Targeting Rev-Erbα to protect against ischemia-reperfusion-induced acute lung injury in rats

Respiratory Research

Research

Wen-I Liao¹  Shih-En Tang²  Shi-Jye Chu³  Shu-Yu Wu⁴  Hsin-Ping Pao⁴ 

[1] Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri- Service General Hospital, National Defense Medical Center, No. 325, Section 2, Chenggong Road, Neihu, Taipei114, Taiwan;Division of Rheumatology, Immunology, and Allergy, Department of Internal Medicine, Tri- Service General Hospital, National Defense Medical Center, Taipei, Taiwan;Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan;

关键词: Acute lung injury;    Ischemia-reperfusion;    Circadian clocks;    Rev-Erbα;    SR9009;    SR8278;   

DOI  :  10.1186/s12931-023-02547-7

 received in 2023-08-13, accepted in 2023-09-22,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe dysregulation of local circadian clock has been implicated in the pathogenesis of a broad spectrum of diseases. However, the pathophysiological role of intrinsic circadian clocks Rev-Erbα in ischemia-reperfusion (IR)-induced acute lung injury (ALI) remains unclear.MethodsThe IR-ALI model was established by subjecting isolated perfused rat lungs to 40 min of ischemia followed by 60 min of reperfusion. Rats were randomly assigned to one of six groups: control, control + SR9009 (Rev-Erbα agonist, 50 mg/kg), IR, and IR + SR9009 at one of three dosages (12.5, 25, 50 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed. In vitro experiments utilized mouse lung epithelial cells (MLE-12) exposed to hypoxia-reoxygenation (HR) and pretreated with SR9009 (10 µM/L) and Rev-Erbα siRNA.ResultsSR9009 exhibited a dose-dependent reduction in lung edema in IR-ALI. It significantly inhibited the production of TNF-α, IL-6, and CINC-1 in BALF. Moreover, SR9009 treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, a SR9009 mitigated IR-induced apoptosis and mitogen-activated protein kinase (MAPK) activation in injured lung tissue. Finally, treatment with Rev-Erbα antagonist SR8278 abolished the protective action of SR9009. In vitro analyses showed that SR9009 attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR, and these effects were significantly abrogated by Rev-Erbα siRNA.ConclusionsThe findings suggest that SR9009 exerts protective effects against IR-ALI in a Rev-Erbα-dependent manner. SR9009 may provide a novel adjuvant therapeutic approach for IR-ALI.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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