Molec. Aspects Med. Vol. 11, pp. 351-423, 1990 Printed in Great Britain. All rights reserved.
0098-2997190 $0.00 + .50 ~) 1990 Pergamon Press plc.
NEURAL CONTROL OF AIRWAY FUNCTION: NEW PERSPECTIVES Peter J. Barnes Department of Thoracic Medicine, National Heart and Lung Institute, London SW3 6L Y, U.K.
Contents
Historical Perspective
353
Autonomic Abnormalities in Airway Disease
355
Afferent Nerves
356
Slowly Adapting (Stretch) Receptors Rapidly Adapting (Irritant) Receptors C-Fibre Endings Neuroendocrine Cells
357 357 358 359
359
Cholinergic Mechanisms Cholinergic Innervation Modulation of Cholinergic Neurotransmission Effects on Secretion Cholinergic Receptors Muscarinic Receptor Subtypes Parasympathetic Airway Ganglia Cholinergic Reflexes Cholinergic Mechanisms in Airway Disease
359 361 361 362 363 364 365 365
368
Adrenergic Mechanisms
368 370 371 371 373 378
Sympathetic Innervation Circulating Catecholamines Beta-blockers and Airway Function Cathecholamines in Asthma Beta-adrenoceptors Alpha-adrenoceptors
351
352
Contents
Non-Adrenergic
Non-Cholinergic
Mechanisms
Non-Adrenergic Inhibitory Nerves Vasoactive Intestinal Peptide Non-Cholinergic Excitatory Nerves Calcitonin Gene-Related Peptide Axon Reflexes Other Neuropeptides
Conclusions Acknowledgement References
and Neuropeptides
381 381 382 386 389 389 391
392 392 393
Neural Control of Airways
353
Historical Perspective For m a n y c e n t u r i e s it has been r e c o g n i s e d that the a i r w a y s are innervated. Nerve branches supplying human bronchi were c l e a r l y d e s c r i b e d by B a r t h o l i n u s (1663) in the 17th c e n t u r y and the e m i n e n t L o n d o n physician, Sir Thomas Willis, s p e c u l a t e d that their function was to c o n t r o l the s p r e a d of i n s p i r e d air, and even p o s t u l a t e d that the f u n c t i o n of these nerves may be abnormal in asthma (Willis, 1679). Floyer, himself a sufferer of asthma, also a s c r i b e d to this n e r v o u s v i e w of asthma and b e l i e v e d that an a t t a c k of a s t h m a o c c u r e d w h e n "Nerves are f i l l e d w i t h W i n d y Spirits" (Floyer, 1698). Salter,who also suffered from asthma, in his b r i l l i a n t d e s c r i p t i o n of asthma over I00 years ago, w r o t e that in asthma "There is no p e c u l i a r i t y in the stimulus, the air b r e a t h e d in is the same in the asthmatic and the non-asthmatic.., nor, probably, is there any p e c u l i a r i t y in the i r r i t a b i l i t y of b r o n c h i a l muscle; the p e c u l i a r i t y is c o n f i n e d to the link that c o n n e c t s these two - the n e r v o u s s y s t e m - and consists in its perverse sensibility, in its r e c e i v i n g and t r a n s m i t t i n g on to the muscle, as a s t i m u l u s to c o n t r a c t i o n , that of w h i c h it s h o u l d take no c o g n i z a n c e . . . i t is c l e a r that the v i c e in a s t h m a consists, not in the p r o d u c t i o n of any s p e c i a l irritant, but in the i r r i t a b i l i t y of the p a r t irritated" (Salter, 1868). T h e s e c l i n i c a l o b s e r v a t i o n s w e r e later s u p p o r t e d by p h y s i o l o g i c a l s t u d i e s in e x p e r i m e n t a l animals. Roy and B r o w n (1885), in a s e r i e s of e x p e r i m e n t s in dogs, s h o w e d that stimulation of the vagus n e r v e c a u s e d s p a s m of the airways, w h i c h c o u l d be b l o c k e d by atropine, a drug w h i c h was k n o w n to be beneficial in some a s t h m a t i c patients. Furthermore, they w e r e able to show that v a g a l s t i m u l a t i o n s o m e t i m e s led to relaxation of the airways, and they proposed that the vagus c o n t a i n e d b o t h b r o n c h o c o n s t r i c t o r and b r o n c h o d i l a t o r nerves. Their findings were later e x t e n d e d by Dixon and B r o d i e (Dixon & Brodie, 1903), w h o c o n f i r m e d vagal b r o n c h o c o n s t r i c t o r nerves, and also f o u n d that b r o n c h o c o n s t r i c t i o n in dogs could o c c u r as a result of r e f l e x m e c h a n i s m s , since s t i m u l a t i o n of the nasal m u c o