The Role of Neuropeptides in Asthma

The Role of Neuropeptlcles In Asthma* }oan D. Boomtma, M.D., F.C.C.l; and Sami I. Said, M.D.

descriptions of airway innervation over Since theyearsearliest ago, it has been suggested that asthma and 300

bronchial hyperresponsiveness might be explained by some abnormality of neural control. 1 In the early 20th century, however, immunologic responses were described, and theories of asthma pathogenesis involving release of immune mediators gained favor over theories based on neural mechanisms. Recently, with increased knowledge about the complexity of airway innervation and the identification ofbiologically active neuropeptides, there has been renewed interest in the role that neural mechanisms may play in asthma. The purpose of this article is to review evidence relating to the presence and effects of neuropeptides in the lung and to examine their potential significance in the pathophysiology and treatment of asthma. EVIDENCE THAT NEUROPEPTIDES MAY PLAY A ROLE IN AsTHMA

Three areas of evidence suggest that peptides in the lung may contribute to asthma pathogenesis or offer novel approaches to therapy First, a large number of peptides have been identified and localized to the lung (Iable 1). The presence of biologically active peptides in the lung was first documented over 20 years ago," and since that time, many more have been characterized. The majority of peptides occurring in the lung are neuropeptides, 3 that is, they are primarily localized in neurons, though some are present in epithelial cells, endothelial cells, and inflammatory cells as well as nerves. 4 The existence of these peptides in the lung has led to speculation regarding their possible function in airway control. Second, a potential role for neuropeptides in asthma is supported by the fact that these recently identified peptides have a variety of potent effects on the airways.3.4 Peptides have been shown to affect bronchial and vascular smooth muscle tone, airway secretion, microvascular permeability and inHammatory cell function. Thus, neuropeptides have the potential to influence airway function in a number of ways although their precise physiologic or pathophysiologic actions remain to be defined. Third, the potential importance of neural control of the airways has been highlighted by the characterization of an extensive network of nonadrenergic noncholinergic (NANC) nerves in the lung,"The existence of a nervous system which is neither adrenergic nor cholinergic was first observed in *From the Pulmonary Division, Department of Internal Medicine, Northwestern University Medicaf School, and the University of Illinois College of Medicine at Chicago and Veterans Affairs West Side Medical Center, Chicago. Boomsma, 250 East Superior Street, Rm 456,

~nt requeBt,: Dr.

Chicago60611

the gastrointestinal tract," but since the lung develops embryologically from the foregut, it is not surprising that NANC nerves are also present in the lung. The NANC nerves provide the principal neural inhibitory pathway in human airways, and stimulation of this pathway results in striking bronchodilatation," Nonadrenergic noncholinergic excitatory pathways have also been identified. 8 Convincing evidence suggests that neuropeptides are among the neurotransmitters ofNANC nerves.• 11 Thus, neuropeptides may playa primary role in control of airway tone. SELEcrED PEP11DES OF POTENTIAL SIGNIFICANCE

Though a large number of peptides have now been

recognized in the lung, the biologic functions of many of

them remain unclear. Nevertheless, several peptides have been particularly well characterized and appear likely to play important roles in the airways. \fuoactive

Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a widely distributed 28 amino acid-residue peptide." It is present in larger concentrations in the lung than most other peptides,3 and exists in efferent ganglia and nerves associated with airway smooth muscle, blood vessels, and mucous glands." When released from nerve terminals, VIP exerts its effects by binding to specific receptors found throughout the airways.13 Considerable data favor VIP as a likely neurotransmitter of NANC inhibitory nerves. 5.8 Vasoactive intestinal peptide has a number of effects on airway function which suggests a possible role in asthma. It is the most potent endogenous bronchodilator known," and thus, may be an important regulator of airway tone. It is often colocalized with acetylcholine," and if coreleased under certain conditions might modify the bronchoconstrictor effect of cholinergic stimulation. Also, VIP is a potent pulmonary vasodilator" and stimulates mucus secretion," as well as ion transport. 18 Additionall~ VIP may have a role as

