Corticosteroid resistance poses a major challenge in chronic inflammatory conditions. Researchers observe it frequently in severe asthma, COPD, rheumatoid arthritis, and other diseases.
Glucocorticoids normally bind to the glucocorticoid receptor (GR). This complex moves to the nucleus. There, it suppresses inflammatory genes through histone deacetylase-2 (HDAC2) recruitment. Moreover, it activates anti-inflammatory genes.
In resistant cases, multiple mechanisms disrupt this process.
Oxidative stress reduces HDAC2 expression and activity. Therefore, inflammatory genes remain active despite treatment. Studies show this prominently in COPD patients and smokers with asthma.
Furthermore, cytokines like IL-2, IL-4, and IL-13 impair GR binding affinity. They hinder nuclear translocation of GR. In severe asthma, elevated GRβ expression acts as a dominant negative inhibitor.
Additionally, mitogen-activated protein kinase (MAPK) pathways activate. p38 MAPK phosphorylates GR. This blocks its function. Pro-inflammatory transcription factors such as AP-1 and NF-κB compete excessively. They override GR suppression.
In type 17 asthma, IL-17A drives neutrophilic inflammation.
It induces steroid-resistant genes like lipocalin-2 (LCN2) and serum amyloid A (SAA). IL-17A collaborates with corticosteroids to upregulate CEBPB transcription factor. Act1 stabilizes CEBPB mRNA posttranscriptionally.
Epigenetic changes contribute significantly. Reduced histone acetylation impairs anti-inflammatory gene activation. Phosphoinositide-3-kinase-δ (PI3Kδ) activation from oxidative stress further decreases HDAC2.
In rheumatoid arthritis, macrophage migration inhibitory factor (MIF) counteracts glucocorticoid effects. It sustains MAPK activation. Prolactin and other factors also oppose cortisol actions.
P-glycoprotein overexpression increases drug efflux. This lowers intracellular corticosteroid levels.
Genetic factors play a role. Mutations in NR3C1 gene cause primary resistance rarely. Secondary resistance arises from chronic inflammation and environmental triggers like smoking or infections.
Researchers explore targeted therapies. p38 MAPK inhibitors restore sensitivity. Theophylline activates HDAC2. Vitamin D enhances IL-10 responses. Antioxidants or PI3Kδ inhibitors counteract oxidative stress.
These insights come from molecular studies and clinical observations. They highlight heterogeneity across diseases and patients. Understanding these pathways guides personalized treatments. Thus, they improve outcomes in resistant chronic inflammation.