Autonomic Control of Airway Function in Asthma

Autonomic Control of Airway Function in Asthma* Peter]. Barnes, D.M., F.R.C.P.

the last century, asthma considered to D uring be a nervous disease because of the excessive irwas

ritability of the airways,' but this view was superceded by immunologic theories. Recently, there has been increased interest in neurologic control of airway function and its possible abnormalities in asthma. Neural control of airways is more complex than was previously appreciated. I In addition to classic cholinergic and adrenergic pathways, a third nervous system, which is neither adrenergic nor cholinergic (NANC), has been identified in the airways of many species, including humans. 3 CHOLINERGIC MECHANISMS

The predominant innervation to human airways is by cholinergic nerves which travel down the vagus nerve and synapse in ganglia located in the airway wall. These ganglia used to be viewed as a simple relay station from which short post-ganglionic fibers travel to innervate target cells, such as smooth muscle and submucosal gland cells. It now seems likely that complex interactions may occur within these ganglia, with modulation of cholinergic neurotransmission." In human airways, sympathetic nerves are closely related to airway ganglia and may, therefore, modulate cholinergic tone. Several neuropeptides have also been localized to these ganglia and may similarly affect cholinergic neurotransmission. Complex integration may, therefore, occur at airway ganglia and it is possible that, in asthma, inflammatory mediators might influence ganglion function and so lead to abnormal neurologic control. Cholinergic nerve terminals release acetylcholine which activates muscarinic receptors. These receptors are blocked by atropine and ipratropium bromide. In normal airways there is a certain degree of cholinergic tone, since anticholinergic drugs cause bronchodilatation. Inhibition of cholinesterase by drugs such as edrophonium and pyridostigimine, prevents breakdown of tonically released acetylcholine, leading to bronchoconstriction. Cholinergic pathways may be activated by reflex mechanisms, stimulation of afferent receptors (irritant receptors and C-fiber endings) in *From the Department of Clinical Pharmacology, Cardiothoracic Institute, Brompton Hospital, London, England,

the airways leading to reflex bronchoconstriction. It therefore proposed that these cholinergic reflexes were exaggerated in asthma. Inflammatory mediators, such as histamine and prostaglandins, might activate irritant receptors in the airway and lead to reflex bronchoconstriction. This would suggest that anticholinergic drugs would be effective in asthma. Although anticholinergic drugs may protect against a variety of bronchoconstrictor challenges, they have not been as effective in controlling the symptoms ofclinical asthma. This may be explained by the fact that anticholinergic drugs will not block the direct effects of mediators (such as histamine, leukotrienes and prostaglandins) on airway smooth muscle and other target cells, and will only inhibit that component of bronchoconstriction which is due to a cholinergic reflex. Another reason why cholinergic antagonists may not be as effective in asthma, as was originally hoped, is that cholinergic receptors are not evenly distributed in the airways. Autoradiographic techniques used to map the distribution of cholinergic receptors, smooth muscle of large airways has a high density of receptors, but, in small airways, the density of receptors is very much less." This implies that anticholinergic drugs will be relatively ineffective in peripheral airways, which are likely to be constricted in asthma. Clinical studies similarly show that the effect of cholinergic antagonists is predominantly in large airways, whereas p-agonists are effective bronchodilators of all airways.6 Anticholinergic drugs appear to be more effective in COPD patients than in asthma. This can be explained by the fact that vagal cholinergic tone may have a greater effect in airways with reduced caliber for geometric reasons. Removing this tone by anticholinergic drugs is therefore likely to be beneficial in these patients, unlike asthmatic patients in whom bronchoconstriction is also due to the direct effects of inflammatory mediators. was

ADRENERGIC MECHANISMS

Beta blockers have no effect on airway function in normal subjects, but cause increased bronchoconstriction in asthmatic patients, suggesting that adrenergic mechanisms are important in protecting against bronchoconstriction. Adrenergic control ofairways involves CHEST I 91 I 5 I MAY, 1987 I Supplement

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sympathetic nerves, circulating catecholamines and adrenergic receptors.