Table I-Neuropeptida in the Lang Calcitonin gene-related peptide (CGRP) Cholecystokinin octapeptide (CCK-8) Endothelin-l (ET-l) Enkepbalin Galanin Gastrin-releasing peptide (GRP) Neurokinin A (NKA) Neuropeptide K (NPK) Neuropeptide Y (NPY) Peptide histidine methionine (PHM) Somatostatin Substance P (SP) Vasoactive intestinal peptide {VIP}

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an endogenous modulator of pulmonary inJIammation, inhibiting inflammatory cell function and antagonizing humoral mediators of Inflammatkm." All of these effects suggest that VIP has an important physiologic role in the lung. Substance P and Other Tachylrinins

Substance P (SP) is the most abundant sensory neuropeptide in human lungs.3 It is localized to afferent ganglia and unmyelinated sensory nerves (C 6bers) in the airwaysJO and exerts its effects via specific receptors.11 A related peptide, neurokinin A (NKA), has also been identified in the lung and may be colocalized with SI!ll There is convincing evidence that the tachykinins, including SP and NKA, serve as neurotransmitters of NANC excitatory nerves. l0 •a Substance P causes contraction of airway smooth muscles. and stimulates mucus secretion.· It also may promote mast cell degranulation- and stimulate neutrophil and mononuclear cell chemotaxis," In response to a variety of inhaled irritants, SP is released from sensory nerves via an axon reflex...• The release ofSP initiates a series of local changes in the airways including alterations in blood fI~ increased microvascular permeability, and bronchoconstriction.... This response has been called "neurogenic inflammation,"30 and combined with other tachykinin effects, may be important in the inJIammatory component of asthma. CalcUonin Gene-Related&ptide

Calcitonin gene-related peptide (CGRP) is another sensory neuropeptide which is frequently colocalized with SI!31 Calcitonin gene-related peptide causes bronchial smooth muscle contraction,at but its more important effect appears to be regulation of blood 80w It causes vasodilatation" and may accentuate the edema formation produced by S~:W thereby participating in neurogenic inJIammation. Endothelm-l

Endothelin-l (ET-l) is a unique 21 amino acid-residue peptide isolated in 1988 from the supernatant of aortic endothelial cells.35 It is now known that ET-l is also produced by epithelial cells- and neurons" and may have widespread activity on smooth muscle. Numerous specific ET-l binding sites are present in the lung,38 and ET-l is produced by endothelial cells of pulmonary vessels, as well as tracheal epithelial cells. 38.40 The potent vasoconstrictor activity of ET1 was part of its original description,35but since then, potent activity on nonvascuIar smooth muscle has also been described. 40 •41 ET-l is an extremely potent bronchoconstrictorG and pulmonary vasoconstrictor," and may be released in the airways of asthmatics..... FinalI~ ET-I may modulate airway tone by stimulating the release of other mediators. 45.46 POSSIBLE ROLE OF NEUROPEPTIDES IN THE PATHOGENESIS OF AsTHMA

The identification and characterization of neuropeptides with potent biologic activity in the human lung has led to speculation regarding their possible role in the pathogenesis of asthma. While the precise physiologic or pathophysiologic role of these peptides is unknown, there are a number of ways in which peptides could potentially participate in the 3IOS

pathogenesis of asthma. First of all, it is conceivable that a defect in NANC innervation might contribute to the bronchial hyperreactivity of asthma. The NANC inhibitory nerves provide the only direct bronchodilatory neural mechanism in human airways,7 and a defect in inhibitory control could certainly account for some of the features of asthma. A primary defect of NANC nerves, however, would likely result in abnormalities of other organ systems innervated by NANC pathways, such as the gastrointestinal tract. And although it is possible that a selective defect in NANC nerves exists in asthma, studies in patients with mild asthma have not demonstrated any flaw in NANC inhibitory innervation." A second hypothesis based on experimental and clinical observations suggests that asthma might be due to decreased biologic activity of VIE This could be caused by a de6ciency of VIP neurons, impaired VIP receptor binding, or presence of a VIP inhibitor. In a recent report, sections of airways from asthmatic subjects failed to show any nerves immunoreactive to VIP in contrast to the vast majority of airway sections from normal subjects. 48 This depletion of VIP nerves appeared to be unique since another neuropeptide, substance ~ was present equally in asthmatic and normal airways. While these data do not establish whether VIP de6ciency is a cause or a result of the disease, they do suggest that VIP may have an essential role in asthma. The sensory neuropeptides may also be involved in the pathogenesis of asthma. Release of tachykinins or CGRP in response to a variety of irritants results in bronchoconstrietion, edema formation, and mucus hypersecretion,· typical features of asthma. Thus, inappropriate activation or regulation of neurogenic inJIammation could contribute to the pathogenesis of asthma. FinalI~ normal airway function and tone could be altered by an abnormality of peptidase regulation of neuropeptides. One of the fundamental features of all neurotransmitters is a mechanism for specific degradation or removal at their target sites. 3 Evidence suggests that there are enzymes, bound to specific airway cells, which are capable of cleaving peptide mediators.· One such membrane-bound enzyme that has been studied extensively is neutral endopeptidase which can specifically inactivate tachykinins. 80 As a result, this peptidase appears to modulate the effects of neurogenic inJIammation and may thereby play a role in asthma pathogenesis. THERAPEUTIC POTENTIAL OF NEUROPEPTIDES

