Glucocorticoid Sensitivity in Airway Inflammatory Diseases

Glucocorticoids are cornerstone anti-inflammatory agents in the management of airway diseases such as asthma, chronic rhinosinusitis and chronic obstructive pulmonary disease. Their actions depend on binding to intracellular glucocorticoid receptors (GRs), which then modulate gene expression via genomic and non-genomic pathways. In most individuals, inhaled or systemic glucocorticoids effectively suppress pro-inflammatory cytokines, restore airway function and prevent exacerbations. However, a subset of patients exhibits reduced sensitivity or outright resistance to these drugs. Mechanisms implicated in this insensitivity include alterations in GR isoform expression, post-translational modifications of the receptor (for example phosphorylation at specific serine residues), dysregulated activities of kinases such as p38 mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K), decreased histone deacetylase 2 (HDAC2) function, and persistent activation of transcription factors including nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Environmental factors (smoking, infections), genetic polymorphisms and systemic comorbidities further modulate glucocorticoid responsiveness. Recent advances in molecular profiling have begun to stratify patients by endotype, enabling targeted interventions—such as kinase inhibitors or biologics—that may restore glucocorticoid sensitivity and optimise personalised care.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Glucocorticoid Sensitivity in Airway Inflammatory Diseases publication trend

The graph below shows the total number of articles in glucocorticoid sensitivity in airway inflammatory diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Glucocorticoid receptor (GRα): The principal receptor isoform that mediates the transcriptional effects of glucocorticoids upon ligand binding and nuclear translocation.

Transrepression: A genomic mechanism where activated GRs inhibit pro-inflammatory transcription factors (e.g. NF-κB, AP-1) without directly binding DNA.

Histone deacetylase 2 (HDAC2): An enzyme that removes acetyl groups from histones, facilitating chromatin compaction and repression of inflammatory gene expression; its activity is essential for full glucocorticoid efficacy.

p38 MAPK: A stress-activated kinase that phosphorylates the GR at specific serine residues, impairing its anti-inflammatory function and contributing to steroid resistance.

Phosphoinositide-3-kinase (PI3K): A lipid kinase activated by oxidative stress and growth factors; overactivation reduces HDAC2 activity and promotes corticosteroid insensitivity.

Nuclear factor-κB (NF-κB): A transcription factor that drives expression of numerous pro-inflammatory cytokines and chemokines in airway cells.

References

1. Genomic and non-genomic actions of glucocorticoids in asthma. Annals of Thoracic Medicine (2010).
2. Why do some asthma patients respond poorly to glucocorticoid therapy?. Pharmacological Research (2020).
3. PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma. Clinical and Translational Medicine (2020).
4. P38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial cells. Journal of Molecular Medicine (2020).