Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway.
Lab Invest
; 97(5): 543-554, 2017 05.
Article
in En
| MEDLINE
| ID: mdl-28218740
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.
Full text:
1
Database:
MEDLINE
Main subject:
Signal Transduction
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Docosahexaenoic Acids
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Phosphatidylinositol 3-Kinases
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Ubiquitin-Protein Ligases
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Receptors, Lipoxin
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Epithelial Sodium Channels
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Acute Lung Injury
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Endosomal Sorting Complexes Required for Transport
Limits:
Animals
Language:
En
Journal:
Lab Invest
Year:
2017
Type:
Article
Affiliation country:
China