Ecotoxicology and Environmental Safety (Sep 2021)
Novel insights into the role of BRD4 in fine particulate matter induced airway hyperresponsiveness
Abstract
Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.
