title: 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.
abstract: Resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) (RvD1), generated from ω-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 μg/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) α, γ, Na,K-adenosine triphosphatase (ATPase) α1, β1 subunit protein expression and Na,K-ATPase activity. In primary rat alveolar type II epithelial cells stimulated with LPS, RvD1 not only upregulated ENaC α, γ and Na,K-ATPase α1 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 α 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.
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital of Wenzhou Medical University, Zhejiang 325027, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: Yi-Lan
authors.initials: YL
authors.lastname: Zhang
authors.forename: Hai-Xu
authors.initials: HX
authors.lastname: Wen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Hao
authors.forename: Ye
authors.initials: Y
authors.lastname: Gao
authors.forename: Liang-Min
authors.initials: LM
authors.lastname: Yang
authors.forename: Fang Gao
authors.initials: FG
authors.lastname: Smith
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Huang
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Jin
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D044067:Receptors, Lipoxin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP; D004281:Docosahexaenoic Acids; D053503:Epithelial Sodium Channels; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D044067:Receptors, Lipoxin; D000254:Sodium-Potassium-Exchanging ATPase; C482540:lipoxin A(4) receptor, rat; C518399:resolvin D1