title: Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway.
abstract: 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.
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Zhuo
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Ling-Chun
authors.initials: LC
authors.lastname: Luo
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Ying
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Hua-Wei
authors.initials: HW
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Jing-Xiang
authors.initials: JX
authors.lastname: Yang
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.|Academic Department of Anesthesia, Critical Care, Pain and Resuscitation, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Fang
authors.initials: F
authors.lastname: Gao Smith
authors.affiliation: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Jin
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D008070:Lipopolysaccharides; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000075702:Nedd4 Ubiquitin Protein Ligases; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D004281:Docosahexaenoic Acids; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D008070:Lipopolysaccharides; D000075702:Nedd4 Ubiquitin Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D044067:Receptors, Lipoxin; D000254:Sodium-Potassium-Exchanging ATPase; D044767:Ubiquitin-Protein Ligases; C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; C482540:lipoxin A(4) receptor, rat; C000618479:NEDD4L protein, rat; C000618484:Nedd4 protein, rat