Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway
Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway
复制标题
Maresin1 通过 ALX/PI3K/Nedd4-2 途径通过肺泡上皮钠通道 Na,K-ATP 酶刺激肺泡液清除
DOI：
10.1038/labinvest.2016.150
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发表时间：
2017-05-01
影响因子：
5
通讯作者：
Jin, Sheng-Wei
中科院分区：
文献类型：
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作者：
Zhang, Jun-Li;Zhuo, Xiao-Jun;Jin, Sheng-Wei
Maresin1 （MaR1）是一种新的二十二碳六烯酸衍生的促溶解剂，可促进炎症的消退。在这项研究中，我们试图探讨MaR1在lps诱导的急性肺损伤中调节肺泡液清除（AFC）的作用及其机制。在LPS （14 mg/kg）给药后8 h静脉注射或滴注（200 ng/kg）给药，并测定活鼠AFC。在原代大鼠肺泡II型上皮细胞中，将100 nM的MaR1添加到脂多糖培养液中6小时，MaR1显著刺激lps诱导的肺损伤中的AFC，结果是肺水肿和肺损伤减少。此外，干预后分离大鼠肺组织蛋白，我们发现MaR1改善上皮钠通道（ENaC）、Na、k -腺苷三磷酸酶（ATPase）蛋白表达和Na、k - atp酶活性。在体内，MaR1通过PI3k/Akt通路下调Nedd4-2蛋白表达，但不通过PI3k/SGK1通路下调Nedd4-2蛋白表达。在LPS刺激的原代大鼠肺泡II型上皮细胞中，mar1上调了质膜中ENaC和Na， k - atp酶蛋白的丰度。最后，脂素A4受体抑制剂（BOC-2）和PI3K抑制剂（LY294002）在体内不仅阻断了MaR1对cAMP/cGMP、磷酸化Akt和Nedd4-2表达的作用，还抑制了MaR1对AFC的作用。总之，MaR1刺激AFC的机制部分依赖于肺泡上皮ENaC和Na， k - atp酶通过ALX/PI3K/Nedd4-2信号通路激活。我们的研究结果揭示了肺水肿液体重吸收的新机制，MaR1可能为解决ALI/ARDS提供新的治疗方法。
Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h. MaR1 markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema and lung injury. In addition, rat lung tissue protein was isolated after intervention, and we found MaR1 improved epithelial sodium channel (ENaC), Na,K-adenosine triphosphatase (ATPase) protein expression and Na,K-ATPase activity. MaR1 down-regulated Nedd4-2 protein expression though PI3k/Akt but not though PI3k/SGK1 pathway in vivo. In primary rat alveolar type II epithelial cells stimulated with LPS, MaR1-upregulated ENaC and Na,K-ATPase protein abundance in the plasma membrane. Finally, the lipoxin A4 Receptor inhibitor (BOC-2) and PI3K inhibitor (LY294002) not only blocked MaR1's effects on cAMP/cGMP, the expression of phosphorylated Akt and Nedd4-2, but also inhibited the effect of MaR1 on AFC in vivo. In conclusion, MaR1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. Our findings reveal a novel mechanism for pulmonary edema fluid reabsorption and MaR1 may provide a new therapy for the resolution of ALI/ARDS.