2. Neuropeptides (VIP and Tachykinins) VIP as a Modulator of Lung Inflammation and Airway Constriction 1- 3 SAMI I. SAID4
Introduction Since its discovery and characterization, the vasoactive intestinal peptide (VIP) has been known to occur in the lung and to have tracheobronchial relaxant activity (1, 2). More recent data suggest that this peptide also has anti-inflammatory effects, and that it may have a physiologic role as an endogenous modulator of both bronchoconstriction and pulmonary inflammation. Evidence for these conclusions is summarized in this review. The evidence is based on the presence of VIP in key structures in the lung and in inflammatory cells, the presence of receptor sites for VIP in the lung and in inflammatory cells, the antispasmodic and anti-inflammatory effects of VIP, the ability of this peptide to reduce or prevent experimental lung injury, and its release in response to this injury. VIP in the Lung Immunohistochemical studies have localized immunoreactive VIP in nerve fibers and nerve terminals within airway smooth muscle, surrounding tracheobronchial mucous and serous glands, and in the walls of pulmonary and bronchial arteries (1-6). VIP-immunoreactive neuronal cell bodies have also been demonstrated in microganglia within the lungs (1-6), and probably serve as a source of intrinsic innervation of pulmonary structures. No VIP-containing nerve fibers have been observed in airway epithelium. VIP in Inflammatory Cells Immunoreactive VIP has been localized, either by radioimmunoassay or by immunohistochemistry or both, in three types of leukocytes: neutrophils, eosinophils, and mononuclear cells (7-9), as well as in pulmonary and peritoneal mast cells (10). Of the human leukocytes, eosinophils contain the highest levels of this peptide (9). The VIP produced by mast cells is a mixture of several structurally related but different peptides (11), and it is released by mast-cell degranulators such as Ca 2 + ionophore A23187 and compound 48/80 (10). Receptor Sites in the Lung Specific, high-affinity receptors for VIP have been identified in membrane preparations of rat, mouse, guinea pig, and human lungs (1), in rat alveolar macrophages (12), and in human lung tumor cells (13, 14). The cellular sites of these receptors have been localized immunocytochemicallyby detection of the increased cellular cyclic AMP content result822
ing from the binding of VIP to its receptors (15). These sites include the submucosal serous and mucous glands of the ferret and the ciliated and basal cells of canine tracheal epithelium (15).The use of autoradiography has demonstrated the presence of extensive VIP uptake sites (and, presumably, receptors) in bronchial epithelium, submucosal glands, smooth muscle, and alveolar cells (16-18). As in most other cells and tissues, the binding of VIP to airway sites is coupled to an adenylate cyclase (19, 20). The VIP-induced accumulation of cyclicAMP levels may be an important mediator of airway relaxation and other biologic effects of the peptide. VIP receptors in human and other mammalian lungs have recently been characterized by covalent cross-linkingand solubilization techniques (21-24). The binding of VIP to its highaffinity receptors in the lung is rapid, reversible, and sensitive to the guanine nucleotide OTP. Receptor Sites on Inflammatory Cells In addition to its presence in cells that mediate and modulate inflammation, VIP binds to specific receptor sites on these cells. Such receptors have been described on murine and human Tdymphocytes (25, 26), MOLT 4b lymphoblasts (27), human blood monocytes (28-30), rat alveolar macrophages, and rabbit platelets (31). Antispasmodic Action of VIP in the Lung VIP relaxes airway smooth muscle both in vitro and in vivo. Thus, it relaxes isolated tracheal or bronchial segments from guinea pigs, rabbits, dogs, and humans and prevents or attenuates their contraction by constrictors, including histamine, POF2 U , kallikrein, leukotriene D4 , neurokinin A and B (1), and endothelin (32). This relaxant action is relatively long-lasting and is independent of adrenergic and cholinergic receptors and of cyclooxygenase activity (1). Inhaled VIP protects against the bronchoconstriction induced by histamine or POF 2U in dogs and by histamine in guinea pigs (33), and infused VIP reverses serotonin-induced bronchoconstriction in cats (34). In human subjects, however, the protective effect of aerosolized VIP against asthmatic or histamine-induced bronchoconstriction has been generally less pronounced than in animal experiments (35-37). The latter discrepancymay be caused by the rapid degradation of VIP by peptidases in asthmatic airways.
