Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Author:

Jiang Yujie12,Zeng Yi3,Huang Xia12,Qin Yueqiu4,Luo Weigui2,Xiang Shulin5,Sooranna Suren R.6,Pinhu Liao7

Affiliation:

1. The First Clinical Medical College of Jinan University, Guangzhou, Guangdong Province, China;

2. Department of Respiratory Medicine;

3. Department of Central Laboratory, Youjiang Medical University for Nationalities, Baise, Guangxi, China;

4. Department of Digestive, Youjiang Medical University for Nationalities, Baise, Guangxi, China; Youjiang Medical University for Nationalities, Baise, Guangxi, China;

5. Department of Intensive Care Unit, the People's Hospital of Guangxi, Nanning, Guangxi, China;

6. Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdon; and

7. Department of Intensive Care Medicine, Youjiang Medical University for Nationalities, Baise, Guangxi, China

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.

Funder

National Natural Science Foundation of China (NSFC)

Science and Technique Research Projects of Guangxi

Key Programs of Naaural Science Foundation of Guangxi

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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