Neurohumoral Regulation of Airway Contractile Responses

strictor agonists. Together, these data suggest a role for the NANC inhibitory nervous system in preventing or attenuating bronchospasm. The functional significance of the airway NANC inhibitory system remains to be defined. It has been suggested that a defect in the function of airway NANC inhibitory innervation may contribute to the elevated airway reactivity observed in asthmatic individuals. The observation that ganglionic blockade does not enhance the airway reactivity of normal subjects would argue against such a contention," since efferent autonomic nerve impulse traffic from the central nervous system to the airways would be blocked. However, bronchomotor responsiveness in normal subjects may be affected by nervous (eg, adrenergic and NANC) and non-nervous (eg, arachidonic acid metabolite) inhibitory influences. Nonnervous influences may be sufficient to regulate airway reactivity under conditions of autonomic blockade. As such, inhibition of both neural and non-neural influences may be necessary to induce a state of bronchial hyperreactivity in normal subjects. In addition, a local reflex may exist in the lung to regulate airway responsiveness, such that an axoaxonal connection would exist between afferent nerves and postganglionic NANC inhibitory nerves. This local reflex would allow the conduction of action potentials from afferent nerves to efferent NANC nerves without the involvement of the central nervous system and peripheral autonomic ganglia. Precise determination of the role of the NANC inhibitory system in the regulation of bronchomotor tone under physiologic and pathophysiologic conditions requires the use of a specific NANC inhibitory receptor antagonist, which has yet to be developed. Aside from effects on airway smooth muscle, the NANC inhibitory system may regulate other lung functions, such as mucus secretion, mediator release or pulmonary vascular tone, and epithelial or endothelial permeability Exploration of these other possible regulatory roles of the NANC system may provide valuable insights into the normal and abnormal physiology of the lung. ACKNOWLEDGMENTS: David C. Thompson is a Parker B. Francis Fellow in Pulmonary Research. This work was supported by research grant HL-27025 from the National Heart, Lung, and Blood Institute.

REFERENCES 1 Diamond L, Altiere RJ. The airway nonadrenergic noncholinergic inhibitory nervous system. In: Barnes ~ Kaliner M, eds. Neural Control of the Airways in Health and Disease. New York: Marcel Dekker (in press) 2 Richardson JB, Beland J. Nonadrenergic inhibitory nervous system in human airways. J Appl Physiol1976; 41:764-71 3 Altiere RJ, Szarek JL, Diamond L. Neural control of relaxation in cat airways smooth muscle. J Appl Physiol1984; 57:1536-44 4 Coleman RA, Levy GE A non-adrenergic inhibitory pathway in guinea-pig trachea. Br J Phannacol1974; 52:167-74 5 Altiere RJ, Szarek JL, Diamond L. Neurally mediated nonadrenergic relaxation in cat airways occurs independent ofcholinergic mechanisms. J Pharmacol Exp Ther 1985; 234:590-97 6 Bai TR, Lam R, Prasad FWF. Functional characteristics of post mortem human tracheal smooth muscle. Tenth International Congress of Pharmacology Sydney Australia, 1987:1360 7 Thompson DC, Altiere RJ, Diamond L. Modulation of neurallymediated responses in airways by endogenous substance E Am Rev Respir Dis 1987; 135:AI79

8 Matsusaki Y, Hamasaki Y, Said SI. Vasoactiveintestinal peptide: a possible transmitter of non-adrenergic relaxation of guinea pig airways. Science 1980; 210: 1252-53 9 Lundberg JM, Fahrenkrug J, Hokfelt 1: Martling CR, Larsson 0, Takemoto K, AnggArd A. Co-existence of peptide HI (PHI) and VIP in nerves regulating blood flow and bronchial smooth muscle tone in various mammals including man. Peptides 1984; 5:593-606 10 Cameron AR, Johnston CF, Kirkpatrick C1: Kirkpatrick MCA. The quest for the inhibitory neurotransmitter in bovine tracheal smooth muscle. Q J Exp PhysioI1983; 68:413-26 11 Thompson DC, Altiere RJ, Diamond L. The effects of antagonists of vasoactive intestinal peptide on nonadrenergic noncholinergic inhibitory responses in feline airways. Peptides (in press) 12 Diamond L, O'Donnell M. A nonadrenergic vagal inhibitory pathway to feline airways. Science 1980; 208: 185-88 13 Matsumoto N, Inoue H, Ishii M, Inoue C, Sasaki H, Takishima 1: Effective sites by sympathetic beta-adrenergic and vagal nonadrenergic inhibitory stimulation in constricted feline airways. Am Rev Respir Dis 1985; 132:1113-17 14 Palmer JBD, Cuss FMC, Barnes PJ. VIP and PHM and their role in nonadrenergic inhibitory responses in isolated human airways. J Appl Physiol1986; 61:1322-28 15 Michoud MC, Amyot R, Jeanneret-Grosjean A, Couture J. Reflex decrease of histamine-induced bronchoconstriction after laryngeal stimulation in humans. Am Rev Respir Dis 1987; 136:618-22 16 Szarek JL, Gillespie MN, Altiere RJ, Diamond L. Reflex activation of the nonadrenergic noncholinergic inhibitory nervous system in feline airways. Am Rev Respir Dis 1986; 133:115962 17 Ichinose I, Inoue H, Miura M, Yafuso N, Nogami H, Takishima 1: Possible sensory receptor of nonadrenergic inhibitory nervous system. J Appl Physiol1987; 63:923-29 18 Bai TR, Macklem n: Martin JG. The effects of parasympathectomy on serotonin-induced bronchooonstriction in the cat. Am Rev Respir Dis 1986; 133:110-15 19 Bai TR, Macklem Pl, Martin JG. Airway responses to aerosolized methacholine in the cat: effects of partial or complete vagosyrnpathectomy Am Rev Respir Dis 1986; 135:190-93 20 Sterk ~ Daniel EE, Zamel N, Hargreave FE. Limited maximal airway narrowing in nonasthmatic subjects: role of neural control and prostaglandin release. Am Rev Respir Dis 1985; 132:865-70

