Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling

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Abstract

Allergic asthma is a chronic inflammatory airway disease whose clinical course is punctuated by acute exacerbations from aeroallergen exposure or respiratory virus infections. Aeroallergens and respiratory viruses stimulate toll-like receptor (TLR) signaling, producing oxidative injury and inflammation. Repetitive exacerbations produce complex mucosal adaptations, cell-state changes, and structural remodeling. These structural changes produce substantial morbidity, decrease lung capacity, and impair quality of life. We will review recent systems-level studies that provide fundamental new insights into how repetitive activation of innate signaling pathways produce epigenetic ‘training’ to induce adaptive epithelial responses. Oxidative stress produced downstream of TLR signaling induces transient oxidation of guanine bases in the regulatory regions of inflammatory genes. The epigenetic mark 8-oxoG is bound by a pleiotropic DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), which induces conformational changes in adjacent DNA to recruit the NFkB·bromodomain-containing protein 4 (BRD4) complex. The NFkB·BRD4 complex not only plays a central role in inflammation, but also triggers mesenchymal transition and extracellular matrix remodeling. Small molecule inhibitors of OGG1-8-oxoG binding and BRD4– acetylated histone interaction have been developed. We present studies demonstrating efficacy of these in reducing airway inflammation in preclinical models. Targeting inducible epigenetic reprogramming pathway shows promise for therapeutics in reversing airway remodeling in a variety of chronic airway diseases.

Keywords: 8-oxoguanine DNA glycosylase (OGG1), airway remodeling, bromodomain-containing protein 4 (BRD4), epigenetics, mesenchymal transition, myofibroblast.

Citation: Brasier AR, Boldogh I. Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling. Drugs in Context 2019; 8: 2019-8-3. DOI: 10.7573/dic.2019-8-3

Contributions: Both authors contributed equally to the preparation of this review. The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosure and potential conflicts of interest: Dr Brasier reports grants from the National Institutes of Health in relation to this work. He is the founder of Quadragenics, but receives no direct funding from this. In addition, he has a patent PCT/US20l 7/066l07 issued. Dr Boldogh declares that he has no conflicts of interest. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at https://www.drugsincontext.com/wp-content/uploads/2019/10/dic.2019-8-3-COI.pdf

Acknowledgments: Funding acknowledgments: US National Institute of Allergy and Infectious Diseases NIAID 2P01AI062885 and the National Center for Advancing Translational Science NCATS UL1TR00237.

Funding declaration: There was no funding associated with the preparation of this article.

Copyright: Copyright © 2019 Brasier AR, Boldogh I. https://doi.org/10.7573/dic.2019-8-3. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Correct attribution: Copyright © 2019 Brasier AR, Boldogh I. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0.

Article URL: https://www.drugsincontext.com/targeting-inducible-epigenetic-reprogramming-pathways-in-chronic-airway-remodeling/

Correspondence: Allan R Brasier, MD, Institute for Clinical and Translational Research, University of Wisconsin-Madison School of Medicine and Public Health, 4246 Health Sciences Learning Center, 750 Highland Ave, Madison, WI 53705, USA. abrasier@wisc.edu

Provenance: invited; externally peer reviewed.

Submitted: 26 August 2019; Peer review comments to author: 11 September 2019; Revised manuscript received: 16 September 2019; Accepted: 19 September 2019; Publication date: 23 October 2019.

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