Leukocytes play an essential role in the body, destroying pathogenic microorganisms and tumor cells, they also have great potential to harm healthy tissue. Because oxidative damage is cumulative, this potential is enhanced in chronic inflammatory diseases like asthma. We have used mass spectrometry to show that eosinophils and neutrophils, via their respective unique heme peroxidases eosinophil peroxidase (EPO) and myeloperoxidase (MPO), promote protein oxidative damage in human asthmatic airways. Reactive brominating species, unique oxidants produced by EPO, were shown to serve as a distinct and novel class of oxidants in vivo. The present proposal is an extension of this earlier research, It is predicated upon the hypothesis that oxidative reactions mediated by leukocytes, via EPO and MPO, affect acute and chronic features of the disease process, including airways remodeling, by promoting specific oxidative alterations to lipid and protein components of the bronchiole wall in asthmatic airways. Our overall goals are to test the hypothesis that EPO and MPO contribute to eicosanoid formation, lipid oxidation and generation of specific protein cross-links and chemical modifications in asthma. We will examine the role of free radical vs. stereoselective processes in formation of lipid oxidation products in asthmatic subjects following allergen challenge. We will use murine models to test the hypothesis that EPO and MPO initiate lipid oxidation and form specific bioactive eicosanoids in lung and airways. In parallel, we will examine the role of leukocyte-generated oxidants in the stimulation of mucus secretion during pulmonary inflammation. We will test the hypothesis that specific protease resistant covalent cross-links, as well as other covalent adducts formed by peroxidases, are produced in airways of asthmatic subjects following allergen challenge. We will explore the potential clinical utility of specific adducts formed by peroxidase-mediated oxidation as non-invasive markers for disease presence, severity and pulmonary function. Finally, we will test the hypothesis that specific protein oxidative modifications and cross-links correlate with the extent of airways remodeling and the degree of fixed obstructive disease.
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