s a produced bronchospasm. These physiological studies strongly supported the g e n e r a l l y held clinical belief that asthma could be e x p l a i n e d by e x c e s s i v e i r r i t a b i l i t y of the airways, p r o d u c e d by n e u r a l m e c h a n i s m s . Unfortunately this subsequently became translated into the popular belief that a s t h m a is due to "nerves", i m p l y i n g tht p s y c h o l o g i c a l f a c t o r s p r e d o m i n a t e . E a r l y in this c e n t u r y a n a p h y l a x i s in g u i n e a pigs was d e m o n s t r a t e d , and was l i k e n e d to human a s t h m a (Meltzer, 1910). A s t h m a then came to be r e g a r d e d as an i m m u n o l o g i c a l disease, and i m m u n o l o g i c a l t h e o r i e s of p a t h o g e n e s i s w h i c h involved r e l e a s e of mediators gained favour over t h e o r i e s b a s e d on n e u r a l m e c h a n i s m s . W i t h f u r t h e r a d v a n c e s in k n o w l e d g e of the complexity of autonomic mechanisms, however, there has b e e n a r e v i v a l of i n t e r e s t in n e u r a l pathways. This i n t e r e s t has i n c r e a s e d recently, w i t h n o t a b l e a d v a n c e s in p h y s i o l o g y and pharmacology and, m o s t recently, w i t h the r e c o g n i t i o n of an e x t e n s i v e peptidergic innervation in the a i r w a y s of s e v e r a l species, i n c l u d i n g humans. The a u t o n o m i c n e r v o u s system controls many aspects of airway function (Richardson, 1979; Nadel & Barnes, 1984; Barnes, 1986a; Leff, 1988; Kaliner & Barnes, 1987). In a d d i t i o n to r e g u l a t i o n of a i r w a y s m o o t h m u s c l e tone, a u t o n o m i c n e r v e s may influence secretion of mucus from s u b m u c o s a l glands, t r a n s p o r t of f l u i d a c r o s s a i r w a y epithelium, p e r m e a b i l i t y and blood flow in the bronchial c i r c u l a t i o n , and release of m e d i a t o r s from m a s t cells a n d o t h e r i n f l a m m a t o r y cells. I n n e r v a t i o n and a u t o n o m i c c o n t r o l of the a i r w a y s is complex and still poorly understood. In a d d i t i o n to classical cholinergic and adrenergic m e c h a n i s m s there e x i s t s a third c o m p o n e n t of n e u r a l control, which is n e i t h e r a d r e n e r g i c nor c h o l i n e r g i c , and c u r r e n t e v i d e n c e has i m p l i c a t e d n e u r o p e p t i d e s as p o s s i b l e n e u r o t r a n s m i t t e r s (Richardson, 1981; Barnes, 1984a; Barnes, 1986b)
354
P.J. Barnes
(Figs 1,2). There have recently been very considerable advances in our u n d e r s t a n d i n g of autonomic regulation of airways. This has resulted from i m p r o v e m e n t in h i s t o c h e m i c a l and ultrastructural t e c h n i q u e s for d e m o n s t r a t i n g nerves, f r o m p h a r m a c o l o g i c a l m e t h o d s for s t u d y i n g a u t o n o m i c receptors, and from physiological methods for m e a s r i n g f u n c t i o n a l e f f e c t s in a i r w a y s m o o t h muscle, g l a n d s a n d the b r o n c h i a l m i c r o c i r c u l a t i o n . Many studies have underlined the significant differences in autonomic i n n e r v a t i o n b e t w e e n d i f f e r e n t species, so that it may be d i f f i c u l t to e x t r a p o l a t e f i n d i n g s from e x p e r i m e n t a l a n i m a l s to m a n (Richardson, 1979). T h e r e are still r e l a t i v e l y few studies on human airways, partly because of the difficulties involved in o b t a i n i n g n o r m a l a i r w a y s and p a r t l y b e c a u s e of the l i m i t a t i o n s i n v o l v e d in s t u d y i n g a i r w a y tone and s e c r e t i o n s in intact man. In r e c e n t years, however, m o r e studies on h u m a n a i r w a y s have been reported, p a r t i c u l a r l y with the recognition that there are no entirely satisfactory animal m o d e l s of h u m a n asthma. In this r e v i e w studies w h i c h r e l a t e to human a i r w a y s are emphasised, a l t h o u g h e v i d e n c e from e x p e r i m e n t a l animals is used w h e r e h u m a n data are not available.
