Chapter 19 - Therapy of Airway Disease: Epigenetic Potential

Abstract

Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes that are involved in obstructive airway disease, such as asthma and chronic obstructive pulmonary disease (COPD). Acetylation of histones by histone acetyltransferases activates inflammatory genes, whereas histone deacetylation results in inflammatory gene repression. Corticosteroids exert their anti-inflammatory effects partly by inducing acetylation of anti-inflammatory genes, but mainly by recruiting histone deacetylase-2 (HDAC2) to activated inflammatory genes. HDAC2 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma. In COPD there is resistance to the anti-inflammatory actions of corticosteroids, which is explained by reduced activity and expression of HDAC2. This can be reversed by a plasmid vector, which restores HDAC2 levels, but may also be achieved by low concentrations of theophylline. Oxidative stress in COPD and severe asthma causes corticosteroid resistance by reducing HDAC2 activity and expression by activation of phosphoinositide-3-kinase-δ, resulting in HDAC2 phosphorylation via a cascade of kinases. Theophylline reverses corticosteroid resistance by directly inhibiting oxidant-activated PI3Kδ and is mimicked by PI3Kδ knockout or by selective inhibitors. Other treatments may also interact in this pathway, making it possible to reverse corticosteroid resistance in COPD, as well as smoking asthmatics and some patients with severe asthma and in smoking asthmatics where similar mechanisms operate. Other histone modifications, including methylation, tyrosine-nitration and ubiquitination may also affect histone function and inflammatory gene expression and better understanding of these epigenetic pathways could lead to novel anti-inflammatory therapies, particularly in corticosteroid-resistant inflammation.