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 NFκB·bromodomain-containing
protein 4 (BRD4) complex. The NFκB·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.