PPAR/SGK1 信号通路促进急性肺损伤中 ENaC 介导的肺泡液清除
DOI：
10.1186/s11658-019-0154-0
复制
发表时间：
2019-05-28
影响因子：
8.3
通讯作者：
Wang, Dao-xin
中科院分区：
文献类型：
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作者：
He, Jing;Qi, Di;Wang, Dao-xin
研究背景肺水肿是急性呼吸窘迫综合征（ARDS）的病理特征之一。上皮钠通道（ENaC）被认为是肺水肿时肺泡液体清除（AFC）的限速因子。过氧化物酶体增殖物激活受体（PPAR）激动剂罗格列酮显示刺激肾脏中ENaC介导的盐吸收。然而，其在肺中的作用仍不清楚。在这里，我们研究了肺中的PPAR激动剂的作用，以了解它是否可以调节AFC在急性肺损伤（ALI）。方法采用C57 BL/6 J小鼠腹腔注射脂多糖（LPS）建立急性肺损伤模型。将小鼠随机分为4组，每组10只。对照组进行假手术，并接受等量的生理盐水。3个实验组分别于腹腔内注入LPS 5 mg/kg，然后腹腔内注射罗格列酮4 mg/kg、罗格列酮4 mg/kg + GW 9662 1 mg/kg或等量生理盐水。观察肺组织形态学改变、支气管肺泡灌洗液（BALF）中TNF-α和IL-1水平、AFC水平、ENaC和血清及糖皮质激素诱导激酶1（SGK 1）的表达。将2型肺泡（AT II）细胞与罗格列酮（15 M）一起孵育，同时加入或不加入GW 9662（10 M）。24 h后检测ENaC和SGK 1的表达。罗格列酮可明显减轻ALI小鼠肺损伤，降低BALF中TNF-α和IL-1水平，增加AFC，促进ENaC和SGK 1表达，而特异性PPAR阻断剂GW 9662可阻断上述作用。在体外，罗格列酮增加ENaC和SGK 1的表达。结论罗格列酮可通过PPAR/SGK 1信号通路改善ENaC介导的AFC，减轻ALI小鼠肺水肿。
BackgroundPulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor (PPAR) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPAR agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this.MethodsOur ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5mg/kg LPS, followed by intraperitoneal injection of 4mg/kg rosiglitazone, 4mg/kg rosiglitazone plus 1mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF- and IL-1 in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of ENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15M) with or without GW9662 (10M). The expressions of ENaC and SGK1 were determined 24h later.ResultsA mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF- and IL-1 levels in the BALF, enhancing AFC, and promoting the expressions of ENaC and SGK1 in ALI mice, which were abolished by the specific PPAR blocker GW9662. In vitro, rosiglitazone increased the expressions of ENaC and SGK1. This increase was prevented by GW9662.ConclusionsRosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPAR/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.