Anti-inflammatory Actions of VIP A considerable body of recent data suggest that VIP has potent anti-inflammatory activity in the lung. These data are based on the ability of the peptide to (1) inhibit inflammatory cell function, (2) antagonize major humoral mediators of inflammation, and (3) attenuate acute edematous lung injury in several experimental models.
Inhibition of Inflammatory Cells Lymphocytes. VIP inhibits mitogen-induced 'f-lymphocyte proliferation and other aspects of TIymphocyte function, including the releaseof cytokines, especiallyinterleukin-2 (38, 39). VIP also modulates natural killer cell activity (40). Infusions of VIP into afferent lymphatics cause prompt and marked reduction of both recirculating and blast lymphocyte traffic in efferent lymph (41). Mononuclear cells. VIP inhibits the respiratory burst in human monocytes (42) and inhibits phagocytosis and superoxide radical production by rat alveolar macrophages (43). Both of these effects are associated with stimulated cyclic AMP production. Mast cells. VIP moderately inhibits antigeninduced release of histamine (and possibly other mast-cell mediators) from guinea pig lung (44). Platelets. VIP elevatescylicAMP levelsand inhibits rabbit platelet aggregation and serotonin secretion induced by platelet-activating factor (PAF) (31). Antagonism of Inflammatory Mediators As mentioned above, VIP inhibits the bronchoconstrictor effects of histamine, POF2U , leukotrienes C4 and D4 , neurokinins A and B, and endothelin. VIP also counteracts the pulmonary vasoconstrictor action of these compounds. Further, as described below,VIP reducesPAF-induced injury and edema in isolated rat lungs.
1 From the University of Illinois at Chicago College of Medicine and the Westside VeteransAffairs Medical Center, Chicago, Illinois. 2 Supported in part by Grants HL-30450and HL35656 from the National Institutes of Health and by the Department of Veterans Affairs. 3 Correspondence and requests for reprints should be addressed to Sami I. Said, M.D., University of Illinois at Chicago, 1940West Taylor, M/C 789, Chicago, IL 60612. 4 Medical Investigator of the Veterans Administration.
AM REV RESPIR DIS 1991; 143:522-524
523
VIP AS MODULATOR OF WNG INFLAMMATION AND AIRWAY CONSTRICTION
Attenuation of Inflammatory Injury In recent experiments on isolated, perfused rat lungs, VIP (l to 10 ug-kgv-rnin') dosedependently reduced all signs of acute lung injury produced by intratracheal instillation of H'Cl and infusion of PAF or of xanthine and xanthine oxidase (45-47). Signs of injury that were attenuated or prevented by VIP treatment were:peak airway pressure, pulmonary artery perfusion pressure, wet/dry lung weight ratio, and protein content in bronchoalveolar lavage. VIP also protected rat lungs against edematous injury caused by prolonged perfusion ex vivo (48) and protected guinea pig lungs from paraquatinduced injury (100 mg/kg) (49). Possible mechanisms by which VIP may reduce or prevent acute lung injury include (1) inhibition of inflammatory cell function and release of cytokines (see above); (2) inhibition of the generation of other inflammatory mediators, including arachidonic acid metabolites and PAP; (3)neutralization of the actions of inflammatory mediators (see above); (4) the antioxidant activity demonstrated in the xanthine-xanthine oxidase model of injury cited previously. Is VIP an Endogenous Modulator of Airway Constriction and Lung Inflammation?