epithelium~ ~ , . gland
I SYMPATHETICI :,.
smoothmuscle
I CIRCULATINGCATECHOLAMINES I ..
ga ncjlion
j pARASYMPATHETIC 1
:-
-.. NON-ADRENERGIC] "L NHIBITORY / Fig I.
I n n e r v a t i o n of a i r w a y s
- a "wiring diagram"
The g e n e r a l p a t t e r n of i n n e r v a t i o n of h u m a n a i r w a y s was d e s c r i b e d long ago (Larsell & Dow, 1933; Gaylor, 1934). L i g h t m i c r o s c o p y s h o w e d that the vagus n e r v e s and f i b r e s f r o m the u p p e r four to five t h o r a c i c s y m p a t h e t i c ganglia form a n t e r i o r and posterior plexuses at the hilum, f r o m w h i c h the two m a i n n e r v e n e t w o r k s arise: the p e r i b r o n c h i a l and p e r i a r t e r i a l plexuses. The peribronchial plexus subdivides into an extrabronchial plexus which is external to the cartilage, a n d a s u b c h o n d r i a l p l e x u s w h i c h lies b e t w e e n the cartilage and the epithelium. Ganglion cells are s c a t t e r e d a l o n g the p e r i b r o n c h i a l p l e x u s down to the level of small bronchi, and are m a i n l y in the extrabronchial plexus. More detailed studies have i n d i c a t e d that n e r v e s s u p p l y a i r w a y s down to the level of r e s p i r a t o r y b r o n c h i o l e s and also s u p p l y s u b m u c o s a l g l a n d s and bronchial vessels (Spencer & Leof, 1964). T h e r e is little i n f o r m a t i o n about the d e v e l o p m e n t of p u l m o n a r y innervation. The a i r w a y s develop embroyologically f r o m the f o r e g u t and the i n n e r v a t i o n may, therefore, s h o w s i m i l a r i t i e s . I n n e r v a t i o n of b r o n c h i has b e e n d e s c r i b e d in the human f o e t u s and neonate (Pessacq, 1971; T a y l o r & Smith, 1971). More recent studies, u s i n g the h i s t o c h e m i c a l n e u r o n a l m a r k e r n e u r o n specific enolase, have shown that neuroblasts, n e r v e fibres and n e u r o e n d o c r i n e cells can be d e t e c t e d in
Neural Control of Airways
355
human lung as early as 8 weeks of gestation, followed by the appearance of c h o l i n e r g i c nerves detected by acetylcholinesterase activity at 10-12 weeks, a d r e n e r g i c nerves, d e t e c t e d by d o p a m i n e - B - h y d r o x y l a s e at 20 weeks and nerves i m m u n o r e a c t i v e for v a s o a c t i v e intetinal p o l y p e p t i d e (VIP) at 20 weeks (Sheppard et al, 1984).
