Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury
Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury
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DOI：
10.4049/jimmunol.1302421
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发表时间：
2014-04-15
影响因子：
4.4
通讯作者：
Jin, Sheng-Wei
中科院分区：
文献类型：
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作者：
Wang, Qian;Zheng, Xia;Jin, Sheng-Wei
Resolvin D1（7S,8R,17S-三羟基-4Z、9E、11E、13Z、15E、19Z-二十二碳六烯酸）(RvD1) 由 omega-3 脂肪二十二碳六烯酸生成，被认为具有抗炎特性，包括抑制中性粒细胞活化和调节炎症细胞因子。在本研究中，我们试图研究 RvD1 在调节肺泡液清除率 (AFC) 中对 LPS 诱导的急性肺损伤的影响。在体内，注射 RvD1。 v. (5μg/kg)LPS(20mg/kg)给药后8小时，显着刺激LPS引起的肺损伤中的AFC，从而减少肺水肿。此外，干预后分离大鼠肺组织蛋白，我们发现 RvD1 改善了上皮钠通道 (ENaC) α、γ、Na,Kadenosine 三磷酸酶 (ATPase) α 1、β 1 亚基蛋白表达和 Na,K-ATP 酶活性。在用LPS刺激的原代大鼠肺泡II型上皮细胞中，RvD1不仅上调ENaCα、γ和Na,K-ATPase α1亚基蛋白表达，而且增加Na+电流和Na,K-ATPase活性。最后，蛋白激酶A和cGMP不负责RvD1的功能，因为蛋白激酶A抑制剂(H89)和cGMP抑制剂(Rp-cGMP)不会降低RvD1的作用。然而，RvD1受体（2型甲酰肽受体[FPR2]，也称为ALX[脂氧素A4受体]）抑制剂（BOC-2）、cAMP抑制剂（Rp-cAMP）和PI3K抑制剂（LY294002）不仅在体外阻断了RvD1对ENaC α表达的影响，而且在体内也抑制了AFC。总之，RvD1 通过 ALX/cAMP/PI3K 信号通路部分依赖于肺泡上皮 ENaC 和 Na,K-ATPase 激活的机制来刺激 AFC。
Resolvin D1 (7S,8R,17S-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid) (RvD1), generated from omega-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory properties including inhibition of neutrophil activation and regulating inflammatory cytokines. In this study, we sought to investigate the effect of RvD1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. In vivo, RvD1 was injected i. v. (5 mu g/ kg) 8 h after LPS (20 mg/ kg) administration, which markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema. In addition, rat lung tissue protein was isolated after intervention and we found RvD1 improved epithelial sodium channel (ENaC) alpha, gamma, Na,Kadenosine triphosphatase (ATPase) alpha 1, beta 1 subunit protein expression and Na,K-ATPase activity. In primary rat alveolar type II epithelial cells stimulated with LPS, RvD1 not only upregulated ENaC alpha, gamma and Na,K-ATPase alpha 1 subunits protein expression, but also increased Na+ currents and Na,K-ATPase activity. Finally, protein kinase A and cGMP were not responsible for RvD1's function because a protein kinase A inhibitor (H89) and cGMP inhibitor (Rp-cGMP) did not reduce RvD1' s effects. However, the RvD1 receptor (formyl-peptide receptor type 2 [ FPR2], also called ALX [ the lipoxin A4 receptor]) inhibitor (BOC-2), cAMP inhibitor (Rp-cAMP), and PI3K inhibitor (LY294002) not only blocked RvD1' s effects on the expression of ENaC alpha in vitro, but also inhibited the AFC in vivo. In summary, RvD1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na, K-ATPase activation via the ALX/ cAMP/ PI3K signaling pathway.