The foregoing observations, together with the presence of VIP and of its specific receptors in all key pulmonary structures as well as in the cells that mediate and modulate inflammation, suggest that VIP may be a physiologic modulator of inflammation in the lung. For this hypothesis to be validated, at least three criteria must be fulfilled: (1) VIP should be capable of preventing or reducing inflammatory injury; (2) VIP should be released in response to injury; (3) inhibition of VIP release or actions should aggravate the inflammatory response.The first criterion has clearly been fulfilled, as outlined above. For the second, there is now evidencethat VIP is released both in vivo and by isolated lungs in response to injury by PAF (46) and oxidant stress (47), respectively. The third requirement must await the availability of specific and potent antagonists of VIP release or action. As a likely transmitter of nonadrenergic relaxation of airways (50), VIP probably also servesas a modulator of bronchoconstriction. Conclusions
The airway relaxant action of VIP is well known and its likely role as a transmitter of nonadrenergic relaxation is widely accepted. In this report, evidence has been briefly presented to support the view that VIP also has anti-inflammatory properties and may be a physiologicmodulator of acute inflammatory injury in the lung.
Acknowledgment The writer thanks Dianna Dichtl and lane Guttman for their invaluable help with the preparation of the manuscript.
References 1. Said SI. Influence of neuropeptides on airway smooth muscle. Am Rev Respir Dis 1987; 136 (Suppl:525-8). 2. Said SI. Vasoactiveintestinal peptide in the lung. Ann N Y Acad Sci 1988; 527:450-64. 3. Dey RD, Shannon WA, Said SI. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats and human subjects. Cell Tissue Res 1981; 220:231-8. 4. Dey RD, Said SI. Lung pep tides and the pulmonary circulation. In: Said SI, ed. The pulmonary circulation and acute lung injury. New York: Futura Publishing Co., 1985; 101-22. 5. Uddman R, Sundler F. VIP nerves in human upper respiratory tract. Otorhinolaryngology 1979; 41:221-6. 6. Laitinen A, Partanen M, Hernonen A, PeltoHuikko M, Laitinen LA. VIP-likeimmunoreactive nerves in human respiratory tract. Histochemistry 1985; 82:313-9. 7. O'Dorisio MS, O'Dorisio TM, Cataland S, Balcerzak SP. Vasoactive intestinal polypeptide as a biochemical marker for polymorphonuclear leukocytes. 1 Lab Clin Med 1980; 96:666-72. 8. Lygren I, Revhaug A, Burhol PG, Giercksky K-E, lenssen TG. Vasoactiveintestinal polypeptide and somatostatin in leukocytes. Scand lClin Lab Invest 1984; 44:347-51. 9. Aliakbari 1, Sreedharan SP, Turck CW, Goetzl El. Selective localization of vasoactive intestinal peptide and substance P in human eosinophils. Biochern Biophys Res Commun 1987; 148:1440-5. 10. Cutz E, Chan W, Track NS, Goth A, Said SI. Releaseof vasoactive intestinal polypeptide in mast cellsby histamine liberators. Nature 1978;275:661-2. 11. Goetzl El, Sreedharan SP, Turck CWo Structurally distinctive vasoactiveintestinal peptides from rat basophilic leukemia cells. 1 BioI Chern 1988; 263:9083-6. 12. Sakakibara H, Luis 1, Lin Y,Berisha HI, Foda HD, Said SI. Binding of vasoactive intestinal polypeptide (VIP) to rat alveolar macrophages: demonstration of specific binding sites coupled with adenylate cyclase (abstract). Clin Res 1989; 37:949A. 13. Laburthe M, Boissard C, Chevalier G, Zweibaum A, Rosselin G. Peptide receptors in human lung tumor cellsin culture: vasoactiveintestinal peptide (VIP) and secretin interaction with CALU-l and SW-9OO cell lines. Regul Pept 1981; 2:219-30. 14. Shaffer MM, Carney DN, Korman LY, Lebovic GS, Moody TW. High-affinity binding of VIP to human lung cancer cell lines. Peptides 1987; 8: 1101-6. 