Although the pathogenesis of asthma remains unclear, increased understanding of the potent biologic effects of neuropeptides in the lung opens the door to a number of areas of potential therapeutic intervention. The neuropeptide with the most therapeutic promise in airway disease at the present time is VIP which has the ability to relax tracheobronchial smooth muscle, to prevent or reduce the bronchoconstriction induced by a number of inflammatory mediators, and to inhibit inJIammatory cell function. These properties make it an excellent candidate as a "natural" therapeutic agent in asthma. Unfortunately, inhaled VIP appears to be minimally effective in asthmatics. 51 This may be due to a failure of aerosolized VIP to reach

smooth muscle receptors, altered responsiveness of asthmatic airways to VI~ or most likely, rapid degradation or inactivation of VIP by airway enzymes. Peptidase inhibitors have been shown to potentiate the bronchodilator effects of VIP on isolated smooth muscle." Combining VIP with selective enzyme inhibitors may therefore be an effective way of administering VIE More stable VIP analogs may also be practical, for example helodermin, a VIP-like peptide with an extended C-terminus, produces prolonged relaxation of tracheobronchial smooth muscle. 53 Its protracted bronchodilator activity may result from its being more resistant to enzymatic degradation. Studies of aerosolized helodermin in asthmatics remain to be performed. Modulation of sensory neuropeptides may also have therapeutic potential. If neurogenic inflammation proves to be an important mechanism in asthma, then agents that inhibit tachykinin receptors or prevent release of sensory neuropeptides may be very useful in asthma. CONCLUSIONS

In the last several years, there has been a tremendous increase in our understanding of the neural control of the airways and the effects of peptides on the lung. The identification ofa large number of neuropeptides with potent biologic activity and the characterization of nonadrenergic noncholinergic nerve pathways with peptide neurotransmitters have expanded our concepts of airway control. Additionally, this new information has led to speculation about the pathogenesis of asthma and the potential for novel therapies. We still know very little about the precise role of these neuropeptides in the normal lung or disease states, but each advance in knowledge brings us closer to the ultimate goal of providing new approaches to the treatment of asthma. REFERENCES

1 Barnes PJ. Neural control of human airways in health and disease. Am Rev Respir Dis 1986; 134:1289-314 2 Said SI. Vasoactive substances in the lung. In: Proceedings of the tenth Aspen emphysema conference. 1967; USPHS publication no. 1787:223-28 3 Said SI. In8uence of neuropeptides on airway smooth muscle. Am Rev Respir Dis 1987; 136:52-58 4 Dey RD t Shimosegawa T, Said SI. Lung peptides and the pulmonary circulation. In: Said SIt ed. The pulmonary circulation and acute lung injury. 2nd ed. Mount Kisco, NY: Futura Publishing Co Inc, 1991; 137-75 5 Richardson J. The third nervous system in the lung: physiology and clinical perspectives. Thorax 1984; 39:561-67 6 Burnstock G t Costa M. Inhibitory innervation of the gut. Gastroenterology 1973; 64:141-44 7 Richardson Jt Beland J. Nonadrenergic inhibitory nervous system in human airways. J Appl Physiol1976; 41:764-71 8 Andersson RGG t Grundstrom N. The excitatory noneholinergic, nonadrenergic nervous system of the guinea-pig airways. Eur J Respir Dis 1983; 64:141-57 9 Matsuzald Yt Hamasaki Yt Said SI. Vasoactive intestinal peptide: a possible transmitter of nonadrenergic relaxation of guinea pig airways. Science 1980; 210:1 t252-53 10 Nicoll RA, Schenker C, Leeman SEe Substance P as a transmitter candidate. Ann Rev Neurosci 1980; 3:227-68 11 Dey RD t Mitchell H~ Coburn RF. Organization and development of peptide-containing neurons in the airways. Am J Respir