Neurohumoral Regulation of Airway Contractile Responses Alan R. Lefj; M.D., F.C.C.R·

B

ronchomotor tone is the net product of moment-tomoment interactions between the autonomic nervous system, circulating humoral influences, and endogenous production of locally secreted mediators. Some degree of airway smooth muscle contraction exists in all individuals. In normal persons, it appears to result largely from parasympathetic innervation to the airway 1 Endogenous bronchomotor tone theoretically is antagonized physiologically by inhibitory parasympathetic reflexes and by circulating epinephrine. 2 Direct innervation to human airways by sympathetic nerves is insignificant. The homeostatic role of sympathetic secretion in regulating broncho• Associate Professor, Department of Medicine, University of Chicago. Reprint requests: Dr. Leff, Department of Medicine, Box 98, 5841 South Maryland, Chicago 60637 CHEST / 93 I 6 I JUNE, 1988

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motor tone, however, remains to be defined. Recent investigations indicate that endogenous secretion of catecholamine does not increase during bronchoconstriction, 3 unless it is associated with severe hypoxemia or hypotension. 3.4 Nonadrenergic inhibitory innervation (NAI) is capable of antagonizing exogenously induced changes in bronchomotor tone." However, the NAI system also is not activated by changes in airway caliber, and the homeostatic significance of this system for airway innervation also remains undefined. In asthmatic individuals, bronchomotor tone is increased substantially Because parasympatholytic agents largely are ineffective in treating asthma, it appears that this increase is not related substantially to increased parasympathetic activit~ Scores of other contractile influences have been suggested to account for the increase in bronchomotor tone in asthmatic individuals. The role of beta-adrenergic "deficiency" seems questionable, since normal individuals show no increase in airway reactivity even under conditions of nearly complete beta-adrenoceptor blockade. Recent studies have elucidated mechanisms for modulation of bronchomotor tone by the overlying airway epithelium and the underlying serosa from which neurohumoral and fixed and circulating blood elements are transported. The epithelium appears to secrete mediator(s) that cause tonic inhibition of bronchomotor tone. Removal of the epithelial layer augments airway contractile responses in dogs to acetylcholine, histamine, and serotonin in vitro. 6 However, these experiments have been performed under conditions greatly removed from the physiologic state, and there is a need to establish the inhibitory role of bronchial epithelium in situ. Under other circumstances, products of granulocytic infiltration and, perhaps, environmental insults (eg, ozone) elicit airway hyperreactivity that appears to be regulated at least in part by the bronchial epithelium. Neutrophilic infiltration appears to be an essential component of immunemediated airway hyperreactivity in the rabbit. 7 The major basic protein of eosinophils appears to augment airway contractility of airway smooth muscle when applied to the tracheal epithelium of the guinea pig. 8 Regional secretion of mediator long has been thought to underlie the pathogenesis of asthmatic bronchoconstriction. However, no specific pharmacologic antagonist reverses asthmatic bronchoconstriction, and all effective therapeutic agents currently used elicit bronchoconstriction by stimulating inhibitory receptors on airway smooth muscle. This finding may reflect the virtual certainty that during asthmatic bronchoconstriction-and perhaps chronically in asthmatic subjects-many mediators are secreted simultaneously Antagonism of a single agent among the amine, peptide, and lipid mediators of airway contraction in this state would not be expected to elicit substantial inhibitory effects. A major unsolved question is the mechanism by which morphologically normal airway smooth muscle is transformed in the asthmatic state to a hypercontractile tissue that also is more difficult to relax." Most investigations have focused on animal models of airway reactivity to agonists taken one at a time. However, several studies have shown that airway contractility to relatively weak agonists may be augmented substantially in the presence of a second agonist 1286