Sympathetic Nemes Histochemical studies have shown that sympathetic innervation of human airways, in contrast to the rich parasympathetic innervation, is very sparse. While sympathetic nerves supply pulmonary and bronchial blood vessels, submucosal glands and ganglia, there are ~ if any, adrenergic nerves in airway smooth muscle. 7 Similarly, functional studies ofhuman airways confirm that there is no direct sympathetic innervation of airway smooth muscle. Selective activation of nerves by electrical field stimulation in human bronchi in vitro causes a cholinergic contraction and a relaxation which is unaffected by adrenergic blockade." Thus, there is a nonadrenergic inhibitory nervous system, but no evidence of adrenergic inhibitory nerves. In vivo tyramine, an indirect sympathomimetic which releases norepinephrine from sympathetic nerves, causes a rise in blood pressure when given by infusion to asthmatic subjects, as norepinephrine is released from sympathetic nerves in vessels. But there is no change in airway function, although the same subjects bronchodilate when infused with a beta, agonist. 8 Thus, sympathetic nerves do not appear to influence resting bronchomotor tone, although an effect via modulation of cholinergic neurotransmission might occur when cholinergic tone is increased.

Circul4ting Catecholamines Because sympathetic nerves do not appear to influence bronchomotor tone, it is possible that circulating catecholamines might account for adrenergic drive in asthmatic subjects. Epinephrine has potent metabolic and airway effects, whereas norepinephrine does not function as a circulating hormone, and it is only recently that sensitive assays have been developed for measuring endogenous epinephrine. In stable asthmatic subjects, plasma epinephrine concentrations are no higher than in age-matched normal subjects and, during bronchoconstriction induced by various challenges, there is no rise in plasma catecholamtnes." With exercise, which is sufficient to precipitate post-exercise bronchoconstriction, circulating epinephrine does not rise as in normal subjects performing the same level of exercise. With more vigorous exercise, however, catecholamine concentrations increase, suggesting that there may be a lag in mobilization of epinephrine from the adrenal medulla in asthma. Even in acute severe asthma plasma epinephrine concentration is not elevated above the normal range, suggesting either a defect in release of catecholamines or exhaustion of epinephrine stores. This latter possibility is unlikely, since insulin-induced hypoglycemia causes the normal increase in epineph48S

rine, showing that the adrenal medulla releases epinephrine under some conditions. The fact that f3-blockers increase bronchoconstriction in asthmatic subjects implies that the normally low concentrations of epinephrine are sufficient to protect against bronchoconstrictor influences, like inflammatory mediators and vagal tone. Any lowering of plasma epinephrine in asthma is therefore likely to be associated with increased bronchoconstriction. Thus, the circadian fall in epinephrine, which occurs at night, may be a contributory factor in development of nocturnal asthma. 10

