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The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states

Hematology, Oncology, and Transplantation Section, Department of Medicine, and the Vascular Biology Center, University of Minnesota, Minneapolis, USA.
Blood (Impact Factor: 9.78). 02/2006; 107(2):558-65. DOI: 10.1182/blood-2005-05-2152
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ABSTRACT In vivo, bromide (Br(-)), nitrite (NO(2)(-)), and thiocyanate (SCN(-)) compete for oxidation by eosinophil peroxidase (EPO) and H(2)O(2), yielding, respectively, HOBr, NO(2)., and HOSCN. We have recently shown that SCN(-) is the strongly preferred substrate for EPO in vivo and that HOSCN, in contrast with other EPO-generated oxidants and HOCl, is a relatively weak, cell-permeant, sulfhydryl (SH)-reactive oxidant. We here show that HOSCN is a uniquely potent (up to 100-fold) phagocyte oxidant inducer of tissue factor (TF) activity in human umbilical vein endothelial cells (HUVECs). This induction is attributable to transcriptional up-regulation of TF gene expression dependent upon both activation of the p65/c-Rel TF-kappaB transcription factor and activity of the ERK1/2 kinase pathway upstream of Egr-1 and was markedly further enhanced in the presence of wortmannin, an inhibitor of the PI3 kinase/Akt pathway. HOSCN also markedly activates the proinflammatory p65/p50 NF-kappaB pathway. Based on these findings we hypothesize that HOSCN generated by adherent and infiltrating eosinophils may provoke the development of a prothrombotic and proinflammatory endothelial/endocardial phenotype that promotes the pronounced thrombotic diathesis characteristic of the hypereosinophilic syndrome.

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