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, Arne Slungaard

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

In vivo, bromide (Br-), nitrite (NO2-), and thiocyanate (SCN-) compete for oxidation by eosinophil peroxidase (EPO) and H2O2, 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-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)558-565
Number of pages8
JournalBlood
Volume107
Issue number2
DOIs
StatePublished - Jan 15 2006

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