Abstract
Pleural fibrosis is characterized by myofibroblast accumulation and increased expression of collagen and other extracellular matrices due to injury to the pleura and remodeling. Mesothelial to mesenchymal transition (MesoMT) is an important pathological event that contributes to the pool of myofibroblasts although its regulation remains incompletely understood. Recent research has reported the role of BRD4, a member of the bromodomain extra terminal domain (BET) family, in developing fibrosis in the heart and the lungs. One recent study showed that MEOX1 is a downstream target of BRD4 and mediated cardiac fibroblast activation. Our joint work also demonstrated that NOX4 is implicated in pleural MesoMT. However, it remains unclear about the role of BRD4 in pleural fibrosis, particularly, the mechanisms of BRD4 in regulation of MesoMT. In this study, we hypothesized that BRD4 mediates MesoMT through MEOX1 and NOX4 and contributes to pleural fibrosis development. To test this hypothesis, primary human pleural mesothelial cells (HPMCs) were treated with different doses of ARV-825 or JQ1, small molecule inhibitors of BETs, followed by TGF-β stimulation to test the effects of BRD4 inhibition on MesoMT. In addition, siRNA targeting BRD4 was used to knock down BRD4, followed by TGF-β treatment to examine its effect on MEOX1, NOX4, and MesoMT markers. The results showed that ARV-825 and JQ1 suppressed TGF-β-induced MEOX1 and NOX4 expression along with MesoMT markers in a dose-dependent manner. In addition, BRD4 knockdown suppressed the expression of MEOX1 and NOX4 at both protein and mRNA levels. Importantly, the knockdown of MEOX1 and NOX4 individually attenuated TGF-β-induced MesoMT marker expression in primary HPMCs. These findings suggest that BRD4 mediates MesoMT through MEOX1 and NOX4 and may hold promise as a novel effective therapeutic target for pleural fibrosis. Further studies can be conducted to investigate the effects of JQ1/ARV-825 in inhibiting pleural fibrosis in vivo. Additionally, a study can be undertaken to find out the effect of JQ1/ARV-825 in suppressing MesoMT and MEOX1/NOX4 expression in vivo, as well as on oxidative stress.
Date of publication
Spring 5-29-2024
Document Type
Thesis
Language
english
Persistent identifier
http://hdl.handle.net/10950/4718
Committee members
Guoqing Qian; Mitsuo Ikebe; Torry Tucker; Xia Guo
Degree
Master of Science
Recommended Citation
Kankam, Felix, "Novel Role and Mechanisms of BRD4 in Mediating Mesothelial to Mesenchymal Transition and Pleural Fibrosis" (2024). Biotechnology Theses. Paper 23.
http://hdl.handle.net/10950/4718