Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils.
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 (O2.-), 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.
Eiserich
J P
JP
Department of Internal Medicine, University of California, Davis 95616, USA. jason.eiserich@ccc.uab.edu
Hristova
M
M
Cross
C E
CE
Jones
A D
AD
Freeman
B A
BA
Halliwell
B
B
van der Vliet
A
A
D000818:Animals; D002417:Cattle; D002712:Chlorides / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*
D002712:Chlorides; D018836:Inflammation Mediators; D009573:Nitrites; D016877:Oxidants; D009569:Nitric Oxide; D006997:Hypochlorous Acid; D009195:Peroxidase