Refractory asthma: mechanisms, targets, and therapy (2014 review)

This free full text review in the EAACI journal Allergy examines the current understanding of refractory asthma. Why do inhaled corticosteroids seem to be ineffective in some patients with severe asthma? Some of the reasons are discussed below.

Inhaled corticosteroids (ICS) target gene transcription through their interactions with the glucocorticoid (GC) receptor (GR) at the glucocorticoid response element (GRE). The GC/GR complex enhances anti-inflammatory but inhibits pro-inflammatory mediator production. Classically, asthma has been described as a Th2-associated eosinophil-predominant disease, but recently alternative models have been described including a Th17-mediated neutrophil-predominant phenotype resulting in patients with more severe disease who may be less responsive to steroids.



Severe asthma - differential diagnosis and management (click to enlarge the image).

Additional mechanisms of steroid resistance include increased activity of GR phosphorylating kinases which modify the interactions of GR with transcription factors to inhibit the ability of GR to bind with GRE, leading to an increase in pro-inflammatory gene transcription. Oxidative stress also affects the balance between pro-inflammatory and anti-inflammatory gene transcription through the modification of transcription factors and cofactors (such as PI3K) leading to the inhibition of histone deacetylase 2.

Continued investigations into the mechanisms behind glucocorticoid resistance will lead to novel treatments that improve control of severe refractory asthma.

References:

Refractory asthma: mechanisms, targets, and therapy. J. L. Trevor andJ. S. Deshane. Allergy, 29 APR 2014, DOI: 10.1111/all.12412.
http://onlinelibrary.wiley.com/doi/10.1111/all.12412/full