Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling

Drugs in Context

article

Allan R Brasier¹  Istvan Boldogh² 

[1] Institute for Clinical and Translational Research, University of Wisconsin-Madison School of Medicine and Public Health, 4246 Health Sciences Learning Center;Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Blvd

关键词: 8-oxoguanine DNA glycosylase (OGG1);    airwayremodeling;    bromodomain-containing protein 4 (BRD4);    epigenetics;    mesenchymal transition;    myofibroblast.;   

DOI  :  10.7573/dic.2019-8-3

学科分类：社会科学、人文和艺术（综合）

来源: C S F Medical Communications Ltd.

【 摘 要 】

Allergic asthma is a chronic inflammatory airway diseasewhose clinical course is punctuated by acute exacerbationsfrom aeroallergen exposure or respiratory virus infections.Aeroallergens and respiratory viruses stimulate toll-likereceptor (TLR) signaling, producing oxidative injury andinflammation. Repetitive exacerbations produce complexmucosal adaptations, cell-state changes, and structuralremodeling. These structural changes produce substantialmorbidity, decrease lung capacity, and impair quality of life.We will review recent systems-level studies that providefundamental new insights into how repetitive activationof innate signaling pathways produce epigenetic ‘training’to induce adaptive epithelial responses. Oxidative stressproduced downstream of TLR signaling induces transientoxidation of guanine bases in the regulatory regions ofinflammatory genes. The epigenetic mark 8-oxoG is boundby a pleiotropic DNA repair enzyme, 8-oxoguanine DNAglycosylase (OGG1), which induces conformational changes inadjacent DNA to recruit the NFkB·bromodomain-containingprotein 4 (BRD4) complex. The NFkB·BRD4 complex notonly plays a central role in inflammation, but also triggersmesenchymal transition and extracellular matrix remodeling.Small molecule inhibitors of OGG1-8-oxoG binding and BRD4–acetylated histone interaction have been developed. Wepresent studies demonstrating efficacy of these in reducingairway inflammation in preclinical models. Targeting inducibleepigenetic reprogramming pathway shows promise fortherapeutics in reversing airway remodeling in a variety ofchronic airway diseases.

【 授权许可】

CC BY-NC-ND