Department of Respiratory and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
Histol Histopathol. 2021 Jan;36(1):101-112. doi: 10.14670/HH-18-283. Epub 2020 Nov 20.
To examine the effect of the BRD4 inhibitor JQ1 on mice with chronic obstructive pulmonary disease (COPD) via NF-κB.
COPD models constructed by exposure to cigarette smoke and intratracheal instillation of lipopolysaccharides (LPS) in mice were treated with JQ1 (15, 25 or 50 mg/kg). HE staining was performed to observe histopathological changes in the lung tissues. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of IL-10, IFN-γ, IL-17, IL-1β, IL-6, TNF-α, MMP-2, MMP-9, MDA, SOD, T-AOC and HO-1, and gelatin zymography assays were used to examine MMP-2 and MMP-9 activity. A TransAMTM NF-κB p65 detection kit was used to test NF-κB p65/DNA binding activity. Western blotting was conducted to analyze NF-κB p65 in the nucleus and its acetylation.
JQ1 dose-dependently improved the histopathological changes in the lung tissues and decreased the mean linear intercept (MLI), destructive index and inflammatory score of the mice with COPD. The mice with COPD showed increased levels of MMP-2, MMP-9, IFN-γ, IL-17, IL-1β, IL-6 and TNF-α with decreased IL-10 level; these changes were reversed by JQ1 in a dose-dependent manner. In addition, JQ1 reduced the MDA level and increased the SOD, HO-1 and T-AOC levels in mice with COPD, with suppression of NF-κB p65 expression in the nucleus, NF-κB/p65 (Lys310) acetylation and NF-κB p65/DNA binding activity in the lung tissues.
The BRD4 inhibitor JQ1 can downregulate MMP-2 and MMP-9 expression, reduce inflammatory responses, and alleviate oxidative stress in mice with COPD, and this mechanism might be related to the inhibition of NF-κB.
通过 NF-κB 研究 BRD4 抑制剂 JQ1 对慢性阻塞性肺疾病（COPD）小鼠的作用。
通过香烟烟雾暴露和气管内滴注脂多糖（LPS）构建 COPD 模型，用 JQ1（15、25 或 50mg/kg）进行治疗。行 HE 染色观察肺组织的组织病理学变化。采用酶联免疫吸附试验（ELISA）检测白细胞介素 10（IL-10）、干扰素-γ（IFN-γ）、白细胞介素 17（IL-17）、白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）、肿瘤坏死因子-α（TNF-α）、基质金属蛋白酶 2（MMP-2）、基质金属蛋白酶 9（MMP-9）、丙二醛（MDA）、超氧化物歧化酶（SOD）、总抗氧化能力（T-AOC）和血红素加氧酶 1（HO-1）水平，明胶酶谱法检测 MMP-2 和 MMP-9 活性。采用 TransAMTM NF-κB p65 检测试剂盒检测 NF-κB p65/DNA 结合活性。采用 Western blot 分析细胞核中 NF-κB p65 及其乙酰化。
JQ1 呈剂量依赖性改善 COPD 小鼠的肺组织组织病理学变化，降低 COPD 小鼠的平均线性截距（MLI）、破坏指数和炎症评分。COPD 小鼠 MMP-2、MMP-9、IFN-γ、IL-17、IL-1β、IL-6 和 TNF-α水平升高，IL-10 水平降低；JQ1 呈剂量依赖性逆转这些变化。此外，JQ1 降低 COPD 小鼠 MDA 水平，增加 SOD、HO-1 和 T-AOC 水平，抑制肺组织核中 NF-κB p65 表达、NF-κB/p65（Lys310）乙酰化和 NF-κB p65/DNA 结合活性。
BRD4 抑制剂 JQ1 可下调 COPD 小鼠的 MMP-2 和 MMP-9 表达，减轻炎症反应，缓解氧化应激，其机制可能与抑制 NF-κB 有关。
