Refractory asthma: mechanisms, targets, and therapy

Abstract

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 NHLBI Expert Panel Report 3 recommends inhaled corticosteroids (ICS) for patients with moderate to severe persistent asthma. Inhaled corticosteroids (ICS) target gene transcription through their interactions with the glucocorticoid (GC) receptor (GR) at the glucocorticoid response element (GRE). The GC/GR 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 GR phosphorylating kinases which modify the interactions of GR with transcription factors to inhibit the ability of GR to bind with GRE, 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 PI3K) 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.

Keywords: asthma; glucocorticoids; oxidative stress; refractory; steroid resistance.

Figure 1

Th2 and Th17 allergen responses in the asthmatic airway. Upon allergen presentation to Th0 cells by antigen-presenting cells (APC), Th cells differentiate into Th2 cells in the presence of IL-4, and Th17 cells in the presence of IL-23. Th2 cells then go on to produce IL-4-, IL-5-, and IL-13-activating B cells to release IgE which attaches to the surface of mast cells. When stimulated by antigen, mast cells release histamine, prostaglandins, and leukotrienes resulting in smooth muscle bronchoconstriction, airway inflammation, and mucous hypersecretion. Eosinophils activated by IL-5 produce cysteinyl leukotrienes and reactive oxygen species (ROS), which act in a similar manner on the airways, and additionally contribute to oxidative stress. Th17 cells producing IL-17 act on airway epithelial cells to stimulate the release of multiple factors. These factors include macrophage chemoattractant protein-1 (MCP-1) which recruits macrophages, IL-5, regulated on activation, normal T cell expressed and secreted (RANTES), and GM-CSF (granulocyte–macrophage colony-stimulating factor) which activate eosinophils, IL-8 which mobilizes neutrophils, stem cell factor (SCF) which works to promote mast cell survival, and IL-25 which induces myeloid cells to release Th2-type cytokines. Neutrophils release matrix metalloproteinase 9 (MMP9), elastase, leukotriene B4, and platelet-activating factor (PAF), which work to enhance the activity of eosinophils. Activated macrophages release IL-1, tumor necrosis factor alpha (TNF-α), and IL-6 which interact with other inflammatory cells and result in a positive feedback loop with airway epithelial cells.

Figure 2

Mechanisms of action of glucocorticoids (GC). GC diffuse across the cell membrane where they bind with GC receptors (GR) in the cytoplasm. Upon binding of the GC, this causes release of inhibitory proteins such as heat shock protein 90 (hsp-90), allowing the GC-bound GR to diffuse across the nuclear membrane where it binds to the glucocorticoid response element (GRE). The GRE is responsible for transcribing anti-inflammatory proteins. Additionally, binding of GC to GR results in recruitment of histone deacetylase 2 (HDAC2), which is responsible for deacetylating GR, permitting its binding to nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1). Upon binding, these transcription factors are deactivated, thereby inhibiting the transcription of pro-inflammatory proteins. Additionally, HDAC2 deacetylates the histone permitting transcription of anti-inflammatory genes by GR.