Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling

American Journal of Respiratory Cell and Molecular Biology
Bing TianAllan R Brasier

Abstract

NF-κB/RelA triggers innate inflammation by binding to bromodomain-containing protein 4 (BRD4), an atypical histone acetyltransferase (HAT). Although RelA·BRD4 HAT mediates acute neutrophilic inflammation, its role in chronic and functional airway remodeling is not known. We observed that BRD4 is required for Toll-like receptor 3 (TLR3)-mediated mesenchymal transition, a cell-state change that is characteristic of remodeling. We therefore tested two novel highly selective BRD4 inhibitors, ZL0420 and ZL0454, for their effects on chronic airway remodeling produced by repetitive TLR3 agonist challenges, and compared their efficacy with that of two nonselective bromodomain and extraterminal (BET) protein inhibitors, JQ1 and RVX208. We observed that ZL0420 and ZL0454 more potently reduced polyinosinic:polycytidylic acid-induced weight loss and fibrosis as assessed by microcomputed tomography and second harmonic generation microscopy. These measures correlated with the collagen deposition observed in histopathology. Importantly, the ZL inhibitors were more effective than the nonselective BET inhibitors at equivalent doses. The ZL inhibitors had significant effects on lung physiology, reversing TLR3-associated airway hyperresponsivenes...Continue Reading

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Citations

Sep 23, 2018·Expert Review of Respiratory Medicine·Allan R Brasier
Feb 5, 2019·Expert Review of Respiratory Medicine·Allan R Brasier
Aug 30, 2018·American Journal of Respiratory Cell and Molecular Biology·Yan Y Sanders, Victor J Thannickal
Apr 28, 2020·American Journal of Respiratory and Critical Care Medicine·Sejal SaglaniAdnan Custovic
Oct 31, 2020·Diseases of the Esophagus : Official Journal of the International Society for Diseases of the Esophagus·Jun TakatsuYasuhiro Shimizu
Jan 20, 2021·Signal Transduction and Targeted Therapy·Nian WangRui Kang
May 22, 2021·Expert Review of Proteomics·Morgan Mann, Allan R Brasier

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Methods Mentioned

BETA
acetylation
transfection
fluorescence microscopy
confocal microscopy
proximity ligation
PCR

Software Mentioned

ImageJ
FlexiVent

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