Postgraduate Medical Journal (1989) 65, 532- 542 Postgrad Med J: first published as 10.1136/pgmj.65.766.532 on 1 August 1989. Downloaded from Mechanisms of Disease Airway receptors Peter J. Barnes Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6L Y, UK. Introduction Airway smooth muscle tone is influenced by many indirect action which, in part, is due to activation of a hormones, neurotransmitters, drugs and mediators, cholinergic reflex, since the bronchoconstriction may which produce their effects by binding to specific be reduced by a cholinergic antagonist. Other surface receptors on airway smooth muscle cells. mediators may have a bronchoconstrictor effect Bronchoconstriction and bronchodilatation may which, in the case of adenosine, is due to mast cell therefore be viewed in terms of receptor activation or mediator release,2 or in the case of platelet-activating blockade and the contractile state of airway smooth factor due to platelet products.3 muscle is probably the resultant effect of interacting excitatory and inhibitory receptors. Epithelial-derived relaxantfactor It is important to recognize that airway calibre is not only the result of airway smooth muscle tone, but in Recently there has been considerable interest in the asthma it is likely that airway narrowing may also be possibility of a relaxant factor released from airway explained by oedema of the bronchial wall (resulting epithelial cells, which may be analogous to relaxant factor.4 The presence of from microvascular leakage) and to luminal plugging endothelial-derived by copyright. by viscous mucus secretions and extravasated plasma airway epithelium in bovine airways in vitro reduces proteins, which may be produced by a 'soup' of the sensitivity to and maximum contractile effect of mediators released from inflammatory cells, including spasmogens, such as histamine, acetylcholine or mast cells, macrophages and eosinophils. Activation serotonin, although not potassium which depolarises of receptors on other target cells, such as submucosal airway smooth muscle directly.5 Similar results have glands, airway epithelium, post capillary venules, mast been obtained in dog,6 guinea pig7 and human air- cells and other inflammatory cells may, therefore, also ways.4 One possibility is that these spasmogens release influence airway calibre. factor from epithelium, rather like endothelium- In this article I will concentrate on some of the derived relaxant factor, which directly relaxes airway receptors present on airway smooth muscle which may smooth muscle. The nature of this putative factor is http://pmj.bmj.com/ be relevant to airway disease. uncertain, but it does not appear to be influenced by either cyclo-oxygenase or lipoxygenase blockade.5'6 Another possibility is that enzymes present in Indirect regulation of airway smooth muscle epithelial cells normally degrade mediators so that epithelial removal enhances their effect. There is a complex interaction between different cells in the airway and, while many stimuli may act directly on September 29, 2021 by guest. Protected on airway smooth muscle cells, others may affect Airway receptors and disease smooth muscle tone indirectly, either via neural con- trol mechanisms, via release of mediators from Since surface receptors may determine tissue respon- inflammatory cells, or possibly via release ofepithelial siveness it is possible that alterations in receptors on factors. Thus, bradykinin is a potent bronchoconstric- airway smooth muscle might account for increased tor when given by inhalation in man, but has little airway responsiveness seen in asthma, and, to a lesser effect on human airway muscle in vitro,' suggesting an extent, in chronic obstructive airways disease. Many different factors are known to alter receptor expres- Correspondence: Professor P.J. Barnes, M.A., D.Sc., D.M., sion and could change either receptor density, affinity, F.R.C.P. or coupling. Thus, inflammatory mediators which are Received: 27 December 1988 formed in the airway wall may have effects on various Supported by Medical Research Council and Asthma receptors which could lead to an increased responsive- Research Council ness. Since in asthma the increased responsiveness is t) The Fellowship of Postgraduate Medicine, 1989 AIRWAY RECEPTORS 533 Postgrad Med J: first published as 10.1136/pgmj.65.766.532 on 1 August 1989. Downloaded from found with many different bronchoconstrictor stimuli, Autonomic receptors in airways it is unlikely that there is an effect on a single type of receptor (e.g. muscarinic or histamine receptors). It is Autonomic innervation ofthe airways is complex.'4 In more probable that there is enhanced coupling of all addition to classical cholinergic pathways which cause