title: Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells.
abstract: A fundamental element of acute lung injury (ALI) is the inflammation that is part of the body's immune response to a variety of local or systemic stimuli. Lipoxins (LXs) are important endogenous lipids that mediate resolution of inflammation. Previously, we demonstrated that LXA4 reduced the LPS inhalation-induced pulmonary edema, neutrophil infiltration and TNF-α production in mice. With the same model, the current investigation focused on the role of the airway epithelium, a first-line barrier and a prime target of inhaled toxicants. We report that LXA4 strongly inhibited LPS-induced ALI in mice, in part by protecting the airway epithelium and preserving the E-cadherin expression and airway permeability. Using a cryo-imaging assay and fluorescence detection, LXA4 was shown to block LPS-induced ROS generation and preserve mitochondrial redox status both in vivo and in vitro. To further assess whether and how NF-E2-related factor 2 (Nrf2) was involved in the protective effect of LXA4, fluorescence resonance energy transfer (FRET) analysis was employed in human epithelial cell line (16HBE), to determine the relative distance between Nrf2 and its negative regulator or cytosolic inhibitor, Kelch-like ECH-associated protein 1 (Keap1). It provided us the evidence that LXA4 further promoted the dissociation of Nrf2 and Keap1 in LPS-treated 16HBE cells. The results also showed that LXA4 activates Nrf2 by phosphorylating it on Ser40 and triggering its nuclear translocation. Moreover, when the plasmid expression dominant negative mutation of Nrf2 was transfected as an inhibitor of wild-type Nrf2, the protective effect of LXA4 on E-cadherin expression was almost completely blocked. These results provide a new mechanism by which LXA4 inhibits LPS-induced ALI through Nrf2-mediated E-cadherin expression.
authors: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors: Xue
authors: X
authors: Cheng
authors: Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China; Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin 541001, China.
authors: Songqing
authors: S
authors: He
authors: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China; MoE Key Laboratory for Biomedical Photonics, Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China.
authors: Jing
authors: J
authors: Yuan
authors: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors: Shuo
authors: S
authors: Miao
authors: Department of Nephrology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Hongyu
authors: H
authors: Gao
authors: Department of Emergency, Union Hospital, Huanzhong University of Science and Technology, Wuhan 430022, China.
authors: Jingnong
authors: J
authors: Zhang
authors: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China; MoE Key Laboratory for Biomedical Photonics, Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China.
authors: Yang
authors: Y
authors: Li
authors: Heart and Lung Institute of Utah, Murray, UT 84107, United States.
authors: Wei
authors: W
authors: Peng
authors: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: wpingwp@mails.tjmu.edu.cn.
authors: Ping
authors: P
authors: Wu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D044045:Lipoxins / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015820:Cadherins; D008070:Lipopolysaccharides; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C040527:lipoxin A4
keywords: Acute lung injury; Airway epithelium; E-Cadherin; LXA(4); Nrf2