Therapeutic potential of BLT1 antagonist for COPD: involvement of inducing autophagy and ameliorating inflammation
Received 12 May 2019
Accepted for publication 10 August 2019
Published 4 September 2019 Volume 2019:13 Pages 3105—3116
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Georgios D. Panos
Li Zhang1,2, Jingwen Huang1,2, Ran Dong3, Yun Feng1,2, Min Zhou1,2
1Department of Respiratory and Critical Care Medicine, Shanghai Institute of Respiratory Disease, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
Correspondence: Min Zhou
Department of Pulmonary and Critical Care Medicine, Shanghai Institute of Respiratory Disease, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.197 Ruijin Er Road, Shanghai 200025, People’s Republic of China
Tel +86 216 437 0045
Fax +86 216 467 4301
Purpose: Leukotriene B4 (LTB4) is a major pro-inflammatory mediator that leads to the persistence of chronic inflammation in chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate therapeutic potential of BLT1 antagonist for cigarette smoke (CS)-induced COPD and to explore the underlying mechanism.
Materials and methods: In vitro, autophagy proteins were determined by Western blotting in RAW264.7 macrophages treated with U75302 (BLT1 antagonist) or autophagy inhibitor in cigarette smoke extract-induced inflammation. In vivo, C57BL/6J mice were randomly divided into three groups: Control group, CS group and CS+U75302 group. After 12-week exposure, histological analysis and lung function tests were performed to evaluate the inflammatory infiltration and emphysema. The expression of inflammatory cytokines was measured by real-time PCR and enzyme-linked immunosorbent assay. Immunohistochemical analysis and Western blotting detected the expression of autophagy-related proteins. Transmission electron microscopy (TEM) showed the alterations of autophagosomes and lysosomes.
Results: Lower levels of inflammatory factors and autophagy markers were detected in U75302-treated cells and mice after CS exposure than control. In vitro, LC3 mRNA expression was elevated when treated with U75302. Autophagy inhibition resulted in augmented inflammatory response and autophagy proteins even with U75302 treatment. Furthermore, BLT1 antagonist decreased the number of lysosomes and autophagosomes in alveolar macrophages of mice and potentially enhanced the expression of transcriptional activation of transcription factor-EB (TFEB) in vitro and vivo.
Conclusion: Insufficient autophagy of macrophages was associated with LTB4-mediated inflammation in CS-exposure models. BLT1 antagonist ameliorated inflammatory response through inducing autophagy.
Keywords: cigarette smoke, inflammation, autophagy, BLT1 antagonist, COPD
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