• CHOLINERGIC
I, ACh
A
]_
0098-2997190 $0.00 + .50 ~) 1990 Pergamon Press plc.
NEURAL CONTROL OF AIRWAY FUNCTION: NEW PERSPECTIVES Peter J. Barnes Department of Thoracic Medicine, National Heart and Lung Institute, London SW3 6L Y, U.K.
Contents
Historical Perspective
353
Autonomic Abnormalities in Airway Disease
355
Afferent Nerves
356
Slowly Adapting (Stretch) Receptors Rapidly Adapting (Irritant) Receptors C-Fibre Endings Neuroendocrine Cells
357 357 358 359
359
Cholinergic Mechanisms Cholinergic Innervation Modulation of Cholinergic Neurotransmission Effects on Secretion Cholinergic Receptors Muscarinic Receptor Subtypes Parasympathetic Airway Ganglia Cholinergic Reflexes Cholinergic Mechanisms in Airway Disease
359 361 361 362 363 364 365 365
368
Adrenergic Mechanisms
368 370 371 371 373 378
Sympathetic Innervation Circulating Catecholamines Beta-blockers and Airway Function Cathecholamines in Asthma Beta-adrenoceptors Alpha-adrenoceptors
351
352
Contents
Non-Adrenergic
Non-Cholinergic
Mechanisms
Non-Adrenergic Inhibitory Nerves Vasoactive Intestinal Peptide Non-Cholinergic Excitatory Nerves Calcitonin Gene-Related Peptide Axon Reflexes Other Neuropeptides
Conclusions Acknowledgement References
and Neuropeptides
381 381 382 386 389 389 391
392 392 393
Neural Control of Airways
353
Historical Perspective For m a n y c e n t u r i e s it has been r e c o g n i s e d that the a i r w a y s are innervated. Nerve branches supplying human bronchi were c l e a r l y d e s c r i b e d by B a r t h o l i n u s (1663) in the 17th c e n t u r y and the e m i n e n t L o n d o n physician, Sir Thomas Willis, s p e c u l a t e d that their function was to c o n t r o l the s p r e a d of i n s p i r e d air, and even p o s t u l a t e d that the f u n c t i o n of these nerves may be abnormal in asthma (Willis, 1679). Floyer, himself a sufferer of asthma, also a s c r i b e d to this n e r v o u s v i e w of asthma and b e l i e v e d that an a t t a c k of a s t h m a o c c u r e d w h e n "Nerves are f i l l e d w i t h W i n d y Spirits" (Floyer, 1698). Salter,who also suffered from asthma, in his b r i l l i a n t d e s c r i p t i o n of asthma over I00 years ago, w r o t e that in asthma "There is no p e c u l i a r i t y in the stimulus, the air b r e a t h e d in is the same in the asthmatic and the non-asthmatic.., nor, probably, is there any p e c u l i a r i t y in the i r r i t a b i l i t y of b r o n c h i a l muscle; the p e c u l i a r i t y is c o n f i n e d to the link that c o n n e c t s these two - the n e r v o u s s y s t e m - and consists in its perverse sensibility, in its r e c e i v i n g and t r a n s m i t t i n g on to the muscle, as a s t i m u l u s to c o n t r a c t i o n , that of w h i c h it s h o u l d take no c o g n i z a n c e . . . i t is c l e a r that the v i c e in a s t h m a consists, not in the p r o d u c t i o n of any s p e c i a l irritant, but in the i r r i t a b i l i t y of the p a r t irritated" (Salter, 1868). T h e s e c l i n i c a l o b s e r v a t i o n s w e r e later s u p p o r t e d by p h y s i o l o g i c a l s t u d i e s in e x p e r i m e n t a l animals. Roy and B r o w n (1885), in a s e r i e s of e x p e r i m e n t s in dogs, s h o w e d that stimulation of the vagus n e r v e c a u s e d s p a s m of the airways, w h i c h c o u l d be b l o c k e d by atropine, a drug w h i c h was k n o w n to be beneficial in some a s t h m a t i c patients. Furthermore, they w e r e able to show that v a g a l s t i m u l a t i o n s o m e t i m e s led to relaxation of the airways, and they proposed that the vagus c o n t a i n e d b o t h b r o n c h o c o n s t r i c t o r and b r o n c h o d i l a t o r nerves. Their findings were later e x t e n d e d by Dixon and B r o d i e (Dixon & Brodie, 1903), w h o c o n f i r m e d vagal b r o n c h o c o n s t r i c t o r nerves, and also f o u n d that b r o n c h o c o n s t r i c t i o n in dogs could o c c u r as a result of r e f l e x m e c h a n i s m s , since s t i m u l a t i o n of the nasal m u c o s a produced bronchospasm. These