Efficacy of novel highly specific bromodomain-containing protein 4 inhibitors in innate inflammation–driven airway remodeling

Bing Tian, Zhiqing Liu, Julia Litvinov, Rosario Maroto, Mohammad Jamaluddin, Erik Rytting, Igor Patrikeev, Lorenzo Ochoa, Gracie Vargas, Massoud Motamedi, Bill Ameredes, Jia Zhou, Allan R. Brasier

Research output: Contribution to journalArticle

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Abstract

NF-kB/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 hyperresponsiveness and increasing lung compliance in vivo. At the molecular level, ZL inhibitors reduced elaboration of the transforming growth factor-b–induced growth program, thereby preventing mucosal mesenchymal transition and disrupting BRD4 HAT activity and complex formation with RelA. We also observed that ZL0454 treatment blocked polyinosinic:polycytidylic acid–associated expansion of the a-SMA11/COL1A1 myofibroblast population and prevented myofibroblast transition in a coculture system. We conclude that 1) BRD4 is a central effector of the mesenchymal transition that results in paracrine activation of myofibroblasts, mechanistically linking innate inflammation to airway hyperresponsiveness and fibrosis, and 2) highly selective BRD4 inhibitors may be effective in reversing the effects of repetitive airway viral infections on innate inflammation–mediated remodeling.

LanguageEnglish (US)
Pages68-83
Number of pages16
JournalAmerican journal of respiratory cell and molecular biology
Volume60
Issue number1
DOIs
StatePublished - Jan 1 2019

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Airway Remodeling
Inflammation
Toll-Like Receptor 3
Histone Acetyltransferases
Myofibroblasts
Proteins
Poly I-C
Fibrosis
Lung Compliance
X-Ray Microtomography
NF-kappa B
Physiology
Transforming Growth Factors
Virus Diseases
Harmonic generation
Coculture Techniques
Tomography
Weight Loss
Microscopy
Microscopic examination

Keywords

  • Airway remodeling
  • Epithelial–mesenchymal transition
  • Lung optical clearing
  • Multiphoton microscopy

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Efficacy of novel highly specific bromodomain-containing protein 4 inhibitors in innate inflammation–driven airway remodeling. / Tian, Bing; Liu, Zhiqing; Litvinov, Julia; Maroto, Rosario; Jamaluddin, Mohammad; Rytting, Erik; Patrikeev, Igor; Ochoa, Lorenzo; Vargas, Gracie; Motamedi, Massoud; Ameredes, Bill; Zhou, Jia; Brasier, Allan R.

In: American journal of respiratory cell and molecular biology, Vol. 60, No. 1, 01.01.2019, p. 68-83.

Research output: Contribution to journalArticle

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abstract = "NF-kB/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 hyperresponsiveness and increasing lung compliance in vivo. At the molecular level, ZL inhibitors reduced elaboration of the transforming growth factor-b–induced growth program, thereby preventing mucosal mesenchymal transition and disrupting BRD4 HAT activity and complex formation with RelA. We also observed that ZL0454 treatment blocked polyinosinic:polycytidylic acid–associated expansion of the a-SMA11/COL1A1 myofibroblast population and prevented myofibroblast transition in a coculture system. We conclude that 1) BRD4 is a central effector of the mesenchymal transition that results in paracrine activation of myofibroblasts, mechanistically linking innate inflammation to airway hyperresponsiveness and fibrosis, and 2) highly selective BRD4 inhibitors may be effective in reversing the effects of repetitive airway viral infections on innate inflammation–mediated remodeling.",
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AU - Liu, Zhiqing

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AU - Maroto, Rosario

AU - Jamaluddin, Mohammad

AU - Rytting, Erik

AU - Patrikeev, Igor

AU - Ochoa, Lorenzo

AU - Vargas, Gracie

AU - Motamedi, Massoud

AU - Ameredes, Bill

AU - Zhou, Jia

AU - Brasier, Allan R.

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