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Azithromycin attenuates wheezing after pulmonary inflammation through inhibiting histone H3K27me3 hypermethylation
Shuqi Wu1, Xiaochun Tian1, Qian Mao1
1Department of Pediatrics, Guizhou Children's Hospital, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, People's Republic of China.
Background:
Histone methylation modification plays an irreplaceable role in the wheezing diseases. The aim of this study was to explore whether azithromycin (AZM) attenuates post-inflammatory wheezing through inhibiting hypermethylation of histone H3K27me3 mediated by EZH2.
Results:
A randomized controlled trial was conducted on 227 children who underwent fiber-optic bronchoscopy, and bronchoalveolar lavage fluid (BALF) was collected for analyses. The expressions of IL-6, IL-2, NF-κB P65, EZH2 and H3K27me3 in the BALF of wheezing cases were significantly increased when compared with levels in non-wheezing cases (P < 0.05), while IL-10 was decreased (P < 0.05). AZM attenuated the overexpression of NF-κB P65, EZH2 and H3K27me3 in wheezing cases (P < 0.05) and shortened the time of wheezing in wheezing cases (P < 0.05). An in vitro model of inflammation was established using rat alveolar macrophages induced by lipopolysaccharide (LPS). AZM, SN50 (a NK-κB inhibitor) and GSK126 (an EZH2 inhibitor) attenuated the overexpression of EZH2, NF-κB P65 and H3K27me3 induced by LPS in rat alveolar macrophages (P < 0.05). AZM, SN50 and GSK126 normalized the decreased expression of IL-10 induced by LPS in the same samples (P < 0.05). Co-immunoprecipitation results showed that H3K27me3 interacted with EZH2 and NF-κB P65, and immunofluorescence data showed that AZM and SN50 inhibited LPS-induced NF-κB P65 nuclear translocation in rat alveolar macrophages.
Conclusion:
Histone H3K27me3 hypermethylation mediated by EZH2 may be involved in wheezing after pulmonary inflammation. AZM attenuated wheezing after pulmonary inflammation by inhibiting NF-κB P65-related hypermethylation of H3K27me3 mediated by EZH2.
Insights
Azithromycin (AZM) reduces post-inflammatory wheezing by inhibiting EZH2-mediated histone H3K27me3 hypermethylation. This mechanism involves the NF-κB pathway, offering a potential therapeutic strategy for wheezing diseases.
Area of Science:
- Molecular Biology
- Immunology
- Pharmacology
Background:
- Histone methylation, specifically H3K27me3, is implicated in the pathogenesis of wheezing diseases.
- The enzyme EZH2 mediates H3K27me3, a process potentially involved in post-inflammatory wheezing.
Purpose of the Study:
- To investigate if azithromycin (AZM) can attenuate post-inflammatory wheezing.
- To determine if AZM inhibits EZH2-mediated histone H3K27me3 hypermethylation in wheezing.
Main Methods:
- A randomized controlled trial involving 227 children with fiber-optic bronchoscopy and bronchoalveolar lavage fluid (BALF) analysis.
- In vitro studies using rat alveolar macrophages stimulated with lipopolysaccharide (LPS).
- Assays included measurement of IL-6, IL-2, IL-10, NF-κB P65, EZH2, and H3K27me3 levels, co-immunoprecipitation, and immunofluorescence.
Main Results:
- Wheezing cases showed increased expressions of IL-6, IL-2, NF-κB P65, EZH2, and H3K27me3, and decreased IL-10 compared to non-wheezing cases.
- AZM treatment attenuated overexpression of NF-κB P65, EZH2, and H3K27me3, and shortened wheezing duration in children.
- In vitro, AZM, SN50 (NF-κB inhibitor), and GSK126 (EZH2 inhibitor) reduced LPS-induced overexpression of EZH2, NF-κB P65, and H3K27me3, and normalized IL-10 levels. AZM and SN50 inhibited NF-κB P65 nuclear translocation.
Conclusions:
- Histone H3K27me3 hypermethylation mediated by EZH2 is likely involved in post-inflammatory wheezing.
- Azithromycin attenuates post-inflammatory wheezing by inhibiting EZH2-mediated H3K27me3 hypermethylation, potentially through the NF-κB pathway.
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