Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils
JP Eiserich, M Hristova, CE Cross, AD Jones… - Nature, 1998 - nature.com
Nature, 1998•nature.com
Nitric oxide (˙ NO) plays a central role in the pathogenesis of diverse inflammatory and
infectious disorders,. The toxicity of˙ NO is thought to be engendered, in part, by its reaction
with superoxide (O˙− 2), yielding the potent oxidant peroxynitrite (ONOO−). However,
evidence for a role of ONOO− in vivo is based largely upon detection of 3-nitrotyrosine in
injured tissues,,,,. We have recently demonstrated that nitrite (NO2−), a major end-product
of˙ NO metabolism, readily promotes tyrosine nitration through formation of nitryl chloride …
infectious disorders,. The toxicity of˙ NO is thought to be engendered, in part, by its reaction
with superoxide (O˙− 2), yielding the potent oxidant peroxynitrite (ONOO−). However,
evidence for a role of ONOO− in vivo is based largely upon detection of 3-nitrotyrosine in
injured tissues,,,,. We have recently demonstrated that nitrite (NO2−), a major end-product
of˙ NO metabolism, readily promotes tyrosine nitration through formation of nitryl chloride …
Abstract
Nitric oxide (˙NO) plays a central role in the pathogenesis of diverse inflammatory and infectious disorders,. The toxicity of ˙NO is thought to be engendered, in part, by its reaction with superoxide (O˙−2), yielding the potent oxidant peroxynitrite (ONOO−). However, evidence for a role of ONOO−in vivo is based largely upon detection of 3-nitrotyrosine in injured tissues,,,,. We have recently demonstrated that nitrite (NO2−), a major end-product of ˙NO metabolism, readily promotes tyrosine nitration through formation of nitryl chloride (NO2Cl) and nitrogen dioxide (˙NO2) by reaction with the inflammatory mediators hypochlorous acid (HOCl) or myeloperoxidase,. We now show that activated human polymorphonuclear neutrophils convert NO2− into NO2Cl and ˙NO2 through myeloperoxidase-dependent pathways. Polymorphonuclear neutrophil-mediated nitration and chlorination of tyrosine residues or 4-hydroxyphenylacetic acid is enhanced by addition of NO2− or by fluxes of ˙NO. Addition of 15NO2− led to 15N enrichment of nitrated phenolic substrates, confirming its role in polymorphonuclear neutrophil-mediated nitration reactions. Polymorphonuclear neutrophil-mediated inactivation of endothelial cell angiotensin-converting enzyme was exacerbated by NO2−, illustrating the physiological significance of these reaction pathways to cellular dysfunction. Our data reveal that NO2− may regulate inflammatory processes through oxidative mechanisms, perhaps by contributing to the tyrosine nitration and chlorination observed in vivo.
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