title: 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: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Wei
authors: http://orcid.org/0000-0001-5245-5574
authors: W
authors: Qi
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Hui
authors: H
authors: Li
authors: Department of Pediatrics, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Xiao-Hong
authors: XH
authors: Cai
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Jia-Qi
authors: JQ
authors: Gu
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Jin
authors: J
authors: Meng
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Hai-Qing
authors: HQ
authors: Xie
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Jun-Li
authors: JL
authors: Zhang
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Jie
authors: J
authors: Chen
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Xian-Guan
authors: XG
authors: Jin
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Qian
authors: Q
authors: Tang
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Yu
authors: Y
authors: Hao
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Ye
authors: Y
authors: Gao
authors: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Ai-Qing
authors: AQ
authors: Wen
authors: Department of Microbiology, Wenzhou Medical University, Zhejiang, China.
authors: Xiang-Yang
authors: XY
authors: Xue
authors: Academic Department of Anesthesia, Critical Care, Pain and Resuscitation, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors: Fang
authors: F
authors: Gao Smith
authors: Department of Anesthesia and Critical Care, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
authors: Sheng-Wei
authors: SW
authors: Jin
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D044045:Lipoxins / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D053503:Epithelial Sodium Channels; D008070:Lipopolysaccharides; D044045:Lipoxins; D035683:MicroRNAs; C040527:lipoxin A4; C546082:mirn21 microRNA, rat; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat