4. Innervation Control of Airway Caliber by Autonomic Nerves in Asthma and in Chronic Obstructive Pulmonary Disease1,2 JOHAN C. DE JONGSTE, ROBERTO C. JONGEJAN, and KAREL F. KERREBIJN
Introduction In chronic obstructive pulmonary disease (COPO) and asthma, airway obstruction is mainly determined by the contractile state of the airway smooth muscle, the thickness of the airway walls, lung elastic recoil, and mucus hypersecretion. The autonomic innervation can influence airway caliber by acting on airway muscle, vessels, and glands in the bronchial wall. It is likely that abnormal activity of autonomic nerves contributes to airway narrowing in COPO and asthma, but the nature of this putative abnormality has been difficult to clarify. Complex interactions occur between components of the parasympathetic and sympathetic system, and a third class of neurotransmitters, the neuropeptides, has been demonstrated in human airways and may prove relevant to the pathogenesis of obstructive airway disease. Inflammatory reactions in the airway wall are clearly involved in airwayobstruction and hyperresponsiveness,and interactions may occur between inflammation and autonomic control. In this report we summarize recent findings on the relevance ofthe autonomic airway innervation in asthma and in COPO. Autonomic Nerve Supply to the Airways The autonomic innervation of the human lung has cholinergic, noradrenergic, and peptidergic efferent components and several types of sensory nerves, the majority of which are nonmyelinated C-fibers (1-3). Cholinergic efferents run from the vagus nuclei in the brainstem through the vagus nerves towards small ganglia in the bronchial wall. Short postganglionic nerves supply bronchial and vascular muscle, mucous glands and, probably, mast cells. Acetylcholine stimulates muscarinic receptors on muscle cells and mucous glands that mediate contraction and mucus secretion. A subset of muscarinic receptors that inhibit acetylcholine release (4) has been localized on the presynaptic membrane and may serve as a negative feedback. Postganglionic parasympathetic nerves also contain vasoactive intestinal peptide (VIP), and this peptide may be coreleased together with acetylcholine (5). Also, the related peptide histidine methionine (PHM) is present in the same nerves (6). Both VIP and PHM have been shown to relax smooth muscle (7). Parasympathetic nerves supply all airway generations and are most prominent in central airways. In contrast to
SUMMARY Autonomic nerves cen Influence airway caliber via their effects on airway smooth muscle, bronchial ve_ls, and mucous glands and may therefore contribute to airway narrowing In asthma or In chronic obstructive pulmonary disease (CaPO). Human lungs receive cholinergic, noradrenerglc, and peptlderglc efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both In asthma and In COPO.Reflex vegal activity may be enhanced beceuse of epithelial damage and exposition of sensory nerve endings to nonspecific Irritants. Other possible mechanisms Include defects In preJunctlonal receptors that Inhibit acetylcholine release, several postJunctlonal fectors that nonspeclflcally enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and Interactions between Inflammatory mediators and the cholinergic ayetem. The main direct bronchodllatlng nerve actiVity In human lungs Is nonadrenerglc, and acenty date suggest that nonadrenerglc Inhibitory nerve activity may be verlably reduced In asthmatics. Humen airway muscle virtually lacks adrenergic Innervation, but adren. erglc nerves may Influence airway caliber by actIng on bronchIal vessels, mucous glands, and pereaympathetlc nerves and ganglia. The response of asthmatic airways to II-agonlsts seemslntrln. slcelly normal, but It may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control Is present In the airways of patients with COPO. The physiologic relevance of excitatory neuropeptldes In sensory nerves In human airways Is uncertain. Tachyklnlns heve prolnflammatory and spasmogenic properties and are therefore of potential Interest as a fector In the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways In asthma but not In capo. AM REV RESPIR DIS 1991; 143:1421-1426
acetylcholine, VIP seems to occur selectively in central airways, whereas VIP fibers, receptors, and in vitro effects are apparently absent in bronchioles (2, 7). The sympathetic innervation of the human lung is sparse. Sympathetic ganglia are localized in the cervical prevertebral region, and postganglionic fibers, containing norepinephrine and neuropeptide Y (6), supply ganglia, blood vessels, and mucous glands in the bronchial wall (1). Airway smooth muscle receives few sympathetic nerves (1, 8, 9), but it has many relaxing lh-receptors (10). In parasympathetic ganglia, sympathetic nerves supply a-receptors, which inhibit cholinergic activity (11). Also, sympathetic fibers end on parasympathetic postganglionic nerves where they seem to inhibit cholinergic output via stimulation of prejunctional Bi-receptors (8). Pulmonary vessels are contracted by norepinephrine via an effect on a receptors, and by neuropeptide Y (6, 12). Human lungs have many noninnervated !3t-receptors on epithelial cells; their function is not clear. Neuropeptides have been identified in ganglia and in nonmyelinated afferents in the bronchial wall (Y, 12, 13). Peptides in sensory nerves are probably released via axon reflexes after stimulation of C-fiber endings between epithelial cells (14, 15). Peptide-containing fibers run in the epithelial layer and surround blood vessels, bronchial muscle bundles, and
ganglia (16-18). They contain the tachykinins substance P (SP), Neurokinins A and B (NKA, NKB), and calcitonin gene-related peptide (CORP) (2, 13, 19). Tachykinins contract bronchial muscle, dilate bronchial arteries, cause leakiness of postcapillary venules and increase mucus secretion. CORP also seems to contract human airway muscle (20). In addition, in the guinea pig tachykinins facilitate cholinergic neurotransmission (21), release mediators from rat mast cells(22), and initiate an inflammatory reaction in the bronchial wallcalled neurogenic inflammation (15, 17, 23). Vicious circles may occur because mediators can, in turn, augment nerve activity or enhance end organ responsiveness (22, 24, 25). Tachykinins and other neuropeptides are probably inactivated via proteases released from mast cells, inflammatory cells, and epithelium (26, 27). It should be remembered that
1 From the Department of Pediatrics, Subdivision of Pediatric Respiratory Medicine, University Hospital Rotterdam/Sophia Children's Hospital, and Erasmus UniversityRotterdam, Rotterdam, The Netherlands. 'Correspondence and requests for reprints should be addressed to Dr. J. C. de Jongste, Department of Pediatric Respiratory Medicine, Sophia Children's Hospital, Gordelweg 160,3038GE Rotterdam, The Netherlands.
1421
DE JONGSTE. JONGEJAN. AND KERREBIJN
1422
some of these effects have been found in animals; the data on human tissue are scanty.
The Cholinergic System Cholinergic nerve activity contributes significantly to the bronchial narrowing both in asthma and in COPD. This is obvious from the beneficial effect of anticholinergic drugs (28, 29), which may even be first choice as a bronchodilator in COPO (29). Cholinergic bronchoconstriction could well be due to increased reflex activity of parasympathetic nerves (2). Vagal reflexes are elicited in the airways after stimulation of afferent nerve endings by cigarette smoke, by other nonspecific irritants or by inflammatory mediators, and epithelial damage could enhance this process by exposing these nerve endings to the noxious stimuli. Apart from increased reflex activity of the cholinergic system, several factors may be responsible for the cholinergic component of airway narrowing, and three of these will be discussed in some detail.
50
00
30
'0
10
o
10
20
]0
1i0
so
60
Defective Braking Mechanisms
Pastjunctional Factors The effect of cholinergic activation may be greatly enhanced by various postjunctional mechanisms, such as the cholinergic responsiveness of airway muscle, and airway wall thickness (35). There is conclusive evidence that patients with COPO have a normal airway smooth muscle responsiveness to cholinergic stimulation (36-39). Concentrationresponse curves to methacholine are similar in airways from patients with COPD and those from control subjects (figure 2), and there is no relation between the position of
70
80
'JO
100
r--i---t---+-+---t---r-+-+--+---1 ,------
M~
_
Fig. 1. Responses of iSOlated central airways from 10 patients with COPO (solid circles) and 10 control subjectswithout COPO(opencircles) to electric field stimulation (EFS) in vitro. The vertical axis depicts the amplitudes of the cholinergic twitch contraction (upper psnel) and of the nonadrenergic relaxation phase (lONer panel) of the responseto EFS,bothexpressedas a percentageof the maximalactivecontraction rangelor each airway (the difference betweenmaximal contractionto 10-' M methacholineand maximal relaxationin Ca-free buffer with 10-' M isoproterenol). Field stimulation responses are shown in relation to the baseline contractile stateof the airway (horizontalaxis) becausethe amplitudesof the contractileand relaxation phasesarecritically dependent on the baseline airway muscle contractile state. Each airwaywas exposed to a range of methacholine concentrations (10-0 to 10-< M),and EFS responseswereelicitedatvariouslevelsof induced stable muscle contraction (see reference 34). NQ significant differences were found betweenCOPO and contrQI airways. Values are means ± SEM.
the dose-response curve and maximal bronchoconstriction in vivo and those in vitro within a group of patients with COPD (38). Airway smooth muscle from asthmatics is difficult to obtain, and a relativelysmall number of studies has shown either exaggerated, normal, or decreased effects of cholinergic stimulation on isolated asthmatic airways (40-45). Different results between various studies are probably due to differences in patient selection and tissue processing. Asthmatic airway muscle hyperresponsiveness in vitro may well depend on smooth muscle hyperplasia (41). It seems likely that the degree of muscle hyperplasia as it is commonly seen in asthma will have a profound effect on the bronchoconstriction that results from a given level of cholinergic stimulation. This is clearly different from COPD, where muscle hyperplasia is much less prominent than in asthma, especially in central airways (as Jeffery pointed out in this Symposium).
- - -r-r- - - - , - - -
I
10- 7
10 B
_ _ BASELINE {%MCl
An increasing number of presynaptic receptors has been identified that inhibit cholinergic output, including muscarinic M 1 , histamine H 3 , adrenergic P1> and probably en kephalin receptors (4, 8, 30-32). Together with ganglionic a-receptors these may be regarded as brakes to reduce cholinergic excitation of airway tissues. Corelease of VIP from cholinergic nerves is another potential braking mechanism underlining the functional importance of the cholinergic system. Defects in any of these brakes may lead to cholinergic bronchoconstriction. A recent study suggested that in asthma presynaptic Ms-receptors might be deficient because pilocarpin, in a concentration that selectively stimulated M.-receptors, could inhibit SO.induced reflex bronchoconstriction in normal subjects but not in asthmatics (33). There are no studies on M.-receptor function in COPO, and results of in vitro experiments where human bronchi werestimulated with electric currents have suggested that airways from patients with COPO have similar responses to activation of postganglionic nerves as control airways, and this argues against a defective presynaptic M 1 mechanism in COPD (34) (figure I).
ISOMETR rc FORCE (mglmg OW)
ISOTONIC RESPONSE TO EFS (% MC)
10 6
-----,
1D- 5
10- 4
THACHOLINE CONCENTRAT ION 1M)
Fig. 2. Cumulative concentration-response curves to methacholine, madeon isolated airwaysfrom10patients with COPO(closed symbols) (mean age,64 ± 2 yr; vital capacity, 91 ± 5 0Al of predicted; FEVtNC%, 53 ± 5%; seven smokers, three ex-smokers) and 10 control SUbjects (opensymbols) (meanage,59 ± 3 yr, VC. 104 ± 4% of predicted; FEV;NC,75 ± 2%; lour smokers, six ex-smokers). Sensitivity to methacholine (-logEC••) was6.05 ± 0.12and 6.24 ± 0.14 for COPDand control airways, respectively. Curveswerenotsignificantly different.Values aremeans ± SEM.(Datafromreference 45.)
Inflammation Inflammation may interact with cholinergic activity in several ways. There are some data indicating that prostaglandins and thromboxanes modulate cholinergic neurotransmission in experimental animals (46-49), and potentiation of cholinergic twitch contractions by exogenous prostaglandin F1
Introduction In chronic obstructive pulmonary disease (COPO) and asthma, airway obstruction is mainly determined by the contractile state of the airway smooth muscle, the thickness of the airway walls, lung elastic recoil, and mucus hypersecretion. The autonomic innervation can influence airway caliber by acting on airway muscle, vessels, and glands in the bronchial wall. It is likely that abnormal activity of autonomic nerves contributes to airway narrowing in COPO and asthma, but the nature of this putative abnormality has been difficult to clarify. Complex interactions occur between components of the parasympathetic and sympathetic system, and a third class of neurotransmitters, the neuropeptides, has been demonstrated in human airways and may prove relevant to the pathogenesis of obstructive airway disease. Inflammatory reactions in the airway wall are clearly involved in airwayobstruction and hyperresponsiveness,and interactions may occur between inflammation and autonomic control. In this report we summarize recent findings on the relevance ofthe autonomic airway innervation in asthma and in COPO. Autonomic Nerve Supply to the Airways The autonomic innervation of the human lung has cholinergic, noradrenergic, and peptidergic efferent components and several types of sensory nerves, the majority of which are nonmyelinated C-fibers (1-3). Cholinergic efferents run from the vagus nuclei in the brainstem through the vagus nerves towards small ganglia in the bronchial wall. Short postganglionic nerves supply bronchial and vascular muscle, mucous glands and, probably, mast cells. Acetylcholine stimulates muscarinic receptors on muscle cells and mucous glands that mediate contraction and mucus secretion. A subset of muscarinic receptors that inhibit acetylcholine release (4) has been localized on the presynaptic membrane and may serve as a negative feedback. Postganglionic parasympathetic nerves also contain vasoactive intestinal peptide (VIP), and this peptide may be coreleased together with acetylcholine (5). Also, the related peptide histidine methionine (PHM) is present in the same nerves (6). Both VIP and PHM have been shown to relax smooth muscle (7). Parasympathetic nerves supply all airway generations and are most prominent in central airways. In contrast to
SUMMARY Autonomic nerves cen Influence airway caliber via their effects on airway smooth muscle, bronchial ve_ls, and mucous glands and may therefore contribute to airway narrowing In asthma or In chronic obstructive pulmonary disease (CaPO). Human lungs receive cholinergic, noradrenerglc, and peptlderglc efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both In asthma and In COPO.Reflex vegal activity may be enhanced beceuse of epithelial damage and exposition of sensory nerve endings to nonspecific Irritants. Other possible mechanisms Include defects In preJunctlonal receptors that Inhibit acetylcholine release, several postJunctlonal fectors that nonspeclflcally enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and Interactions between Inflammatory mediators and the cholinergic ayetem. The main direct bronchodllatlng nerve actiVity In human lungs Is nonadrenerglc, and acenty date suggest that nonadrenerglc Inhibitory nerve activity may be verlably reduced In asthmatics. Humen airway muscle virtually lacks adrenergic Innervation, but adren. erglc nerves may Influence airway caliber by actIng on bronchIal vessels, mucous glands, and pereaympathetlc nerves and ganglia. The response of asthmatic airways to II-agonlsts seemslntrln. slcelly normal, but It may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control Is present In the airways of patients with COPO. The physiologic relevance of excitatory neuropeptldes In sensory nerves In human airways Is uncertain. Tachyklnlns heve prolnflammatory and spasmogenic properties and are therefore of potential Interest as a fector In the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways In asthma but not In capo. AM REV RESPIR DIS 1991; 143:1421-1426