Cell Mol Bioi 1990; 3:187-88 12 Dey RD t Shannon WA, Said Sf. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats and human subjects. Cell TIssue Res 1981; 220:231-38 13 Paul S, Said SI. Characterization of receptors for vasoactive intestinal peptide solubilized from the lung. J Bioi Chern 1987; 262:158-62 14 Palmer JB t Cuss FMC, Barnes PJ. VIP and PHM and their role in nonadrenergic inhibitory responses in isolated human airways. J Appl Physioll986; 61:1 t322-88 15 Laitinen At Partanen M, Hervonen A, et ale VIP-like immunoreactive nerves in human respiratory tract: light and electron microscopic study. Histochemistry 1985; 82:313-19 16 Hamasaki Y, Mojarad Mt Said Sf. Relaxant action of VIP on cat pulmonary artery: comparison with acetylcholine, isoproterenol, and PGE•. J Appl Physioll983; 54:1607-11 17 Peat6eld ACt Barnes PJt Bratcher C, et ale Vasoactive intestinal peptide stimulates tracheal submucosal gland secretion in ferret. Am Rev Respir Dis 1983; 128:89-93 18 Nathanson It Widdicombe JH, Barnes PJ. Effect of vasoactive intestinal peptide on ion transport across dog tracheal epithelium. J Appl Physioll983; 55:1844-88 19 Said SI. VIP as a modulator of lung in8ammation and airway constriction. Am Rev Respir Dis 1991; 143:22-24 20 Lundberg JM t Hokfelt Tt Martling C-R t et ale Substance Pimmunoreactive sensory nerves in the lower respiratory tract of various mammals including man. Cell TIssue Res 1984; 235: 251-61 21 Carstairs JR, Barnes PJ. Autoradiographic mapping of substance P receptors in lung. Eur J Pharmacoll986; 127:295-96 22 Hua X-Yt Theodorsson-Norbeim s. Brodin E, et ale Multiple tachykinins (neurokinin At neuropeptide K and substance P) in capsaicin-sensitive sensory neurons in the guinea-pig. Regul Pept 1985; 13:1-19 23 Saria At Theodorsson-Norheim E, Gamse R, et ale Release of substance P- and substance K-like immunoreactivities from the isolated perfused guinea-pig lung. Eur J Pharmacol 1984; 106: 207-08 24 Lundberg JM t Martling C-R, Saria A. Substance P and capsaicin-induced contraction of human bronchi. Acta Physiol Scand 1983; 119:49-53 25 Coles SJt Neill KH t Reid LM. Potent stimulation of glycoprotein secretion in canine trachea by substance P J Appl Physiol 1984; 57:1323-27 26 Hagermark 0, Hokfelt T, Pernow B. Flare and itch induced by substance P in human skin. J Invest Dermatoll978; 71:233-35 27 Payan G~ Levine JD, Goetzl EJ. Modulation of immunity and hypersensitivity by sensory neuropeptides. J Immunol 1984; 132:1601-04 28 Widdicombe JG. Neural control of airway vasculature and edema. Am Rev Respir Dis 1991; 143:18-21 29 McDonald OM. Neurogenic in8ammation in the respiratory tract: actions of sensory nerve mediators on blood vessels and epithelium of the airway mucosa. Am Rev Respir Dis 1987; 136: 65-72 30 Jancso N, Jancso-Gabor A, Szolesanyi J. Direct evidence for neurogenic in8ammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol 1967; 31:13851 31 Lundberg JM, Anders F-C t Hua X, et ale Coexistence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin. Eur J Pharmacoll985; 108:315-19 32 Palmer JBD, Cuss FMC t Mulderry PK t et aI. Calcitonin generelated peptide is a potent constrictor of buman airway smooth muscle. Thorax 1985; 40:713 CHEST I 101 I 8 I JUNE, 1992 I Supplement