receptors, perhaps via phosphoinositide hydrolysis, or bronchoconstriction and adrenergic mechanisms that there is a defect in inhibitory receptors (e.g. which are usually bronchodilator, there is a more beta-adrenoceptors). recently recognized component of autonomic control which is neither cholinergic nor adrenergic. Autonomic nerves influence airway tone by activating Receptor coupling and second messengers specific receptors on airway smooth muscle. In the case of cholinergic pathways acetylcholine released There have recently been considerable advances in from postganglionic nerve endings stimulates mus- molecular pharmacology of receptors. Several recep- carinic cholinergic receptors. Adrenergic mechanisms tors have now been cloned and expressed and this has include sympathetic nerves which release noradrena- given important insights into the mechanisms of line, and circulating adrenaline secreted from the receptor activation. Many receptors are linked to adrenal medulla; these catecholamines activate alpha- adenylate cyclase by a coupling protein (G protein), or beta-receptors. The neurotransmitters of the non- which either stimulates (Gs) or inhibits the enzyme adrenergic non-cholinergic (NANC) nervous system (Gi).8 Thus, beta-adrenoceptors and vasoactive- are not certain, but the most likely candidate for intestinal peptide (VIP) stimulate adenylate cyclase in non-adrenergic inhibitory nerves is VIP, whereas that airway smooth muscle, resulting in increased intracel- of non-cholinergic excitatory nerves is probably subs- lular cyclic-AMP and bronchodilatation. Conversely, tance P (SP) or a related peptide. These neuropeptides acetylcholine inhibits adenylate cyclase, resulting in interact with specific receptors on target cells. reduced cyclic-AMP and bronchoconstriction. It is The different components ofthe autonomic nervous now apparent that several receptors which interact system interact with each other in a complex way, both with G proteins have C-terminal homology and thus a by affecting release of neurotransmitter (via prejunc- common sequence of amino acids may be involved in tional receptors), at ganglia in the airways, and by by copyright. the interaction with these coupling proteins.9 Indeed, interaction at postjunctional receptors. Thus, airway there are remarkable similarities in structure between tone may be determined by a complex interplay these receptor proteins with severe hydrophobic mem- between different components of the autonomic ner- brane spanning sections, hydrophilic loops on the vous system. external surface which contain the ligand recognition sites, and the hydrophilic intracellular loops which link with the G protein. Beta-adrenoceptors It is now apparent that several receptors are coupled in a different fashion and activation leads to the Both histochemical and functional studies indicate hydrolysis of membrane phosphoinositides (PI) with that there are few, if any, adrenergic nerve fibres http://pmj.bmj.com/ the formation ofinositol trisphosphate which releases directly supplying airway smooth muscle in human calcium from intracellular stores.'0 This stimulation of airways,14 although in other species, such as cat and PI turnover is initiated by activation ofphospholipase dog, adrenergic bronchodilator nerves have been C via a distinct G protein. In airway smooth muscle described. This suggests that beta-receptors in airway many spasmogens stimulate PI hydrolysis." For smooth muscle are under the control of circulating acetylcholine there is a close relationship between adrenaline. muscarinic receptor occupancy and the stimulation of Direct receptor binding studies indicate that beta- on September 29, 2021 by guest. Protected PI turnover'2 and, in general, there is a close relation- receptors are present in high density in lung of many ship between receptor density and the magnitude ofPI species, including humans. 5 Autoradiographic studies hydrolysis. The discovery of this transduction have revealed that beta-receptors are found on many mechanism clarifies the mechanisms of bronchocon- different cell types within lung, including airway striction and may, in the future, lead to novel broncho- smooth muscle from trachea down to terminal bron- dilator drugs. chioles.'6 This is consistent with functional studies Activation of PI hydrolysis also leads to the forma- indicating that beta-agonists are potent relaxants of tion ofdiacyl glycerol which stimulates protein kinase bronchi, bronchioles and peripheral lung strips.'7 C, a key enzyme involved in phosphorylation of While a direct relaxant effect of beta-agonists on several regulatory proteins, including receptors and G airway smooth muscle is undoubtedly their major proteins.'3 Thus, activation of one