acetylcholine, VIP seems to occur selectively in central airways, whereas VIP fibers, receptors, and in vitro effects are apparently absent in bronchioles (2, 7). The sympathetic innervation of the human lung is sparse. Sympathetic ganglia are localized in the cervical prevertebral region, and postganglionic fibers, containing norepinephrine and neuropeptide Y (6), supply ganglia, blood vessels, and mucous glands in the bronchial wall (1). Airway smooth muscle receives few sympathetic nerves (1, 8, 9), but it has many relaxing lh-receptors (10). In parasympathetic ganglia, sympathetic nerves supply a-receptors, which inhibit cholinergic activity (11). Also, sympathetic fibers end on parasympathetic postganglionic nerves where they seem to inhibit cholinergic output via stimulation of prejunctional Bi-receptors (8). Pulmonary vessels are contracted by norepinephrine via an effect on a receptors, and by neuropeptide Y (6, 12). Human lungs have many noninnervated !3t-receptors on epithelial cells; their function is not clear. Neuropeptides have been identified in ganglia and in nonmyelinated afferents in the bronchial wall (Y, 12, 13). Peptides in sensory nerves are probably released via axon reflexes after stimulation of C-fiber endings between epithelial cells (14, 15). Peptide-containing fibers run in the epithelial layer and surround blood vessels, bronchial muscle bundles, and
ganglia (16-18). They contain the tachykinins substance P (SP), Neurokinins A and B (NKA, NKB), and calcitonin gene-related peptide (CORP) (2, 13, 19). Tachykinins contract bronchial muscle, dilate bronchial arteries, cause leakiness of postcapillary venules and increase mucus secretion. CORP also seems to contract human airway muscle (20). In addition, in the guinea pig tachykinins facilitate cholinergic neurotransmission (21), release mediators from rat mast cells(22), and initiate an inflammatory reaction in the bronchial wallcalled neurogenic inflammation (15, 17, 23). Vicious circles may occur because mediators can, in turn, augment nerve activity or enhance end organ responsiveness (22, 24, 25). Tachykinins and other neuropeptides are probably inactivated via proteases released from mast cells, inflammatory cells, and epithelium (26, 27). It should be remembered that
1 From the Department of Pediatrics, Subdivision of Pediatric Respiratory Medicine, University Hospital Rotterdam/Sophia Children's Hospital, and Erasmus UniversityRotterdam, Rotterdam, The Netherlands. 'Correspondence and requests for reprints should be addressed to Dr. J. C. de Jongste, Department of Pediatric Respiratory Medicine, Sophia Children's Hospital, Gordelweg 160,3038GE Rotterdam, The Netherlands.
1421
DE JONGSTE. JONGEJAN. AND KERREBIJN
1422
some of these effects have been found in animals; the data on human tissue are scanty.
The Cholinergic System Cholinergic nerve activity contributes significantly to the bronchial narrowing both in asthma and in COPD. This is obvious from the beneficial effect of anticholinergic drugs (28, 29), which may even be first choice as a bronchodilator in COPO (29). Cholinergic bronchoconstriction could well be due to increased reflex activity of parasympathetic nerves (2). Vagal reflexes are elicited in the airways after stimulation of afferent nerve endings by cigarette smoke, by other nonspecific irritants or by inflammatory mediators, and epithelial damage could enhance this process by exposing these nerve endings to the noxious stimuli. Apart from increased reflex activity of the cholinergic system, several factors may be responsible for the cholinergic component of airway narrowing, and three of these will be discussed in some detail.
