BRD4 is involved in viral exacerbation of chronic obstructive pulmonary disease

Abstract

Background Our previous studies have suggested that bromodomain protein 4 (BRD4) is increased in the lung of stable chronic obstructive pulmonary disease (COPD) patients, which has been shown to be involved in inflammatory responses. We investigated its role in the viral exacerbation of COPD. Methods BRD4, interleukin (IL)-6 and IL-8 were measured in the blood and sputum of stable COPD patients and patients with viral exacerbation. Mice were exposed to cigarette smoke (CS) and/or infected with influenza virus as an in vivo model. BRD4, IL-6 and keratinocyte-derived chemokine (KC) were measured in the lung. BEAS-2B cells were treated with CS extract and/or influenza virus as an in vitro model. BRD4, IL-6 and IL-8 were measured in the cells and/or culture supernatant. Results BRD4 was increased in COPD patients with viral exacerbation compared with those in stable condition and its expression was correlated with IL-6 and IL-8 expression. Inflammatory cells, IL-6, KC and BRD4 were synergistically induced in the lung of mice by viral infection and CS exposure, and the former three were decreased by JQ1 (BRD4 inhibitor) treatment. IL-6, IL-8 and BRD4 were significantly induced by CS extract and influenza virus in bronchial epithelial cells, and this upregulation was suppressed by knockdown of BRD4 expression. Conclusions Our findings indicate that CS and viruses may synergistically induce IL-6 and IL-8 expression through their synergistic induction of BRD4 expression, which might contribute to the enhanced inflammatory response in the viral exacerbation of COPD.

Targeting BRD4 Ameliorates Experimental Emphysema by Disrupting Super-Enhancer in Polarized Alveolar Macrophage

“…Moreover, the results exhibited a signi cant correlation between BRD4 expression and macrophage with the help of GSEV analysis, which was veri ed in the experimental emphysema mouse model. The present outcomes were also supported by a study from Duan et al (2023) [51], which reported that BRD4 expression was strongly associated with COPD viral exacerbation and also demonstrated that BRD4 expression both in the blood and in the sputum were signi cantly correlated with FEV1% predicted in stable COPD patients. Tang et al (2019) [52] reported a correlation between BRD4 expression and lung function by analyzing COPD lung tissue samples and detected an increased expression of BRD4 in the nuclei of bronchial epithelial cells by immuno-histo uorescence.…”

BRD4 as a Therapeutic Target in Pulmonary Diseases

“…This study demonstrates the efficacy of BETi in reversing established preclinical COPD. During viral exacerbation, researchers recently noticed elevated mRNA expression of BRD4 in the blood and sputum of COPD patients compared to those in a stable state [54]. Consistently, elevated BRD4 expression was found in the lungs of mice undergoing influenza infection and cigarette smoke exposure.…”

Histone acetylation, BET proteins, and periodontal inflammation

“…In stable or viral exacerbation of chronic obstructive pulmonary disease patients, BRD4 mRNA levels were elevated in patient blood and sputum (Duan et al, 2023). BRD4 expression was also upregulated up to sevenfolds in severe early-onset preeclampsia placenta (Liong et al, 2018).…”

“…For example, BRD4 expression was increased in both pulmonary artery and coronary artery smooth muscle cells in rat models of pulmonary arterial hypertension (PAH) and in humans with PAH (Meloche et al., 2017). In stable or viral exacerbation of chronic obstructive pulmonary disease patients, BRD4 mRNA levels were elevated in patient blood and sputum (Duan et al., 2023). BRD4 expression was also upregulated up to sevenfolds in severe early‐onset preeclampsia placenta (Liong et al., 2018).…”