Mechanisms of Corticosteroid Resistance in COPD
Corticosteroid resistance in COPD primarily occurs through oxidative stress-induced reduction in histone deacetylase 2 (HDAC2) activity and expression, which prevents corticosteroids from effectively switching off inflammatory gene transcription. 1
Primary Molecular Mechanisms
HDAC2 Dysfunction (Central Mechanism)
Cigarette smoking and oxidative stress markedly reduce HDAC2 function and expression in COPD patients, which is the key mechanism preventing corticosteroids from recruiting HDAC2 to actively transcribing inflammatory genes. 1
Oxidative stress generates peroxynitrite, which impairs HDAC2 activity through nitration of critical tyrosine residues, fundamentally blocking the anti-inflammatory action of corticosteroids. 1
HDAC2 normally mediates corticosteroid action by reversing histone acetylation and switching off inflammatory gene transcription—when this enzyme is impaired, corticosteroids lose their therapeutic efficacy. 2
Glucocorticoid Receptor (GR) Alterations
Reduced nuclear translocation of glucocorticoid receptor alpha (GRα) after corticosteroid binding occurs due to phosphorylation by activated kinases (p38 MAPK-α, p38 MAPK-γ, and c-Jun N-terminal kinase 1). 2
Decreased expression of GRα itself is found in senescent CD28null CD8+ pro-inflammatory lymphocytes in COPD patients, further contributing to steroid resistance. 3
Increased expression of GRβ competes with and inhibits activated GRα, preventing effective corticosteroid signaling. 2
Reduced activity and expression of phosphatases (MAPK phosphatase 1 and protein phosphatase A2) lead to persistent GR phosphorylation and dysfunction. 2
Cellular and Immunological Mechanisms
Heat Shock Protein Dysfunction
Loss of molecular chaperone Hsp90 expression from CD28null CD8+ T cells and NKT-like cells prevents the glucocorticoid receptor from acquiring its high-affinity steroid binding conformation and trafficking to the nucleus. 3
The GR must be bound to Hsp70 and Hsp90 to function properly; loss of Hsp90 correlates directly with increased IFNγ and TNFα production by pro-inflammatory lymphocytes. 3
Pro-inflammatory Cell Involvement
Macrophages, neutrophils, airway epithelial cells, and lymphocytes all contribute to corticosteroid resistance through altered inflammatory responses and cytokine release. 4
Lung inflammation and released pro-inflammatory cytokines directly affect GR, HDAC2, and surfactant protein D (SP-D) activities across multiple cell types. 4
Oxidative Stress Pathway
Oxidative stress activates phosphoinositide 3-kinase delta (PI3Kδ), which in turn reduces HDAC2 activity and expression in COPD patients, smokers with asthma, and patients with severe asthma. 2
This oxidative stress-PI3Kδ-HDAC2 pathway represents a targetable mechanism for reversing corticosteroid resistance. 2
Additional Contributing Mechanisms
Increased secretion of macrophage migration inhibitory factor interferes with corticosteroid signaling. 2
Competition with transcription factor activator protein 1 (AP-1) reduces corticosteroid effectiveness at the gene transcription level. 2
Increased pro-inflammatory signaling pathways overwhelm the anti-inflammatory capacity of corticosteroids even when receptors are functional. 5
Clinical Context and Implications
The chronic inflammatory response and oxidative stress from tobacco smoke create a self-perpetuating cycle where inflammation generates oxidative stress, which impairs HDAC2, leading to corticosteroid resistance and uncontrolled inflammation. 6, 1
These mechanisms explain why corticosteroids provide little clinical benefit in COPD compared to asthma, despite both diseases involving activated inflammatory genes. 1
The disease continues to progress even after cessation of smoking due to persistent oxidative stress and established molecular resistance mechanisms. 6