Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

Viral respiratory infections are the most common cause of an acute asthma exacerbation in both children and adults. Respiratory viruses that have been linked with asthma exacerbations include rhinoviruses, respiratory syncytial virus (RSV), enteroviruses, influenza A/B, parainfluenza viruses, coronavirus and adenovirus. Of these viruses, rhinoviruses are the most commonly detected virus in acute asthma exacerbations. The potential mechanisms by which rhinoviruses could trigger airway remodeling have been investigated in vitro in airway epithelial cells. These studies demonstrated that rhinovirus infection of human epithelial cells induced marked up-regulation of amphiregulin, activin A and VEGF levels. 71 Since these mediators have been implicated in the remodeling processes, it is possible that rhinovirus infection induction of these or other mediators can induce airway remodeling during an asthma exacerbation triggered by rhinovirus. Interestingly, there is a genetic predisposition to the development of rhinovirus wheezing illness in early life. 72 Chromosome 17q21 variants (linked to genes ORMDL3 and GSDMB) were associated with rhinovirus wheezing illnesses in early life, but not with RSV wheezing illnesses. 72 The associations of 17q21 variants with asthma were restricted to children who had had rhinovirus wheezing illnesses, resulting in a significant gene virus interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and GSDMB were significantly increased in rhinovirus-stimulated peripheral blood mononuclear cells (PBMCs), as compared to unstimulated PBMCs. 72 Further studies are needed to determine whether children harboring 17q21 variants and exposed to rhinovirus have an accelerated decline in lung function or increased airway remodeling.