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Nitric oxide, peroxynitrite, and lower respiratory tract inflammation

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Introduction

The release of a factor from endothelium that relaxes smooth muscle surrounding blood vessels has been recognized for a number of years (Furchgott and Zawadski, 1980). However, the identity of this endothelial-derived relaxing factor (EDRF) remained obscure due to its nonprotein nature and exceedingly short half-life until two groups independently reported that EDRF was analogous to nitric oxide (NO) Palmer et al., 1987, Ignarro et al., 1987. Simultaneously, two groups investigating the mechanisms of murine macrophage-induced cytotoxicity attributed this activity to NO Hibbs et al., 1987, Iyengar et al., 1987. Together, these initial investigations laid the foundation on which many of the more recent advances have occurred.

Section snippets

Chemistry

NO is relatively unstable in the presence of molecular oxygen and will rapidly and spontaneously auto-oxidize to yield a variety of nitrogen oxides:2NO(nitricoxide)+O2→2NO2(nitrogendioxide),2NO+2NO2→2N2O3(dinitrogentrioxide),2N2O3+2H2O→4NO2(nitrite)+4H+.

NO may also interact with the superoxide anion radical (O2) in a radical–radical coupled interaction to generate the peroxynitrite anion (ONOO) (Pryor and Squadrito, 1995). Although ONOO is relatively stable, it has a pKa of 6.6, which

Synthesis and degradation

NO is formed when one of the chemically equivalent guanido groups of the essential amino acid, l-arginine, is oxidized by five electrons forming NO and l-citrulline. The reaction is catalyzed by a group of enzymes called nitric oxide synthase (NOS) and several cofactors (Moncada and Higgs, 1993). NOS exists in several isoforms which account for much of the variation in NOS activity. In endothelial cells, a constitutive NOS (cNOS, Type III NOS) exists, which is a constitutively expressed,

Biological role of NO and peroxynitrite

The role of NO in respiratory disease is rapidly evolving. Inhalation of NO results in bronchodilation in rodents (Dupuy et al., 1992), while inhalation does not or weakly dilates human bronchi Hulks et al., 1993, Högman et al., 1993. However, NO or its metabolites can react readily with oxygen, superoxide, water, nucleotides, metalloproteins, thiols, amines, and lipids to form products with biochemical actions such as bacteriostasis, modulation of ciliary beating, cytotoxicity, and pulmonary

NO and asthma

NO has been detected in the exhaled air of normal humans and animals, and several studies have now documented that exhaled NO levels are increased in asthma (Kharitonov et al., 1994). Exhaled NO levels are increased in asthmatics several hours after antigen challenge corresponding to the time of the late asthmatic reaction (Kharitonov et al., 1995). These observations would seem most consistent with induction of cytokines during the late asthmatic reaction leading to an increase in iNOS

NO and CF

The interaction of NO with superoxide affects NO concentrations in cellular systems in vitro (Jones et al., 1998). Confluent cultures of LA-4 cells, a murine lung epithelial cell line, were stimulated to produce NO. Subsequently, human PMNs stimulated to produce superoxide were added and the concentration of NO in the headspace above the cultures sampled. A marked reduction in NO was observed with the addition of PMNs. These data demonstrate that O2 released from PMNs can decrease NO and

Nitrotyrosine and eosinophil chemotaxis

The formation of nitrotyrosine may have functional significance. Current concepts suggest that the chemokines such as eotaxin, RANTES (regulated upon activation, normal T cell expressed and secreted), and IL-5 lead to eosinophil locomotion by binding to receptors. Studies with several chemokines have suggested that tyrosine residues may be critical in this binding. The chemotactic responses of human eosinophils to eotaxin, RANTES, and IL-5 incubated with peroxynitrite and other compounds were

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