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The BRD4 inhibitor JQ1 protects against chronic obstructive pulmonary disease in mice by suppressing NF-κB activation
Yan Liu1, Zhi-Zhen Huang2, Li Min3
1Department of Respiratory and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
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.
Insights
The BRD4 inhibitor JQ1 effectively treats chronic obstructive pulmonary disease (COPD) in mice by reducing inflammation and oxidative stress. This therapeutic effect is linked to the inhibition of the NF-κB pathway.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Pharmacology
Background:
- Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory lung disease characterized by persistent respiratory symptoms.
- The NF-κB signaling pathway plays a critical role in mediating inflammatory responses and tissue remodeling in COPD.
- Targeting key regulators of NF-κB, such as BRD4, presents a potential therapeutic strategy for COPD.
Purpose of the Study:
- To investigate the therapeutic efficacy of the BRD4 inhibitor JQ1 in mouse models of COPD.
- To elucidate the underlying mechanisms by which JQ1 affects inflammatory and oxidative stress markers in COPD.
- To determine the role of the NF-κB signaling pathway in mediating the effects of JQ1 in COPD.
Main Methods:
- COPD models were established in mice using cigarette smoke exposure and lipopolysaccharide (LPS) instillation.
- Mice were treated with varying doses of JQ1 (15, 25, or 50 mg/kg).
- Histopathological changes, inflammatory cytokine levels (IL-10, IFN-γ, IL-17, IL-1β, IL-6, TNF-α), oxidative stress markers (MDA, SOD, T-AOC, HO-1), matrix metalloproteinase (MMP-2, MMP-9) activity, and NF-κB signaling pathway activation (p65 nuclear translocation, acetylation, and DNA binding) were assessed.
Main Results:
- JQ1 treatment dose-dependently ameliorated lung tissue damage and reduced inflammatory scores in COPD mice.
- JQ1 reversed the elevated levels of pro-inflammatory cytokines (IFN-γ, IL-17, IL-1β, IL-6, TNF-α) and MMPs, while increasing anti-inflammatory IL-10 levels.
- JQ1 suppressed oxidative stress markers, inhibited NF-κB p65 nuclear translocation, acetylation, and DNA binding activity in lung tissues.
Conclusions:
- The BRD4 inhibitor JQ1 demonstrates significant therapeutic potential for COPD by downregulating MMP expression and inflammatory responses.
- JQ1 alleviates oxidative stress in COPD, suggesting a protective role against disease progression.
- The observed therapeutic effects of JQ1 in COPD are likely mediated through the inhibition of the NF-κB signaling pathway.
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