Histol Histopathol

Original Article Open Access

The BRD4 inhibitor JQ1 protects against chronic obstructive pulmonary disease in mice by suppressing NF-κB activation

Yan Liu1, Zhi-Zhen Huang2, Li Min3, Zhi-Feng Li4 and Kui Chen5

1Department of Respiratory and Critical Care Medicine, 2Department of Stomatology, 3Department of Critical Care Medicine, 4Department of Orthopedics, Taihe Hospital, Hubei University of Medicine and 5Department of Emergency Medicine, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei, China


Corresponding Author: Kui Chen, Department of Emergency Medicine, Affiliated Dongfeng Hospital, Hubei University of Medicine, No. 10, Daling Road, Zhangwan District, Shiyan 442000, Hubei, China. e-mail: ckck_kui5@126.com


Summary. Objective. To examine the effect of the BRD4 inhibitor JQ1 on mice with chronic obstructive pulmonary disease (COPD) via NF-κB.
Methods. 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.
Results. 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.
Conclusion. 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. Histol Histopathol 36, 101-112 (2021)

Key words: Chronic obstructive pulmonary disease, BRD4, JQ1, NF-κB

DOI: 10.14670/HH-18-283


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©The Author(s) 2021. Open Access. This article is licensed under a Creative Commons CC-BY International License.