Beta-adrenoceptors Beta-adrenoceptors influence many aspects of lung function and, using direct receptor binding assays, it can be shown that the density of f3-receptors in lung is high. Autoradiographic studies of human lung have shown that f3-receptors are widely distributed." As expected, l3-agonists are found in airway smooth muscle from bronchi down to terminal bronchioles, so that l3-agonists are able to relax all airways. Beta-receptors are also localized to airway epithelial cells, and l3-agonists may influence ion and fluid transport across these cells, and may also stimulate the release ofan unidentified relaxant product from epithelial cells. IS p-receptors are also found on submucosal gland cells and f3-agonists stimulate mucus secretion. Thus, p-agonists may increase mucociliary clearance, reversing the impairment of clearance found in asthma. p-agonists are also potent mast cell stabilizers and reduce the release of inflammatory mediators, but whether this contributes to their bronchodilator effect in asthma is not certain. In animal studies, p-agonists reduce acetylcholine release from airway cholinergic nerves and modulate cholinergic neurotransmission. Beta-agonists also reduce the leak and plasma exudation in the bronchial microcirculation, which has been precipitated by inHammatory mediators. Both P-l and 13-2 receptors are found in human lung. In dog tracheal smooth muscle which has direct sympathetic innervation, the ratio of P-l:P-2 receptors is approximately 1:4. Functional studies show that p-agonists relax canine tracheal smooth muscle only via P-2 receptors, whereas the sympathetic nerves relax airway smooth muscle only via P-l receptors, suggesting that 13-1 receptors are regulated by sympathetic nerves, whereas 13-2 receptors are controlled by circulating eatecholamines." In human airway smooth muscle, which lacks direct sympathetic innervation, no P-l receptors would be expected. Both autoradiographic and functional studies confirm that human airway smooth muscle has only 13-2 receptors. Submucosal glands, which have a sparse sympathetic nerve supply, do have a small number ofP-l receptors, as predicted. 11 The possibility that p-receptor function may be imAJrway FunctIon In Asthma (Peter J. Bamea)

paired in asthma has been investigated extensively.14 Early studies showed reduced cardiovascular and leukocyte responses to p-agonists in asthmatic patients, but these changes could be explained by tolerance due to prior exposure to p-agonist therapy. In untreated asthmatic patients, the response to p-agonists has usually been found to be normal. Whether p-receptor function in airways is normal in asthma is still uncertain, however, Higher doses of p-agonists may be required to produce maximal bronchodilation in asthmatic patients than in normal subjects, which could be interpreted as defective airway p-receptor function in asthma." The more constricted the airway is initially, then the greater the dose of p-agonists that is required to reverse this bronchoconstriction. This apparent "defect" in p-receptor function could, therefore, be explained by functional antagonism, so that the more contracted smooth muscle is initially the higher the concentration ofp-agonist required to release the contraction. Studies on (.i-receptor function in isolated airways from asthmatic patients are conHicting. Some have shown defective relaxant responses to isoproterenol, so it is possible that some small defect in (.i-receptor function, as a result of asthma (perhaps due to inflammatory mediators), is possible. ALPHA-ADRENOCEPTORS

Beta-agonists may constrict human airways under certain conditions and various lines of evidence suggest that a-receptor function may be enhanced in asthma. Thus, while normal human airways fail to respond to norepinephrine in vitro, diseased airways contract, suggesting that a-adrenergic responses have been activated." Similarly, in canine airways, norepinephrine has no contractile effect, but pre-exposure to histamine "turns on" a-adrenergic contraction. This activation of a-adrenergic responses is not due to any measurable change in a-receptors, howeven 17 Similarly, in clinical studies, o-agonlsts have no effect on normal subjects but cause bronchoconstriction in asthmatic subjects." If a-receptor activation contributed to bronchoconstriction in asthma, a-antagonists should be beneficial. Several studies have reported that a-antagonists protect against various bronchoconstrictor challenges, but the drugs used have had other pharmacologic effects (such as antihistamine activity) which might account fur the beneficial effect. With a specific a-blocker; such as prazosin, there is no significant change in lung function or effect on histamine responsiveness in asthmatic subjects, although there is a small protective effect against exercise-induced asthma (and this could be explained by an effect on bronchial blood flow which may counteract airway cooling). Current evidence suggests that a-receptors play little part in the pathogenesis of asthma.

NON-ADRENERGIC, NON-CHOLINERGIC MECHANISMS

A third nervous system, which is neither adrenergic nor cholinergic, has been demonstrated in the airways of many species, including humans. The role of these nerves in controlling airwayfunction is unknown, since the neurotransmitters are not yet certain, and there are no specific antagonists available." There is increasing evidence that neuropeptides may be involved and several neuropeptides have now been localized to nerves in human airways.

