The proposed experiments will test the hypothesis that ALX axis dysregulation underlies persistent asthma and airway inflammation despite corticosteroid therapy in a cohort of patients with severe asthma. Lipoxin A4 (LXA4) is an anti-inflammatory and pro-resolving mediator that can interact with specific receptors (i.e., ALX/FPR2) to inhibit allergic airway inflammation and hyper-responsiveness in model systems. Severe asthma is characterized by decreased LXA4, suggesting that this condition may stem from a defect in counter-regulation. There are three additional ligands for ALX/FPR2 receptors, namely 15- epimer-LXA4, annexin A1 and serum amyloid A. All four ALX/FPR2 ligands are generated in asthma and together with ALX/FPR2 receptors comprise the "ALX axis." Of note, both protein ligands can be induced in vitro by corticosteroids, the most common asthma controller therapy, and unlike the other three ligands, serum amyloid a interactions with ALX/FPR2 paradoxically promotes inflammation, raising the possibility that a subset of patients with severe asthma may experience detriment rather than benefit from corticosteroids. Consistent with the requests of this RFA, we will recruit and characterize a cohort of severe and moderate adults and children with asthma and follow them for three years. The effects of corticosteroids on the ALX axis and the interaction with inflammatory and remodeling markers will be examined by obtaining blood and respiratory specimens before and 1 month after parenteral corticosteroids at enrollment. The clinical course of these subjects (particularly exacerbations and spirometry) will be monitored over 3 years followed by a repeat course of parenteral corticosteroids. The stability of the ALX axis phenotype post-corticosteroids will be assessed In blood and sputum, and its relationship to airway remodeling will be assessed by comparing high resolution CT scans performed (after corticosteroids) at the beginning and after 3 years in the study. To test our hypothesis, we propose two principal specific aims: 1. Determine the effect of corticosteroids on the ALX axis in severe and non-severe asthma, and 2. Define the relationship between the ALX aberrant phenotype and airway inflammation and progressive disease. The long-term goals for this research is to develop a comprehensive understanding of the perturbations in the ALX axis to the pathogenesis of severe asthma and the potential for components of this axis (lipoxins in particular) as possible novel therapeutic agents to alleviate severe asthma's excess morbidity.
Severe asthma leads to daily symptoms with excess morbidity and mortality and a disproportionate share of the economic costs related to asthma. Despite the availability of many therapeutic options for asthma, these patients'asthma remains uncontrolled. In this proposal, we are investigating the possibility that dysregulation of a natural anti-inflammatory signaling pathway is related to the pathogenesis of severe asthma with a long- term goal of identifying novel therapeutic targets for this and other diseases of chronic inflammation.
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