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. We find that 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-. We hypothesize 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 our proposed work is to examine the hypothesis that that EPO-generated oxidants impose damage in a substrate-determined manner to host tissue and EOs themselves. Our first specific aim s 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. Our second specific aim is to test the hypothesis that in a novel murine IL- 5/Eotaxin-2 (I5/E2) transgenic model of asthma, 1) crossbreeding with EPO-/- mice, 2) pharmacologic inhibition of EPO enzymatic activity, and 3) dietary SCN- supplementation all ameliorate the severe asthmatic phenotype which 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-(B-dependent mechanism to inhibit eosinophil apoptosis and deleterious secondary necrotic degranulation. These studies, if successful, will prove a role for EPO-mediated oxidant damage in the pathogenesis of asthma and IBD and suggest a simple strategy for its treatment-- i.e., dietary supplementation with inexpensive and innocuous SCN/-- that could be applied to these and other allergic inflammatory diseases even in impoverished communities.
In this grant we will test whether thiocyanate, a simple, inexpensive and non-toxic chemical compound found in vegetables, can be ingested to treat asthma and ulcerative colitis, two serious allergic diseases. We believe this is possible because thiocyanate blunts tissue damage caused by eosinophils, a type of white cell that causes allergic symptoms and diseases. If these studies succeed, we will have discovered a simple, cheap and safe way to treat allergies.
|Hebbel, Robert P; Vercellotti, Gregory M; Pace, Betty S et al. (2010) The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice. Blood 115:2483-90|