Non-adrenergic Inhibitory Nemes As discussed above, there is an inhibitory neural pathway in human airways which is non-adrenergic, and this neural mechanism may assume particular importance in human airways because;lin the absence of adrenergic innervation, it is the sole inhibitory pathway. It is possible that defective function of this mechanism may contribute to bronchial hyperresponsiveness." Although a purine was originally proposed as a neurotransmitter; there is increasing evidence in favor of a neuropeptide. Of the many regulatory peptides now localized to nerves in airways, only vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) relax airway smooth muscle. These peptides coexist and are localized to efferent nerves which supply airway and vascular smooth muscle and submucosal glands. The distribution ofVIP-immunoreactive nerves in airways is similar to the distribution of cholinergic nerves, and there is some evidence that VIP may be a co-transmitter of acetylcholine. VIP and PHI in vitro are potent relaxants of human bronchi, and are some 50 times more potent than isoproterenol, making them the most potent endogenous bronchodilators so far described. 11 VIP is released when nonadrenergic inhibitory nerves are stimulated in vitro. 21 The main problem in confirming VIP as a neurotransmitter is that there are no specific blockers, although studies with antibodies, and the development of tolerance to VI~ show a reduction in nonadrenergic relaxation which supports the idea that VIP and PHI may be neurotransmitters of non-adrenergic inhibitory nerves, As VIP may be a co-transmitter in cholinergic nerves, there may be a functional relationship between VIP and acetylcholine. VIP reduces the contractile effect of acetylcholine in airway smooth muscle, and so may act as a "brake" to cholinergic bronchoconstriction. In asthma there is an inflammatory response in the airway and inflammatory cells, such as mast cells, eosinophils and neutrophils, release peptidases which may increase the degradation of VIE This would remove the braking effect of VIP on cholinergic neurotransmission, leading to exaggerated effects, which might contribute to bronchial hyperresponsiveness. CHEST I 91 I 5 I MAY, 1987 I Supplement

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VIP may have several other effects in airways. VIP is a potent stimulant of mucus secretion and epithelial ion transport and is likely to have potent effects on the bronchial circulation. Autoradiographic studies show that VIP receptors in human airways are localized to smooth muscle, epithelium and submucosal glands. i3 Non-cholinergic Excitatory Mechanisms In guinea pigs there is evidence for non-cholinergic excitatory nerves in airways, and that substance P may be a neurotransmitter; Substance P is localized to afferent nerves in airways of several species, including humans. fA SP has several effects on airways, including contraction of airway smooth muscle, development of edema and plasma extravasation, and stimulation of mucus secretion~ SP also degranulates mast cells in skin, although this has not yet been demonstrated in airways. A more recently discovered, peptide, calcitonin gene-related peptide (CGRP), is also localized to sensory nerves in human airway, and is probably colocalized with SE CGRP is a more potent contractile agent than S~ and is among the most potent constrictors of human airways so far discovered. Sensory neuropeptides may contribute to the pathology of asthma, since they could be released by local (axon) reflex mechanisms. In asthma, airway epithelium is often disrupted, possibly due to release of eosinophil products, such as airway or basic protein. This may expose unmyelinated nerve endings. Inflammatory mediators (and particularly bradykinin) may stimulate these nerve endings, leading to antidromic activation of collaterals of the sensory nerves with release of potent sensory neuropeptides. J5 This would cause bronchoconstriction, edema and plasma extravasation from increased microvascular permeability and also mucus secretion. Perhaps continued stimulation of axon reflexes may lead to permanent changes which could account for bronchial hyperresponsiveness. REFERENCES 1 Salter HH. On asthma: its pathology and treatment, 2nd ed. London; Churchill, 1868 2 Nadel]A, Barnes PJ. Autonomic regulation of the airways. Ann Rev Med 1984; 35:451-67 3 Barnes PJ. The third nervous system in the lung: physiology and clinical perspectives. Thorax 1984; 39:561-67 4 Skoogh B-E. 1i'ansmission through airway ganglia. Eur J Respir Dis 1983; 131:159-70

