Surfactant Protein-A regulation of eosinophil apoptosis in asthma

University Of Arizona, Tucson AZ

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Abstract

DESCRIPTION (provided by applicant): Asthma is a chronic disease, which is increasing in prevalence, and imposes a considerable burden on health care in the United States and in many regions around the world. The increasing rate of asthma diagnosis and the evolving knowledge that subsets of asthmatics respond differently to therapies, has led to the notion that a better approach to treatment may be found by matching clinical asthma phenotypes with specifically targeted biologic therapeutics. Eosinophils, usually present in relatively small numbers in healthy individuals, become predominant effector cells in asthma. Despite the well-documented presence of elevated levels of eosinophils in allergic asthma, the mechanisms regulating eosinophil apoptosis and resolution of allergic airways remain enigmatic. Surfactant protein (SP)-A, a protein secreted by resident lung cells, plays a critical role in host defense. Our preliminary findings show that SP-A interacts with eosinophils to repress degranulation and promote apoptosis. Genetic variants of SP-A exist in the population and may be associated with lung disease. We have found that specific SP-A variants are less effective at regulation of eosinophil activities. Therefore, we hypothesize that specific motifs within SP-A facilitate resolution of allergic airways inflammation by directly initiating eosinophil apoptosis through receptor recognition and specific signaling events. Furthermore, in the asthmatic lung, genetic variation of SP-A results in impaired eosinophil apoptosis and therefore persistent eosinophilic airways inflammation. We will test our hypothesis with three specific aims: Aim 1) Determine the mechanisms by which SP-A induces eosinophil apoptosis, Aim 2) Determine the mechanisms by which SP-A allelic variants differentially mediate eosinophil apoptosis, Aim 3) Determine whether the SP-A genotype contributes to the clinical eosinophilic phenotype of asthma. Our research team is well poised to conduct these innovative studies in mouse and man that will incorporate the use of novel humanized SP-A transgenic mice, SP-A2 allelic variant peptide fragments and SP-A variant oligomers to test our hypotheses. We anticipate that our approach will define the molecular and functional interactions that occur between SP-A and eosinophils in regulating resolution of allergic airway responses. Consequently, we believe that the data generated from this application will provide the groundwork needed for surfactant protein-based therapies to treat individuals with eosinophil predominant asthma.