50
00
30
'0
10
o
10
20
]0
1i0
so
60
Defective Braking Mechanisms
Pastjunctional Factors The effect of cholinergic activation may be greatly enhanced by various postjunctional mechanisms, such as the cholinergic responsiveness of airway muscle, and airway wall thickness (35). There is conclusive evidence that patients with COPO have a normal airway smooth muscle responsiveness to cholinergic stimulation (36-39). Concentrationresponse curves to methacholine are similar in airways from patients with COPD and those from control subjects (figure 2), and there is no relation between the position of
70
80
'JO
100
r--i---t---+-+---t---r-+-+--+---1 ,------
M~
_
Fig. 1. Responses of iSOlated central airways from 10 patients with COPO (solid circles) and 10 control subjectswithout COPO(opencircles) to electric field stimulation (EFS) in vitro. The vertical axis depicts the amplitudes of the cholinergic twitch contraction (upper psnel) and of the nonadrenergic relaxation phase (lONer panel) of the responseto EFS,bothexpressedas a percentageof the maximalactivecontraction rangelor each airway (the difference betweenmaximal contractionto 10-' M methacholineand maximal relaxationin Ca-free buffer with 10-' M isoproterenol). Field stimulation responses are shown in relation to the baseline contractile stateof the airway (horizontalaxis) becausethe amplitudesof the contractileand relaxation phasesarecritically dependent on the baseline airway muscle contractile state. Each airwaywas exposed to a range of methacholine concentrations (10-0 to 10-< M),and EFS responseswereelicitedatvariouslevelsof induced stable muscle contraction (see reference 34). NQ significant differences were found betweenCOPO and contrQI airways. Values are means ± SEM.
the dose-response curve and maximal bronchoconstriction in vivo and those in vitro within a group of patients with COPD (38). Airway smooth muscle from asthmatics is difficult to obtain, and a relativelysmall number of studies has shown either exaggerated, normal, or decreased effects of cholinergic stimulation on isolated asthmatic airways (40-45). Different results between various studies are probably due to differences in patient selection and tissue processing. Asthmatic airway muscle hyperresponsiveness in vitro may well depend on smooth muscle hyperplasia (41). It seems likely that the degree of muscle hyperplasia as it is commonly seen in asthma will have a profound effect on the bronchoconstriction that results from a given level of cholinergic stimulation. This is clearly different from COPD, where muscle hyperplasia is much less prominent than in asthma, especially in central airways (as Jeffery pointed out in this Symposium).
- - -r-r- - - - , - - -
I
10- 7
10 B
_ _ BASELINE {%MCl
An increasing number of presynaptic receptors has been identified that inhibit cholinergic output, including muscarinic M 1 , histamine H 3 , adrenergic P1> and probably en kephalin receptors (4, 8, 30-32). Together with ganglionic a-receptors these may be regarded as brakes to reduce cholinergic excitation of airway tissues. Corelease of VIP from cholinergic nerves is another potential braking mechanism underlining the functional importance of the cholinergic system. Defects in any of these brakes may lead to cholinergic bronchoconstriction. A recent study suggested that in asthma presynaptic Ms-receptors might be deficient because pilocarpin, in a concentration that selectively stimulated M.-receptors, could inhibit SO.induced reflex bronchoconstriction in normal subjects but not in asthmatics (33). There are no studies on M.-receptor function in COPO, and results of in vitro experiments where human bronchi werestimulated with electric currents have suggested that airways from patients with COPO have similar responses to activation of postganglionic nerves as control airways, and this argues against a defective presynaptic M 1 mechanism in COPD (34) (figure I).
ISOMETR rc FORCE (mglmg OW)
ISOTONIC RESPONSE TO EFS (% MC)
10 6
-----,
1D- 5
10- 4
THACHOLINE CONCENTRAT ION 1M)
Fig. 2. Cumulative concentration-response curves to methacholine, madeon isolated airwaysfrom10patients with COPO(closed symbols) (mean age,64 ± 2 yr; vital capacity, 91 ± 5 0Al of predicted; FEVtNC%, 53 ± 5%; seven smokers, three ex-smokers) and 10 control SUbjects (opensymbols) (meanage,59 ± 3 yr, VC. 104 ± 4% of predicted; FEV;NC,75 ± 2%; lour smokers, six ex-smokers). Sensitivity to methacholine (-logEC••) was6.05 ± 0.12and 6.24 ± 0.14 for COPDand control airways, respectively. Curveswerenotsignificantly different.Values aremeans ± SEM.(Datafromreference 45.)
Inflammation Inflammation may interact with cholinergic activity in several ways. There are some data indicating that prostaglandins and thromboxanes modulate cholinergic neurotransmission in experimental animals (46-49), and potentiation of cholinergic twitch contractions by exogenous prostaglandin F1