postsynaptically 10.11 Other studies have suggested that postsynaptic mediator-mediator interactions increase refractoriness to airway relaxing influences, such as isoproterenol. 12 These data point to the need to consider models of airway hyperreactivity that results from complex postsynaptic interactions between regionally secreted mediators. Similar consideration has been applied to bronchoconstriction elicited by mediators secreted from respiratory mast cells and circulating blood elements. Mast cell secretion is a dynamic process, which itselfis regulated by endogenous secretory influences. Beta-adrenergic stimulation may substantially downregulate mast cell secretion of preformed mediators such as histamine" and de novo synthesis of bronchoactive products of the lipoxygenase and cycloxygenase pathways. Parasympathetic influences may augment mast cell secretion of mediator to antigenic stimulation. 14 Considerable recent attention has focused on the role of platelet activating factor (PAF), a lipid secreted from numerous cells, including mast cells, during immune activation. The complex interactions of this mediator in eliciting bronchoconstriction typifies the multieffector action of some mediators in eliciting bronchoconstriction. In the dog, PAF causes hypotension comparable to that in anaphylaxis. IS This appears to result from a direct effect of PAF on vascular smooth muscle. PAF also is an extremely potent contractile agent in canine airways; however, this does not appear to result from any direct action of PAF on an airway smooth muscle receptor. PAF causes release of serotonin from platelets, and its actions in causing airway smooth muscle contraction in vitro are blocked completely by serotonin or by pretreatment of platelets with receptor specific PAFantagonist. 16 In vivo, contractility elicited by PAF is blocked partially but not completely by atropine but is unaffected by ganglion blockade with hexamethonium. IS This indicates a second mode of action, where contraction results from postganglionic stimulation of efferent parasympathetic nerves. A similarly complex mode of action has been suggested for substance £ which also acts at least in part through parasympathetic activation. 17.18 Future investigations are likely to uncover even more complex actions of single mediators, further compounded, of course, by subsequent mediator-mediator interactions. The complexity of these interactions is confounding, and research continues to be focused clarifying the relevant mechanisms that underlie airway hyperreactivity The innovations of cellular and molecular biological investigations now in progress will serve to elucidate these mechanisms in the next generation. REFERENCES 1 Nadel JA. Autonomic control of airway smooth muscle and airway secretions. Am Rev Respir Dis 1977; 115:117-26 2 Weiner N, Taylor E Neurohumoral transmission: the autonomic and somatic motor nervous system. In: Gilman AG, Goodman LS, RaIl rw Mura F, eds. The pharmacological basis of therapeutics, 7th edt New York: Macmillan, 1985:66-127 3 Sands MF, Douglas FL, Green J, Banner A, Robertson GL, Leff AR. Homeostatic regulation of bronchomotor tone by sympathetic activation during bronchoconstriction in normal and asthmatic humans. Am Rev Respir Dis 1985; 131:995-98 4 White SR, Sands MF, Murphy TM, Munoz NM, Blake J, Mack M, et aI. Homeostatic regulation of airway smooth muscle tone Symposium (Garrard at aI)

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by catecholamine secretion in swine. J Appl Physiol 1987; 62:972-77 Szarek JL, Gillespie MN, Altiere RJ, Diamond L. Reflex activation of the nonadrenergic noncholinergic inhibitory nervous system in feline airways. Am Rev Respir Dis 1986; 133:115962 Flavahan NA, Aarhus LL, Rimele TJ, Vanhoutte PM. Respiratory epithelium inhibits bronchial smooth muscle tone. J Appl Physiol 1985; 58:834-38 Murphy KR, Wilson MC, Irvin CG, Glezen LS, Marsh ~ Haslett C, et al. The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model. Am Rev Respir Dis 1986; 134:6268 Gleich GJ, Loegering DA, Kueppers F, Bajaj S~ Mann KG. Physiochemical and biological properties of the major basic protein from guniea pig eosinophil granules. J Exp Med 1974; 140:313-32 Anthonisen NR. Conference summary (27th Aspen Lung Conference: Asthma). Chest 1985; 87:223S-226S Leff AR, Munoz NM. Cholinergic and alpha adrenergic augmentation of histamine-induced contraction of canine airway smooth muscle. J Pharmacol Exp Ther 1981; 218:582-87 Loring SH, Drazen JM, Snapper JR, Ingram RH Jr. Vagal and aerosol histamine interactions on airway responses in dogs. J Appl Physiol 1978; 45:40-44 White SR, Popovich KJ, Munoz NM, Mack MM, LefT AR. Multiple agonist interactions inhibiting tracheal smooth muscle relaxing response. Clin Res 1987; 35:633A Garrity ER, Stimler N~ Munoz NM, Tallet J, David AC, Leff AR. Sympathetic modulation of biochemical and physiological response to immune degranulation in canine bronchial airways in vivo. J Clin Invest 1985; 75:2038-46 LefT AR, Stimler N~ Munoz NM, Shioya T, Tallet J, Dame C. Augmentation of respiratory mast cell secretion of histamine caused by vagus nerve stimulation during antigen challenge. J Immunoll985; 136:1066-73 LefT AR, White SR, Munoz NM, Popovich KJ, Shioya'l: StimlerGerard N. Parasympathetic involvement in PAF-induced contraction in canine trachealis in vitro. J Appl Physiol 1987; 62: 599-605 Popovich KJ, Sheldon G, Mack MM, Munoz NM, Denberg ~ Blake J, et ale Role of platelets in contraction of canine trachealis muscle elicited by platelet activating factor in vitro. Am Rev Respir Dis 1987; 135:AI59 Tanaka D'I: Grunstein MM. Mechanisms of substance P-induced contraction of rabbit airway smooth muscle. J Appl Physioll9B4; 57:1551-57 Grunstein MM, Tanaka D'I: Grunstein JS. Mechanisms of substance P-induced bronchoconstriction in maturing rabbit. J Appl Physioll9B4; 57:1238-46

