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

Abstract

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.

• Authors: Yan Liu, Zhi-Zhen Huang, Li Min, Zhi-Feng Li, Kui Chen
• Journal: Histology and histopathology (Histol Histopathol) Vol. 36 Issue 1 Pg. 101-112 (Jan 2021) ISSN: 1699-5848 [Electronic] Spain
• PMID: 33215396 (Publication Type: Journal Article)

Chemical References

• (+)-JQ1 compound
• Azepines
• Brd4 protein, mouse
• Cytokines
• Lipopolysaccharides
• NF-kappa B p50 Subunit
• Nuclear Proteins
• Transcription Factors
• Triazoles
• Nfkb1 protein, mouse

Topics

• Animals
• Azepines (pharmacology)
• Cytokines (metabolism)
• Gene Expression Regulation
• Inflammation
• Leukocytes (cytology)
• Lipopolysaccharides (metabolism)
• Lung (pathology)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B p50 Subunit (biosynthesis)
• Nuclear Proteins (antagonists & inhibitors, genetics)
• Oxidative Stress
• Pulmonary Disease, Chronic Obstructive (drug therapy, genetics, metabolism)
• Respiratory Function Tests
• Signal Transduction
• Transcription Factors (antagonists & inhibitors)
• Triazoles (pharmacology)