title: Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model.
abstract: Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.
authors.affiliation: The First Clinical Medical College of Jinan University, Guangzhou, Guangdong Province, China.|Department of Respiratory Medicine.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Central Laboratory, Youjiang Medical University for Nationalities, Baise, Guangxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: The First Clinical Medical College of Jinan University, Guangzhou, Guangdong Province, China.|Department of Respiratory Medicine.
authors.forename: Xia
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Digestive, Youjiang Medical University for Nationalities, Baise, Guangxi, China; Youjiang Medical University for Nationalities, Baise, Guangxi, China.
authors.forename: Yueqiu
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Respiratory Medicine.
authors.forename: Weigui
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Intensive Care Unit, the People's Hospital of Guangxi, Nanning, Guangxi, China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdon; and.
authors.forename: Suren R
authors.initials: SR
authors.lastname: Sooranna
authors.affiliation: Department of Intensive Care Medicine, Youjiang Medical University for Nationalities, Baise, Guangxi, China liaopinhu@163.com.
authors.forename: Liao
authors.initials: L
authors.lastname: Pinhu
mesh_terms: D000072283:A549 Cells; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010648:Phenylacetates / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; C539821:NR4A1 protein, human; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; D012333:RNA, Messenger; C531461:cytosporone B; D048051:p38 Mitogen-Activated Protein Kinases
keywords: acute respiratory distress syndrome; nuclear factor-κB; p38 mitogen-activated protein kinase