Refractory asthma: mechanisms, targets, and therapy

<jats:title>Abstract</jats:title><jats:p>Asthma is a common medical condition affecting 300 million people worldwide. Airway inflammation, smooth muscle bronchoconstriction leading to airflow obstruction, and mucous hypersecretion are clinical hallmarks of asthma. The <jats:styled-content style="fixed-case">NHLBI</jats:styled-content> Expert Panel Report 3 recommends inhaled corticosteroids (<jats:styled-content style="fixed-case">ICS</jats:styled-content>) for patients with moderate to severe persistent asthma. Inhaled corticosteroids (<jats:styled-content style="fixed-case">ICS</jats:styled-content>) target gene transcription through their interactions with the glucocorticoid (<jats:styled-content style="fixed-case">GC</jats:styled-content>) receptor (<jats:styled-content style="fixed-case">GR</jats:styled-content>) at the glucocorticoid response element (<jats:styled-content style="fixed-case">GRE</jats:styled-content>). The <jats:styled-content style="fixed-case">GC</jats:styled-content>/<jats:styled-content style="fixed-case">GR</jats:styled-content> 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. Additional mechanisms of steroid resistance include increased activity of <jats:styled-content style="fixed-case">GR</jats:styled-content> phosphorylating kinases which modify the interactions of <jats:styled-content style="fixed-case">GR</jats:styled-content> with transcription factors to inhibit the ability of <jats:styled-content style="fixed-case">GR</jats:styled-content> to bind with <jats:styled-content style="fixed-case">GRE</jats:styled-content>, 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 <jats:styled-content style="fixed-case">PI</jats:styled-content>3K) 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.</jats:p>