Department of Pediatrics, Guizhou Children's Hospital, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, People's Republic of China.
Clin Epigenetics. 2023 Jan 23;15(1):12. doi: 10.1186/s13148-023-01430-y.
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.
背景：组蛋白甲基化修饰在喘息性疾病中发挥着不可替代的作用。本研究旨在探讨阿奇霉素（AZM）是否通过抑制 EZH2 介导的组蛋白 H3K27me3 过度甲基化来减轻炎症后喘息。
结果：对 227 例行纤维支气管镜检查的儿童进行了一项随机对照试验，并收集支气管肺泡灌洗液（BALF）进行分析。喘息病例的 BALF 中 IL-6、IL-2、NF-κB P65、EZH2 和 H3K27me3 的表达明显高于非喘息病例（P < 0.05），而 IL-10 降低（P < 0.05）。AZM 减弱了喘息病例中 NF-κB P65、EZH2 和 H3K27me3 的过度表达（P < 0.05），并缩短了喘息病例的喘息时间（P < 0.05）。通过脂多糖（LPS）诱导大鼠肺泡巨噬细胞建立炎症体外模型。AZM、SN50（一种 NK-κB 抑制剂）和 GSK126（一种 EZH2 抑制剂）减弱了 LPS 诱导的大鼠肺泡巨噬细胞中 EZH2、NF-κB P65 和 H3K27me3 的过度表达（P < 0.05）。AZM、SN50 和 GSK126 使 LPS 诱导的同样样本中 IL-10 表达降低得到正常化（P < 0.05）。共免疫沉淀结果表明 H3K27me3 与 EZH2 和 NF-κB P65 相互作用，免疫荧光数据表明 AZM 和 SN50 抑制了 LPS 诱导的大鼠肺泡巨噬细胞核内 NF-κB P65 易位。
结论：EZH2 介导的组蛋白 H3K27me3 过度甲基化可能参与了肺炎症后喘息。AZM 通过抑制 EZH2 介导的 NF-κB P65 相关 H3K27me3 过度甲基化来减轻肺炎症后的喘息。
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