Molecular mechanisms in the development and progression of asthma: The role of epigenetic regulation and the airway epithelium

Abstract

Asthma is increasingly recognised as a heterogeneous disease, with multiple phenotypes that differ in severity, pathology, therapeutic response and long-term outcome. A combination of genetic, epigenetic and environmental factors are thought to contribute to the molecular diversity of the disease, with sensitisation (T-cell differentiation) dependent on the local microenvironment and the nature of the invading pathogen. A strong body of evidence exists associating numerous environmental and genetic components in asthma development, with multiple asthma genes involved independently (through the inheritance of polymorphisms) or through the interaction with the environment to increase risk. However, the inability to reproduce inheritance patterns and the dramatic increase in incidence over the last decade provides strong evidence that changes in the environment have activated a pre-existing susceptibility, including the alteration in epigenetic regulation, to play an important role in disease. The role of epigenetic regulation and modulation in the development of asthma and allergy has been widely speculated. Interestingly, factors known to be involved in disease susceptibility including genetic predisposition and exposure to environmental stimuli (in utero and post-natal) have been explored as factors involved in the mechanisms associated with the epigenome. Thus, it is proposed that modification of the epigenome in the regulation of important pathways, including those involved in asthma-associated gene expression and T-cell differentiation play a direct role in disease. In addition, current research focuses on the central role of the airway epithelium in asthma development and progression. Inherently defective in disease, the mechanisms associated with epithelial dysfunction, including the increased susceptibility to injury and the inability to activate normal repair processes are yet to be completely elucidated. Trefoil factor 2 (TFF2), previously shown to be upregulated in asthma and involved in airway epithelial restitution fails to protect the epithelium from pathogen-induced injury. By focusing on the role of epigenetic mechanisms, the epithelium and TFF2 in asthma pathogenesis, this chapter highlights their potential as targets in future therapeutic research.