Archives of Disease in Childhood 1995; 72: 259-262 259 CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.72.3.259 on 1 March 1995. Downloaded from Nitric oxide and asthma Bozhena Zoritch Since nitric oxide (NO) was first described as Role ofNO as vasodilator endothelium derived relaxing factor (EDRF),I NO dependent vasodilator tone is entirely there has been compelling evidence that NO is locally regulated and as such is probably one of involved in very many biological processes.2-9 the simplest and most fundamental of adaptive It has at least four roles in the lungs.3 These are mechanism in the cardiovascular system. as a pulmonary vasodilator, bronchodilator, Endothelium dependent relaxation was non-adrenergic non-cholinergic transmitter, demonstrated in many vascular preparations, and inflammatory mediator. There are three including veins, arteries, and microvessels.'5 types of NO synthase, the enzyme catalysing However, while the arteries and arterioles are the formation of NO - endothelial, neuronal in a continuous state ofNO mediated vasodila- (both known as constitutive or cNOs), and tion, basal release of NO does not control the macrophage or inducible (iNOs) forms (fig resting tone of peripheral veins, although it 1).8 Agonists activate cNOs by an increase in may have an effect in central veins. Endothelial calcium ion (Ca2+) concentration resulting in NO synthesis influences the adhesion and release of NO in seconds.10 iNOs is part of the aggregation of platelets and leucocytes. immune system and is induced by cytokines, Endothelial dysfunction, either genetic or endotoxin, and lipopolysaccharide resulting in acquired, can lead to cardiovascular disease formation of larger amounts of NO.11 including atherosclerosis, essential and preg- However, this reaction involves gene transcrip- nancy induced hypertension.6 In the lung, tion, and is therefore much slower, resulting in pulmonary vessels also synthesise NO continu- increased production ofNO over several hours ously and this seems to be important for or even days. It can be blocked by glucocorti- maintaining blood flow within the lungs and costeroids. Once formed, NO activates soluble matching ventilation to perfusion.'6 Reduced guanylyl cyclase (sGG) after binding to its NO release may be the mechanism under- http://adc.bmj.com/ haem moiety to initiate a three dimensional lying hypoxic pulmonary vasoconstriction. change in the shape of the enzyme which Inhalation of NO can have a therapeutic effect increases its activity and consequently the pro- in diseases associated with pulmonary vaso- duction of cyclic guanosine 3'5'monophos- constriction.'7-'9 NO was first used in adult University of phate (cGMP).12 13 The rise in cGMP results respiratory distress syndrome as a pulmonary Deparment of Child in relaxation of smooth muscle but the mech- vasodilator.20 In 1992 two groups in North Health, Southampton anism by which this happens is unknown. America used NO in treating persistent fetal on September 25, 2021 by guest. Protected copyright. General Hospital, When produced in large quantities, NO is Tremona Road, circulation successfully without causing Southampton involved in tissue damagecnannand cell death. hypotension or methaemoglobinaemia.21 22 It S016 6YD Inactivation of enzymes containing transition is already recognised that NO is an alternative Correspondence to: metals, including mitochondrial enzymes, is to extracorporeal membrane oxygenation in Dr Zoritch. one of the proposed toxic effects. 4 selected cases. NO in higher concentrations can have adverse influences on capillary permeability, Vasodilator Cytokines Steroids causing oedema and plasma leak. In inflamma- tory lung conditions, such as asthma, induc- A Receptor B receptor lInhibitors tion of NOs in endothelium as well as epithelium may contribute to hyperaemia of L-arginine ^, + , L-arginine Induction mucosa, airway narrowing, and broncho- cNsN Ca2NO constriction. L-citrulline L-Citrullif' Endothelial cell NO Endothelial cell Epithelial cell NO as a bronchodilator Glyceryl trinitrate and sodium nitroprusside, whose vasodilator activity is partly mediated sGC) by NO production, relax airway smooth mus- cGMP GTP cle in vitro, resulting in an increase in sGC Relaxation Smooth muscle cell activity and increase in cGMP.23 It has been proposed that the epithelial lining produces an Figure 1 (A) cNOs is activated by a rise in Ca2+ in response to activation to a surface epithelial derived relaxing factor, which is receptor. (B) iNOs is induced by cytokines or lipopolysaccharide resulting in larger similar to EDRF, but is not certain to be amounts ofNOformation (from Barnes and BelvisP). GTP=guanosine triphosphate. NO.24 There is some evidence that relaxation 260 Zoritch of precontracted