Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury.

Abstract

Lipoxin A4 (LXA4), as an endogenously produced lipid mediator, promotes the resolution of inflammation. Previously, we demonstrated that LXA4 stimulated alveolar fluid clearance through alveolar epithelial sodium channel gamma (ENaC-γ). In this study, we sought to investigate the mechanisms of LXA4 in modulation of ENaC-γ in lipopolysaccharide (LPS)-induced inflammatory lung injury. miR-21 was upregulated during an LPS challenge and downregulated by LXA4 administration in vivo and in vitro. Serum miR-21 concentration was also elevated in acute respiratory distress syndrome patients as compared with healthy volunteers. LPS increased miR-21 expression by activation of activator protein 1 (AP-1). In A549 cells, miR-21 upregulated phosphorylation of AKT activation via inhibition of phosphatase and tensin homolog (PTEN), and therefore reduced the expression of ENaC-γ. In contrast, LXA4 reversed LPS-inhibited ENaC-γ expression through inhibition of AP-1 and activation of PTEN. In addition, an miR-21 inhibitor mimicked the effects of LXA4; overexpression of miR-21 abolished the protective effects of LXA4. Finally, both AKT and ERK inhibitors (LY294002 and UO126) blocked effects of LPS on the depression of ENaC-γ. However, LXA4 only inhibited LPS-induced phosphorylation of AKT. In summary, LXA4 activates ENaC-γ in part via the miR-21/PTEN/AKT signaling pathway.

• Authors: Wei Qi, Hui Li, Xiao-Hong Cai, Jia-Qi Gu, Jin Meng, Hai-Qing Xie, Jun-Li Zhang, Jie Chen, Xian-Guan Jin, Qian Tang, Yu Hao, Ye Gao, Ai-Qing Wen, Xiang-Yang Xue, Fang Gao Smith, Sheng-Wei Jin
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 95 Issue 11 Pg. 1258-68 (Nov 2015) ISSN: 1530-0307 [Electronic] United States
• PMID: 26302186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Epithelial Sodium Channels
• Lipopolysaccharides
• Lipoxins
• MicroRNAs
• lipoxin A4
• mirn21 microRNA, rat
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Pten protein, rat

Topics

• Animals
• Cell Line
• Down-Regulation
• Epithelial Sodium Channels (metabolism)
• Lipopolysaccharides (toxicity)
• Lipoxins (physiology)
• Male
• MicroRNAs (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Pneumonia (chemically induced, enzymology, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Up-Regulation