Abstract
Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.
Highlights
Asthma is a chronic airways disease clinically characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), and inflammation, affecting more than 334 million people worldwide [1,2,3,4]
We have provided evidence that systemic and local eosinophilopoiesis are important contributing processes to airway eosinophilia in asthma
There is a complex interplay of surrounding mediators that influence eosinophil-lineage committed progenitor cells (EoP) egress from bone marrow (BM), trafficking to the airways, and in situ eosinophilopoiesis (Figure 2)
Summary
Asthma is a chronic airways disease clinically characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), and inflammation, affecting more than 334 million people worldwide [1,2,3,4]. Over 80% of asthma-related deaths occur in low-and lower-middle income countries, indicating that treatment and effective management of asthma saves lives. The most common phenotype of asthma is eosinophilic asthma that is effectively managed by corticosteroid therapy [1,2,3]. A small proportion (5–10%) of patients continue to have symptoms and persistent eosinophilia, despite high-dose oral corticosteroid therapy with substantial treatment-related side effects, and it accounts for the majority of the socio-economic and healthcare burden of asthma [4]. We will discuss the evidence for hematopoietic processes in eosinophilic asthma and the effect of various therapeutic targets on eosinophil levels and asthma management
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