physiological studies strongly supported the g e n e r a l l y held clinical belief that asthma could be e x p l a i n e d by e x c e s s i v e i r r i t a b i l i t y of the airways, p r o d u c e d by n e u r a l m e c h a n i s m s . Unfortunately this subsequently became translated into the popular belief that a s t h m a is due to "nerves", i m p l y i n g tht p s y c h o l o g i c a l f a c t o r s p r e d o m i n a t e . E a r l y in this c e n t u r y a n a p h y l a x i s in g u i n e a pigs was d e m o n s t r a t e d , and was l i k e n e d to human a s t h m a (Meltzer, 1910). A s t h m a then came to be r e g a r d e d as an i m m u n o l o g i c a l disease, and i m m u n o l o g i c a l t h e o r i e s of p a t h o g e n e s i s w h i c h involved r e l e a s e of mediators gained favour over t h e o r i e s b a s e d on n e u r a l m e c h a n i s m s . W i t h f u r t h e r a d v a n c e s in k n o w l e d g e of the complexity of autonomic mechanisms, however, there has b e e n a r e v i v a l of i n t e r e s t in n e u r a l pathways. This i n t e r e s t has i n c r e a s e d recently, w i t h n o t a b l e a d v a n c e s in p h y s i o l o g y and pharmacology and, m o s t recently, w i t h the r e c o g n i t i o n of an e x t e n s i v e peptidergic innervation in the a i r w a y s of s e v e r a l species, i n c l u d i n g humans. The a u t o n o m i c n e r v o u s system controls many aspects of airway function (Richardson, 1979; Nadel & Barnes, 1984; Barnes, 1986a; Leff, 1988; Kaliner & Barnes, 1987). In a d d i t i o n to r e g u l a t i o n of a i r w a y s m o o t h m u s c l e tone, a u t o n o m i c n e r v e s may influence secretion of mucus from s u b m u c o s a l glands, t r a n s p o r t of f l u i d a c r o s s a i r w a y epithelium, p e r m e a b i l i t y and blood flow in the bronchial c i r c u l a t i o n , and release of m e d i a t o r s from m a s t cells a n d o t h e r i n f l a m m a t o r y cells. I n n e r v a t i o n and a u t o n o m i c c o n t r o l of the a i r w a y s is complex and still poorly understood. In a d d i t i o n to classical cholinergic and adrenergic m e c h a n i s m s there e x i s t s a third c o m p o n e n t of n e u r a l control, which is n e i t h e r a d r e n e r g i c nor c h o l i n e r g i c , and c u r r e n t e v i d e n c e has i m p l i c a t e d n e u r o p e p t i d e s as p o s s i b l e n e u r o t r a n s m i t t e r s (Richardson, 1981; Barnes, 1984a; Barnes, 1986b)
354
P.J. Barnes
(Figs 1,2). There have recently been very considerable advances in our u n d e r s t a n d i n g of autonomic regulation of airways. This has resulted from i m p r o v e m e n t in h i s t o c h e m i c a l and ultrastructural t e c h n i q u e s for d e m o n s t r a t i n g nerves, f r o m p h a r m a c o l o g i c a l m e t h o d s for s t u d y i n g a u t o n o m i c receptors, and from physiological methods for m e a s r i n g f u n c t i o n a l e f f e c t s in a i r w a y s m o o t h muscle, g l a n d s a n d the b r o n c h i a l m i c r o c i r c u l a t i o n . Many studies have underlined the significant differences in autonomic i n n e r v a t i o n b e t w e e n d i f f e r e n t species, so that it may be d i f f i c u l t to e x t r a p o l a t e f i n d i n g s from e x p e r i m e n t a l a n i m a l s to m a n (Richardson, 1979). T h e r e are still r e l a t i v e l y few studies on human airways, partly because of the difficulties involved in o b t a i n i n g n o r m a l a i r w a y s and p a r t l y b e c a u s e of the l i m i t a t i o n s i n v o l v e d in s t u d y i n g a i r w a y tone and s e c r e t i o n s in intact man. In r e c e n t years, however, m o r e studies on h u m a n a i r w a y s have been reported, p a r t i c u l a r l y with the recognition that there are no entirely satisfactory animal m o d e l s of h u m a n asthma. In this r e v i e w studies w h i c h r e l a t e to human a i r w a y s are emphasised, a l t h o u g h e v i d e n c e from e x p e r i m e n t a l animals is used w h e r e h u m a n data are not available.
