ReviewNitric oxide, peroxynitrite, and lower respiratory tract inflammation
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:
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
References (29)
- et al.
Induction of nitric oxide synthase in asthma
Lancet
(1993) - et al.
Peroxynitrite-mediated oxidative protein modifications
FEBS Lett.
(1995) - et al.
Increased nitric oxide in exhaled air of asthmatic patients
Lancet
(1994) - et al.
Effects of reactive oxygen and nitrogen metabolites on RANTES- and IL-5 induced eosinophil chemotactic activity in vitro
Am. J. Pathol.
(1999) - et al.
The relationship between infection and inflammation in the early stages of lung disease from CF
Pediatr. Pulmonol.
(1995) - et al.
Eosinophilic inflammation in asthma
N. Engl. J. Med.
(1990) - et al.
Airway nitric oxide in asthmatic children and patients with cystic fibrosis
Eur. Respir. J.
(1996) - et al.
Bronchodilator action of inhaled nitric oxide in guinea pigs
J. Clin. Invest.
(1992) - et al.
Nitric oxide and interleukin-8 as inflammatory components of cystic fibrosis
Inflammation
(1995) - et al.
The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine
Nature
(1980)
The biology of nitrogen oxides in the airways
Am. J. Respir. Crit. Care Med.
Sputum tumor necrosis factor alpha and leukotriene concentrations in CF
Arch. Dis. Child.
Macrophage cytotoxicity: role of l-arginine deimmunase activity and imino nitrogen oxidation to nitrite
Science
Inhalation of nitric oxide modulates adult human bronchial tone
Am. Rev. Respir. Dis.
Cited by (22)
Nitric Oxide and Nitrogen Oxides
2021, Encyclopedia of Respiratory Medicine, Second EditionExhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status
2018, Respiratory MedicineCitation Excerpt :The elevated NOx levels in EBC in subjects with current asthma confirmed that nitric oxide (NO) plays a biological role in the inflammatory process. Indeed, nitric oxide production involve pro-inflammatory and oxidative response that generate nitric oxide products such as nitrite and nitrate by reacting free radicals of NO with oxygen [35,39,43]. Nevertheless, this difference is weak.
Effects of occupational exposure to poorly soluble forms of beryllium on biomarkers of pulmonary response in exhaled breath of workers in machining industries
2016, Toxicology LettersCitation Excerpt :Biomarkers of local inflammation and oxidative stress – cytokines, nitric-oxide-related products, arachidonic acid metabolites, hydrogen peroxide, aldehydes – were reported as potential sensitive endpoints when identifying early biochemical changes in the airways of workers exposed to various pneumotoxic subtances (Chérot et al., 2012). Nitric oxide (NO) is an important mediator involved in several physiological processes that induces respiratory tract injuries via the interaction of NO with reactive oxygen species resulting in reactive nitrogen intermediates (Sugiura and Ichinose, 2011; Robbins et al., 2000). NO-related products, which are found in EBC, are formed in the airways by oxidation of NO in nitrogen oxides (NOx, namely nitrite and nitrate) (Kubáň and Foret, 2013).
Pathophysiology of asthma
2009, Asthma and COPDPathophysiology of asthma
2008, Asthma and COPD: Basic Mechanisms and Clinical Management