Pleural fibrosis (PF) is a respiratory disorder that refers to the thickening and scarring of the pleura. Currently, there is a lack of pharmaceutic treatment options for PF. Pleural mesothelial to mesenchymal transition (MesoMT) is a critical process that contributes to the development of PF. Bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, has recently been implicated in a wide range of lung injuries. However, whether BRD4 is involved in regulating MesoMT and the development of PF remains unclear and was explored in this study. Primary human pleural mesothelial cells (HPMCs) were used to test the role of BRD4 in regulating MesoMT. Western blotting and qPCR were conducted to examine protein or mRNA alteration of BRD4 and MesoMT-related markers, such as alpha-smooth muscle actin (α-SMA), collagen type I (Col-1), and fibronectin (FN). Small molecular inhibitors of BRD4 (JQ1 and ARV-825) and small interfering RNA (siRNA) were also employed. We found that BRD4 was induced by TGF-β in HPMCs. Blockade of BRD4 with JQ1 or ARV-825 inhibited TGF-β-induced MesoMT marker expression (α-SMA, Col-1, FN) at both protein and mRNA levels. Consistently, knockdown of BRD4 using siRNA also attenuated MesoMT marker expression (α-SMA, Col-1, FN) induced by TGF-β in HPMCs. In conclusion, BRD4 is involved in MesoMT regulation and may contribute to the development of PF. Future experiments will determine whether BRD4 mediates the induction of MesoMT through the regulation of oxidative stress and the efficacy of targeting BRD4 in the progression of PF induced by Streptococcus pneumoniae.
Date of publication
Guoqing Qian, Ph.D., Mitsuo Ikebe Ph.D., Torry Tucker Ph.D., Xia Guo Ph.D.
Masters of Science in Biotechnology
Adewumi, Joy, "Targeting BRD4 in the Treatment of Pleural Fibrosis" (2023). Biotechnology Theses. Paper 12.