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Slungaard_A

Research Abstracts Online
January 2009 - March 2010

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University of Minnesota Twin Cities
Medical School
Department of Medicine

PI: Arne Slungaard

Eosinophil Peroxidase in Allergic Inflammation

Eosinophil (EO) phagocytes can damage host tissue and contribute to the pathogenesis of allergic inflammatory diseases such as asthma and inflammatory bowel diseases (IBD). EO-specific granules are endowed with abundant amounts of EO peroxidase (EPO) and a vigorous respiratory burst that generates H2O2 to fuel the generation of other oxidants. However, little is known about the contribution of EPO-mediated oxidative damage to the pathology of eosinophilic inflammatory states. Three unusual substrates—bromide (BR–), nitrite (NO2–), and thiocyanate (SCN–)—compete for oxidation by EPO in physiologic fluids in the presence of H2O2, yielding, respectively, HOBr, NO2•, and HOSCN. The relative toxicity of these oxidants for human cells is HOBr > NO2• >> HOSCN; yet EPO preferentially oxidizes SCN– > NO2– > BR–. The hypothesis of this work is that SCN– "buffers” against generation by EPO of the more cytotoxic NO2–- and BR–- based oxidants and consequently serum SCN– levels, which are dietarily determined, may modulate EPO toxicity.

The overall goal of this work is to examine the hypothesis that that EPO-generated oxidants impose damage in a substrate-determined manner to host tissue and EOs themselves. The first specific aim is to test the hypothesis that substrate modulation of EPO toxicity by dietary supplementation with either thiocyanate or its metabolic precursors, cyanide-like compounds, ameliorates the severity of inflammatory bowel disease in a murine dextran sulfate model. The second specific aim is to test the hypothesis that in a novel murine IL-5/Eotaxin-2 (I5/E2) transgenic model of asthma, crossbreeding with EPO-/- mice, pharmacologic inhibition of EPO enzymatic activity, and dietary SCN– supplementation all ameliorate the severe asthmatic phenotype that develops in these animals both spontaneously and after ovalbumin (OVA) sentitization and challenge. The third specific aim is to test the hypothesis that the EPO/ H2O2/SCN- system functions through an NF-κB-dependent mechanism to inhibit eosinophil apoptosis and deleterious secondary necrotic degranulation.