Glucocortiosteroid subsensitivity and asthma severity

PURPOSE OF REVIEW: Glucocorticosteroids (GCSs) remain the cornerstone of therapy for treating the inflammatory component of asthma. Clinical response to GCS is heterogeneous, varying both within asthma 'endotypes', as well as the same individual. Different factors and micro-environment can alter the canonical GCS-induced signalling pathways leading to reduced efficacy, collectively termed as GCS subsensitivity, which includes the entire spectrum of steroid insensitivity and steroid resistance. RECENT FINDINGS: In the past, steroid subsensitivity has been associated with dysregulated expression of glucocorticoid-receptor isoforms, neutrophilic inflammation and Th17 cytokines, oxidative stress-inducing factors and their downstream effect on histone deacetylase activities and gene expression. The review highlights recent observations, such as GCS-induced dysregulation of key transcription factors involved in host defence, role of airway infections altering expression of critical regulatory elements like the noncoding microRNAs, and the importance of interleukin (IL)-10 in reinstating steroid response in key immune cells. Further, emerging concepts of autoimmunity triggered because of delayed resolution of eosinophilic inflammation (due to GCS subsensitivity) and observed lymphopenia (plausibly a side-effect of continued GCS use) are discussed. SUMMARY: This review bridges concepts that have been known, and those under current investigation, providing both molecular and clinical insights to aid therapeutic strategies for optimal management of asthmatics with varying degree of steroid subsensitivity and disease severity, with particular emphasis on the PI3 kinase pathways.