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Blood, 15 January 2006, Vol. 107, No. 2, pp. 558-565.
Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-05-2152.
 Previous Article | Table of Contents | Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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
Jian-Guo Wang,
Shawn A. Mahmud,
Jacob A. Thompson,
Jian-Guo Geng,
Nigel S. Key, and
Arne Slungaard
From the Hematology, Oncology, and Transplantation Section, Department of Medicine, and the Vascular Biology Center, University of Minnesota, Minneapolis.
In vivo, bromide (Br–), nitrite (NO2–), and thiocyanate (SCN–) compete for oxidation by eosinophil peroxidase (EPO) and H2O2, yielding, respectively, HOBr, NO2·, 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- B 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-B 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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