The Late Asthmatic Response* Gary L. Larsen, M.D.

T ate phase reactions have been observed in the skin as L well as the upper- and lower airways of man. 3 The late 1

phase reaction within the lower airways, the late asthmatic response (LAR), occurs hours after exposure to an appropri-

*From the

Department of Pediatrics, University of Colorado School of Medicine, and National Jewish Center for Immunology and Respiratory Medicine, Denver. Reprint requests: Dr. Larsen, Department of Pediatrics; 1400 jackson Street, Denver 80206

ate stimulus and for many reasons is thought to resemble more closely the problems for which patients seek assistance than the immediate asthmatic response (IAR) that occurs within minutes of challenge. For example, the airway obstruction produced during LAR may be more severe and prolonged than that associated with IAR.3 In addition, the IAR may be easily reversed with inhaled or injected adrenergic drugs, while the LAR is less responsive to this form of therapy While pretreatment with cromolyn prevents both IAR and LAR, corticosteroids given just before antigen exposure will not prevent IAR but will abolish or diminish LAR. The LAR has also been noted to correlate with frequent attacks of asthma and under laboratory conditions may occur in as many as 50 percent of challenged subjects.' LARs that occur after either laboratory or natural exposure to antigen have been associated with subsequent increases in airways reactivity 3This finding has led to the hypothesis that atopic asthmatic patients with LARs may develop a vicious circle in which heightened airway reactivity leads to enhanced responsiveness to allergens and nonimmunologic stimuli such as irritants and exercise, S thus producing more persistent symptoms of asthma. This review presents current thoughts on possible mechanisms that lead to the LAR. While the focus is on the antigen-induced LAR, observations of late phase reactions in the skin (late cutaneous response) and upper airways (late nasal response) that may give clues to the immunopathogenesis of late phase reactions in the lung are also cited. IMPORTANCE OF ANTIGEN-SPECIFIC IGE IN ANTIGEN-INDUCED

LAR

Studies by Pepys et al in patients with allergic bronchopulmonary aspergillosis and late reactions in skin and lung led to the hypothesis that late reactions were Arthus phenomena. However, recent studies of late phase reactions in the skin suggest that events with this time course are not necessarily type 3 events. For example, Solley and associates' reported heating of atopic human serum used for passive sensitization reduced the capacity to transfer immediate and late cutaneous responses. Removal of IgE by passing the serum over an anti-IgE immunoabsorbent abolished the ability to transfer the reactions, while IgE from the immunoabsorbent restored the responses. Thus, within the skin of man, the evidence is strong that late responses to antigen can be dependent on IgE. The hypothesis that late phase reactions within the airways may also depend on IgE is more difficult to study in man. A recent report by Kirby et al7 did find that inhalation of sheep anti-human IgE led to LAR in one atopic asthmatic patient. With use of a rabbit model of the LAR, the importance of antigen-specific IgE and IgG to this pattern of airway obstruction has been investigated in more detail. 8,9 In a study involving neonatal immunization to Alternaria tenuis; rabbits with predominantly or only IgE to this mold developed both early and late airway obstruction." When rabbits were passively sensitized with intravenous infusions of sera containing IgE to this antigen, late responses were again noted. 8,9 In both actively and passively sensitized rabbits, antigen-specific IgG appeared to blunt the LAR in immune rabbits. Evaluation of histologic specimens did not show evidence of immunoglobulin and complement deposition in the lungs of rabbits with late re6

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