epithelium~ ~ , . gland
I SYMPATHETICI :,.
smoothmuscle
I CIRCULATINGCATECHOLAMINES I ..
ga ncjlion
j pARASYMPATHETIC 1
:-
-.. NON-ADRENERGIC] "L NHIBITORY / Fig I.
I n n e r v a t i o n of a i r w a y s
- a "wiring diagram"
The g e n e r a l p a t t e r n of i n n e r v a t i o n of h u m a n a i r w a y s was d e s c r i b e d long ago (Larsell & Dow, 1933; Gaylor, 1934). L i g h t m i c r o s c o p y s h o w e d that the vagus n e r v e s and f i b r e s f r o m the u p p e r four to five t h o r a c i c s y m p a t h e t i c ganglia form a n t e r i o r and posterior plexuses at the hilum, f r o m w h i c h the two m a i n n e r v e n e t w o r k s arise: the p e r i b r o n c h i a l and p e r i a r t e r i a l plexuses. The peribronchial plexus subdivides into an extrabronchial plexus which is external to the cartilage, a n d a s u b c h o n d r i a l p l e x u s w h i c h lies b e t w e e n the cartilage and the epithelium. Ganglion cells are s c a t t e r e d a l o n g the p e r i b r o n c h i a l p l e x u s down to the level of small bronchi, and are m a i n l y in the extrabronchial plexus. More detailed studies have i n d i c a t e d that n e r v e s s u p p l y a i r w a y s down to the level of r e s p i r a t o r y b r o n c h i o l e s and also s u p p l y s u b m u c o s a l g l a n d s and bronchial vessels (Spencer & Leof, 1964). T h e r e is little i n f o r m a t i o n about the d e v e l o p m e n t of p u l m o n a r y innervation. The a i r w a y s develop embroyologically f r o m the f o r e g u t and the i n n e r v a t i o n may, therefore, s h o w s i m i l a r i t i e s . I n n e r v a t i o n of b r o n c h i has b e e n d e s c r i b e d in the human f o e t u s and neonate (Pessacq, 1971; T a y l o r & Smith, 1971). More recent studies, u s i n g the h i s t o c h e m i c a l n e u r o n a l m a r k e r n e u r o n specific enolase, have shown that neuroblasts, n e r v e fibres and n e u r o e n d o c r i n e cells can be d e t e c t e d in
Neural Control of Airways
355
human lung as early as 8 weeks of gestation, followed by the appearance of c h o l i n e r g i c nerves detected by acetylcholinesterase activity at 10-12 weeks, a d r e n e r g i c nerves, d e t e c t e d by d o p a m i n e - B - h y d r o x y l a s e at 20 weeks and nerves i m m u n o r e a c t i v e for v a s o a c t i v e intetinal p o l y p e p t i d e (VIP) at 20 weeks (Sheppard et al, 1984).
• CHOLINERGIC
I, ACh
A
]_
