Asthma is a common chronic illness with higher rates of hospitalization for exacerbation than many other chronic conditions. Standard treatment for acute asthma includes systemic corticosteroids to suppress inflammation. However, the benefits of systemic steroids are not effective for several hours after administration and do not target neutrophilic inflammation, a shared feature of both viral- and allergen-induced exacerbations. Currently there is an urgent need for treatments that work quickly and effectively in acute asthma exacerbations, characterized by increased airway hyper-reactivity, neutrophilic and eosinophilic inflammation, and mucous secretion with impaired clearance. We hypothesize that parenteral interventions targeted at inflammatory cytokines implicated in acute asthma may prove to be useful adjuncts to standard treatment of exacerbations. Our studies with allergic asthmatics have shown enhanced airway IL-1β responses after exposure to pollutants. Numerous studies in murine models of allergic asthma indicate that IL-1β is a central mediator of airway reactivity, granulocyte recruitment, mast cell activation, and mucus hypersecretion; however, the exact source of IL-1β has yet to be elucidated. Thus, IL-1 blockade presents a novel and targeted strategy to treat broad features of an exacerbation. Anakinra is a FDA-approved IL-1 receptor antagonist with a fast onset of action and short half-life. We have successfully and safely used anakinra in reducing neutrophilic airway inflammation after environmental endotoxin challenge in healthy volunteers. Using a model of inhaled allergen challenge frequently used to test novel asthma therapies, we will test the central hypothesis that IL-1 blockade with anakinra will reduce three features of asthma exacerbations in subjects with allergic airway disease: airway hyperreactivity, inflammation, and mucous secretion and clearance. Aim 1 will test if IL-1 blockade mitigates allergen-induced bronchial reactivity. Aim 2 will test if IL-1 blockade mitigates allergen-induced bronchial inflammation. Aim 3 will test if IL-1 blockade mitigates allergen-induced mucus secretion and slowed clearance. We will be the first to determine if anakinra alleviates these key features of asthma exacerbations using two dosing schemes that reflect potential asthma rescue regimens. These proof-of-concept studies are essential to the development of well-designed clinical trials that can test if this therapy is a useful adjunct in exacerbations of respiratory disease for use in emergency care settings.

Project Narrative: Although systemic corticosteroids are used to treat asthma exacerbations, they are not effective for several hours and do not target all features of an exacerbation. We will test the ability of anakinra, a FDA-approved IL- 1 receptor antagonist with a fast onset of action and short half-life, to suppress features of allergic airway inflammation using a model of inhaled allergen challenge. These studies will demonstrate the feasibility of using anakinra as an effective adjunctive therapy to treat asthma exacerbations.