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Virus Induced Asthma Exacerbations: Immunologic Mechanisms and Metabolomic Biomarkers

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  • Asthma is a complex multifaceted chronic inflammatory disease that is characterized clinically by reversible airflow obstruction, shortness of breath, coughing, and wheezing. Asthma is the most common chronic disease in children, and is differentiated into many phenotypes with multiple triggers. The most abundant phenotype is allergic (or atopic) asthma. Allergic asthma is defined by the allergic of the airway inflammation made up of IgE, mast cells, CD4+ T helper cells, and eosinophils. Additionally the most common trigger for asthma exacerbations (attacks) in children is common respiratory virus infections. For a reason that has yet to be fully discovered, individuals with allergic asthma have longer and more severe responses to respiratory viral infections then healthy individuals. Why this occurs so often and so severely is not known, but several hypotheses exist. My research attempted to explain the mechanism behind how this occurs in individuals with allergic asthma who are repeatedly exposed to the same respiratory virus in their home or work environment. I hypothesized that the inflammatory cells in the asthmatic airway, particularly eosinophils, are activated by re-exposure to viral antigens due to immunological memory, and subsequently cause increased airway reactivity. My model demonstrated that the atopic status of an animal with virus specific immune memory altered its response to inert viral antigens. Both atopic (n=5) and non-atopic (n=5) animals with immune memory demonstrated increased airway reactivity in response to re-exposure to a live virus; this response is similar to that seen in atopic and non-atopic animals exposed to virus for the first time. Non-atopic animals with immune memory do not demonstrate increased airway reactivity when re-exposed to inert viral antigens (n=5), while atopic animals do demonstrate increased airway reactivity when re-exposed to inert viral antigens (n=8). Atopic animals also demonstrate an influx of inflammatory cells into the airways when re-exposed to inert viral antigens (n=5), while non-atopic animals do not (n=5). Therapies targeting the influx of inflammatory cells into the airways do impact the effects of inert viral antigens on airway reactivity. Treatment with corticosteroids decreased the degree of airway reactivity in atopic animals with immune memory when re-exposed to inert viral antigens (n=5). Anti-Interleukin 5 antibodies are able to eliminate the airway reactivity in atopic animals re-exposed to inert viral antigens (n=5); this treatment also decreases the number of eosinophils and macrophages in the animal’s airways (n=5). These results suggest a new mechanism for the triggering of asthma exacerbations via virus specific immune memory. This mechanism can be altered by directly targeting the pathways leading to eosinophilic inflammation. Diagnosing and prognosticating asthma in children is a field lacking precise and non-invasive techniques. The other aspect of my research was to identify urinary biomarkers of asthma that can diagnose the disease, and determine its severity ranging from mild stable asthma to severe asthma causing respiratory failure and acute hypoxia. Using metabolomics, the study of breakdown products of physiological and pathological processes; I hypothesized that I could identify phenotypes of asthma and acute hypoxia in animal models (n=7). The metabolomic analysis of acute neonatal hypoxic injury identified 14 metabolites including alanine, citrate, creatine, fumarate, lactate, succinate, and valine, 7 of which have not been reported elsewhere (1-methylnicotinamide, 2-oxoglutarate, asparagine, betaine, hippurate, N-acetylglycine, and N-carbamoyl-β-alanine). These metabolites may provide the basis of a new diagnostic able that can rapidly identify acute hypoxic injury in neonates. Analysis of urinary metabolites of my animal models of respiratory virus exposure resulted in the identification of 13 metabolites (n=6). These experiments have identified metabolites that can be used to determine asthma phenotypes and mild to moderate acute hypoxic episodes. This thesis examines the pathophysiology of the asthma, attempts to determine the cellular mechanisms behind viral-induced immune memory mediated asthma exacerbations, and investigates urinary metabolomic biomarkers of asthma and neonatal hypoxia.

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    Attribution 3.0 International
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    • Skappak C, Regush S, Cheung PY, Adamko DJ. “Identifying hypoxia in a newborn piglet model using urinary NMR metabolomic profiling” PLOS One. 2013 May 31;8(5):e65035. doi: 10.1371/journal.pone.0065035. Print 2013.