Therapeutic potential of BLT1 antagonist for COPD: involvement of inducing autophagy and ameliorating inflammation
Identifieur interne : 000326 ( Main/Exploration ); précédent : 000325; suivant : 000327Therapeutic potential of BLT1 antagonist for COPD: involvement of inducing autophagy and ameliorating inflammation
Auteurs : Li Zhang [République populaire de Chine] ; Jingwen Huang [République populaire de Chine] ; Ran Dong [République populaire de Chine] ; Yun Feng [République populaire de Chine] ; Min Zhou [République populaire de Chine]Source :
- Drug Design, Development and Therapy [ 1177-8881 ] ; 2019.
Abstract
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.
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.
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.
Insufficient autophagy of macrophages was associated with LTB4-mediated inflammation in CS-exposure models. BLT1 antagonist ameliorated inflammatory response through inducing autophagy.
Url:
DOI: 10.2147/DDDT.S215433
PubMed: 31564828
PubMed Central: 6732561
Affiliations:
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<front><div type="abstract" xml:lang="en"><sec id="S2001"><title>Purpose</title>
<p>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.</p>
</sec>
<sec id="S2002"><title>Materials and methods</title>
<p>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.</p>
</sec>
<sec id="S2003"><title>Results</title>
<p>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.</p>
</sec>
<sec id="S2004"><title>Conclusion</title>
<p>Insufficient autophagy of macrophages was associated with LTB4-mediated inflammation in CS-exposure models. BLT1 antagonist ameliorated inflammatory response through inducing autophagy.</p>
</sec>
</div>
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