391S

33 McCormack DG, Mak JCW: Coupe MO, et al. Calcitonin generelated peptide vasodilation of human pulmonary vessels. J Appl Physioll989; 67:1265-70 34 Gamse R, Saria A. Potentiation of tachykinin-induced plasma protein extravasation by calcitonin gene-related peptide. Eur J Pharmacoll985; 114:61-66 35 Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411-15 36 Black PN, Ghatei MA, Takahashi K, et al. Formation of endothelin by cultured airway epithelial cells. FEBS Lett 1989; 255:129-32 37 Yoshizawa 1: Shinmi 0, Giaid A, et ale Endothelin: a novel peptide in the posterior pituitary system. Science 1990; 247: 462-64 38 Power RF, Wharton J, Zhao Y, et ale Autoradiographic localization of endothelin-l binding sites in the cardiovascular and respiratory systems. J Cardiovasc Pharmacol 1989; 13(suppl 5): 50-55 39 Ryan US, Glassberg MK, Nolop KB. Endothelin-l from pulmonary artery and microvessels acts on vascular and airway smooth muscle. J Cardiovasc Pharmacoll989; 13(suppl5):57~ . 40 Maggi CA, Giuliani S, Patacchini R, et ale Potent contractile activity of endothelin on the human isolated urinary bladder. Br J Pharmacoll989;96:75S-57 41 Ishikawa T, Yanagisawa M, Kimura S, et aI. Positive inotropic action of novel vasoconstrictor peptide endothelin on guinea pig atria. Am J Physioll988; 255:970-73 42 Uchida Y, Ninomiya H, Saotome M, et aI. Endothelin, a novel vasoconstrictor peptide, as potent bronchoconstrictor. Eur J Pharmacoll988; 154:227-28 43 Boom~ma JD, Foda HD, Said SI. Vasoactive intestinal peptide (VIP) reverses endothelin-induced contractions of guinea pig trachea and pulmonary artery. Biomed Res 1~1; 12:273-77

392S

44 Marini M, Fasoli A, Mattoli S. Release of endothelin in the airways of patients with symptomatic asthma and reversible airflow obstruction [abstract]. Am Rev Respir Dis 1991; 143:

158

45 Boarder MR, Marriott DB. Characterization of endothelin-l stimulation of catecholamine release from adrenal chromaffin cells. J Cardiovasc Pharmacoll989; 13(supplS):223-24 46 DeNucci G, Thomas R, D'Orleans-juste ~ et aI. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the 'release of prostacyclin and endothelium-derived relaxirig factor. Proc Natl Acad Sci USA 1988; 85:9797-800 47 Lammers J-~ Minette ~ McCusker M, et al. Capsaicin-mduced brorichodilation in asthmatic patients: role of non-adrenergic inhibiting system, J Appl Physioll989; 98:325-30 48 Ollerenshaw S, Jarvjs D, Woolcock A, et ale Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N Engl J Med 1989; 320: 1244-48 " 49 Kenny AJ, Bowes MA, Gee NS, et ale Endopeptidase-24.1l: a cell-surface enzyme for metabolizing regulatory peptides. Biochem SocTrans 1985; 13:293-95 50 Nadel JA, Borson DB. Modulation of neurogenic inHammation by neutral endopeptidase. Am Rev Respir Dis 1991; 143:33-6 51 Mojarad M,""GrodeTL, Cox C~ et ale Differential responses of human asthmatics to inhaled vasoactive intestinal peptide (VIP) [abstract]. Am Rev Respir Dis 1985; 131:281 52 Tam EK, Franconi GM, Nadel JA,et ale Protease inhibitors potentiate smooth muscle relaxation induced by vasoactive intestinal peptide in isolated human bronchi. Am J Respir Cell Mol Bioi 1990; 2:449-52 53 Foda HD, Said SI. Helodermin, a C-terminally extended VIP. like peptide, evokes long-lasting tracheal relaxation, Biomed Res 1980; 10:107-10 .

Role of Neuropeptides in Asthma (Boomsma, SaJd)