guinea pig trachea is induced hydroxyl radicals.32 High concentration of NO by NO.2526 In asthma, the high concentration may have effects on DNA and be genotoxic and ofNO produced by iNOs in epithelial cells may cytotoxic.33 Arch Dis Child: first published as 10.1136/adc.72.3.259 on 1 March 1995. Downloaded from suppress the activity of cNOs, and cause enhancement in intracellular calcium concen- tration and airway constriction. The histamine Role ofNO as neurotransmitter and carbachol induced increase in cGMP pro- There is increasing evidence that NO may duction in the respiratory system has been function as a neurotransmitter of inhibitory shown to be an L-arginine dependent process.26 non-adrenergic non-cholinergic (NANC) It could be speculated that the epithelial layer, nerves or purinergic pathways as they were by releasing NO, acts as a negative feedback sys- previously described34 (fig 2). NO appears to tem to histamine induced contractions. In account for the bronchodilator NANC response asthma, high concentrations of NO produced in vitro in human central and peripheral by inducible NO synthases in inflammatory or airways. Nerves containing NOs appear to epithelial cells may downregulate the activity of supply bronchial vessels, airway smooth muscle, cNOs. This may disturb the breaking mech- and submucosal glands. Parasympathetic, anism that prevents enhanced airway constric- sympathetic, and sensory ganglia supplying the tions. Damage or removal of epithelium airways also contain NOs. NOs inhibitors increases smooth muscle responsiveness.27 In potentiate the cholinergic neural response asthma, epithelium is often damaged which may by acting as a functional antagonist to also affect production of NO by cNOs which acetylcholine in airway smooth muscle. would contribute to bronchospasm.28 Airway There is evidence that NO modulates reflex responsiveness to histamine is increased bronchoconstriction.35 Bronchodilator NANC after intratracheal inoculation of parainfluenza nerves are the only neural bronchodilator type 3 virus and can be blocked by inhaling pathway in the human airway. L-arginine.29 Therefore, it is likely that the The question for research is whether there is deficiency in endogenous NO production any defect in those nerves in diseased airways. after a viral infection is due to a dysfunction of There is some evidence for this. Although the cNOs. A challenging hypothesis is that NANC responses in tissues from patients with bronchial hyperresponsiveness may be sup- mild asthma were not altered, responses were pressed by blocking the activity of the inducible significantly reduced from patients with cystic form of NOs by using glucocorticosteroids. fibrosis.36 Further information is needed on This would prevent downregulation of cNOs by the NANC neural bronchodilator pathway to iNOs. The effect of NO as a bronchodilator in unravel whether it has a part to play in the humans has been disappointing. High concen- pathophysiology of early asthma in children. trations of inhaled NO (>20 000 parts per Persson et al demonstrated that NO in billion) caused an increase in airway resistance exhaled air increased with exercise in healthy in healthy subjects.30 An alternative might be to volunteers.37 It would be of value to study the http://adc.bmj.com/ manipulate release of neuronal NO which change of NO concentration in exercise should give selective bronchodilatation. This induced asthma to establish if there is any might be particularly effective in wheezy infants abnormality in the modulation of broncho- who respond poorly to P agonists or in chronic constriction in response to exercise in obstructive pulmonary disease. However, there asthmatics. Perhaps the bronchoconstriction are potential dangers ofinhaling NO in the pres- produced during exercise in subjects with ence of oxygen because of the formation of asthma and cystic fibrosis is due to the on September 25, 2021 by guest. Protected copyright. nitrate and nitrous and nitric acid which may increased NO release. increase airway responsiveness and in high con- Active smoking decreases the amount of centration may cause pulmonary oedema.31 NO in exhaled air in healthy people.38 The Peroxynitrite may generate tissue damaging regulation of NO synthesis by neuronal cNOs may be impaired in children whose mothers smoke in pregnancy and who were exposed Airway smooth to passive smoking in infancy which may muscle cell predispose them to wheezing illnesses. Peripheral nerve NO-cysteine complex A L-Citrulline Role of NO as an inflammatory mediator Macrophages express iNOs after exposure to * L-arginine / NO --w NO0 cytokines, in particular tumour necrosis factor- 1 ct, interferon y, and interleukin- 1 l as well as NOs endotoxins. Thus NO contributes