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5 Barnes PJ, Basbaum CB, Nadel JA. Autoradiographic localization of autonomic receptors in airway smooth muscle: marked diffeJlences between large and small airways. Am Rev Respir Dis 1983; 127:758-62 6 Ingram RH, Wellman J], McFadden ER, Mead J. Relative contribution of large and small airways to flow limitation in normal subjects before and after atropine and isoproterenol. J Clin Invest 1977; 59:696-703 7 Richardson JB. Nerve supply to the lungs. Am Rev Respir Dis 1979; 119:785-802 8 Ind P~ Scriven AJI, Dollery CI: Use of tyramine to probe pulmonary noradrenaline release in asthma. Clin Sci 1983; 64:9 9 Barnes PJ. Endogenous catecholamines and asthma. J Allergy Clin Immunol (in press) asthma 10 Barnes ~ FitzGerald G, Brown M, Dollery C. N~ and changes in circulating epinephrine, histamine and cortisol. N Engl J Med 1980; 303:263-67 11 Carstairs Jft, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta-adrenoeeptor subtypes in human lung. Am Rev Respir Dis 1985; 132:541-47 12 Flavahan NA, Aarhus LL, Rimele 1}, Vanhoutte PM. Respiratory epithelium inhibits bronchial smooth muscle tone. J Appl Physioll985; 58:834-838 13 Barnes PJ, Nadel JA, Skoogh B-E, Roberts JM. Characterization of beta-adrenoceptor subtypes in canine airway smooth muscle by radioligand binding and physiologic responses. J Pharmacol Exp Ther 1983; 225:456-61 14 Barnes P1 Ind P~ Dollery CI: Beta adrenoeeptors in asthma and their response to agonists. In: Kay AS, Austen KF, Lichtenstein LM, eds. Asthma: Physiology, immunopharmacology and treatment. London: Academic Press, 1984; 339-58 15 Barnes P], Pride NB. Dose-response curves to inhaled betaadrenoceptor agonists in normal and asthmatic subjects. Br J Clin Pharmacoll983; 15:677-82 16 Kneussl M~ Richardson JB. Alpha-adrenergic receptors in human and canine tracheal and bronchial smooth muscle. J Appl Physioll978; 45:307-11 17 Barnes PJ, Skoogh B-E, Brown JK, Nadel JA. Activation of alphaadrenergic responses in tracheal smooth muscle: a post-receptor mechanism. J Appl Physioll983; 54:1469-76 18 Black JL, Salome C, Yan Ie, Shaw J. The action of prazosin and propylene glycol on methoxamine-induced bronchoconstriction in asthmatic subjects. Br J Clin Pharmac 1984; 18:349-53 19 Barnes PJ. The third nervous system in the lung: physiology and clinical perspectives. Thorax 1984; 39:561-67 20 Richardson JB. Nonadrenergic inhibitory innervation of the lung. Lung 1981; 159:315-22 21 Palmer JB, Cuss FMC, Barnes PJ. Vasoactiveintestinal peptide, peptide histidine methiomne and non-adrenergic inhibitory nerves in human airways. J Appl Physiol (in press) 22 Said SI. Vasoactivepeptides in the lung, with special reference to vasoactive intestinal peptide. Exp Lung Res 1982; 3:343-48 23 Barnes PJ, Carstairs JR. Autoradiographic localization of VIP receptors in guinea pig and human lung. Br J Pharmacoll986; 87:174 24 LundbergJM, MartlingC-R, SariaA. Substance P and capsaicininduced contraction of human bronchi. Acta Physiol Scand 1983; 119:49-53 25 Barnes PJ. Asthma as an axon reflex. Lancet 1986; i:242-45

Airway Function In Asthma (Peter J. Bames)