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: 10.43). 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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Available from: Nigel S Key, Mar 22, 2015
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    • "Disruption of the normally anticoagulant endothelial lining exposes von Willebrand factor (vWf), collagen, and tissue factor (TF). VWf and collagen bind platelets, and TF binds activated factor VII (fVIIa) to start the biochemical reactions that generate a fibrin thrombus [15] [16]. In HES, the stimulation of fibrin formation by TF may be especially important since eosinophils contain TF in their specific granules, and they can induce endothelium to express it [17] [18]. Secreted eosinophil proteins may also impair the anticoagulant properties of the endothelial membrane by binding to thrombomodulin [19]. "
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