15. Lazarus SC, Basbaum CB, Barnes Pl, Gold WM. Mapping of VIP receptors by use of an immunocytochemical probe for the intracellular mediator cyclic AMP. Am 1 Physiol1986; 251:C115-9. 16. Carstairs lR, Barnes Pl. Visualization of vasoactive intestinal peptide receptors in human and guinea pig lung. 1 Pharmacol Exp Ther 1986; 239:249-55. 17. Leroux P, Vaundry H, Fournier A, St-Pierre S, Pelletier G. Characterization and localization of vasoactive intestinal peptide receptors in the rat lung. Endocrinology 1984; 114:1506-12. 18. Leys K, Morice A, Hughes A, Schachter M, Sever P. Autoradiographic visualization of VIP receptors in human lung. FEBS Lett 1986; 199: 198-202. 19. Frandsen EK, Krishna GA, Said SI. Vasoactive intestinal polypeptide promotes cyclic adenosine 3',5'-monophosphate accumulation in guinea pig trachea. Br 1 Pharmacol 1978; 62:367-9. 20. Robberecht P, Chatelain P, De Neef P, Camus 1-C, Waelbroeck M, Christophe 1. Presence of vasoactive intestinal peptide receptors coupled
to adenylate cyclase in rat lung membranes. Biochim Biophys Acta 1981; 678:76-82. 21. Laburthe M, Couvineau A. Molecular analysis of vasoactive intestinal peptide receptors. Ann N Y Acad Sci 1988; 257:296-313. 22. Paul S, Said SI. Solubilization of active receptors for VIP from guinea pig lung. Peptides 1986; 7:147-9. 23. Dickinson KE1, Schachter M, Miles CMM, Coy DH, Sever PS. Characterization of vasoactive intestinal peptide (VIP) receptors in mammalian lung. Peptides 1986; 7:791-900. 24. Velicelebi G, Patthi S, Provow S, Akong M, Simerson S. Structural characterization of vasoactive intestinal peptide receptors from rat lung membranes. Ann N Y Acad Sci 1988; 527:266-81. 25. Danek A, O'Dorisio MS, O'Dorisio TM, George 1M. Specific binding sites for vasoactive intestinal polypeptide on nonadherent peripheral blood lymphocytes. 1 Immunol 1983; 131:1173. 26. Ottaway CA, Greenberg GR. Interaction of vasoactive intestinal peptide with mouse lymphocytes: specific binding and the modulation of mitogen responses. 1 Immunol 1984; 132:417-23. 27. Beed EA, O'Dorisio S, O'Dorisio TM, Gaginella TS. Demonstration of a functional receptor for vasoactive intestinal polypeptide on Molt 4b T lymphoblasts. Regul Pept 1983; 6:1. 28. Guerrero 1M, Prieto lC, Elorza L, Ramirez R, Goberna R. Interaction of vasoactive intestinal peptide with human blood mononuclear cells. Mol Cell Endocrinol 1981; 21:151. 29. Ottaway CA, Bernaerts C, Chan B, Greenberg GR. Specific binding of vasoactive intestinal peptide to human circulating mononuclear cells. Can 1 Physiol Pharmacol 1983; 61:664. 30. Wiik P, Opstad PK, Boyum A. Binding of vasoactive intestinal polypeptide (VIP) by human blood monocytes: demonstration of specific binding sites. Regul Pept 1985; 12:145-53. 31. Cox CP, Linden 1, Said SI. VIP elevatesplatelet cyclicAMP (cAMP) levelsand inhibits in vitroplatelet activation induced by platelet-activating factor (PAF). Peptides 1984; 5:325-8. 32. Boomsma ro, Foda HD, Said SI. Vasoactive intestinal peptide (VIP) reversesendothelin-induced contraction of guinea pig trachea and pulmonary artery (abstract). Clin Res 1989; 37:974A. 33. Said SI, Geumei A, Hara N. Bronchodilator effect of VIP in vivo: protection against bronchoconstriction induced by histamine or prostaglandin F 2u • In: Said SI, ed. Vasoactive intestinal peptide. New York: Raven Press, 1982; 185-91. 34. Diamond L, Szarek lL, Gillespie MN, Altiere RJ. In vivo bronchodilator activity of vasoactive intestinal peptide in the cat. Am Rev Respir Dis 1983; 128:827-32. 35. Morice AH, Unwin Rl, Sever PS. Vasoactive intestinal peptide as a bronchodilator in asthmatic subjects. Peptides 1984; 5:439-40. 36. Barnes P1, Dixon CMS. The effect of inhaled vasoactive intestinal peptide on bronchial reactivity to histamine in humans. Am RevRespirDis 1984; 130:162-6. 37. Mojarad M, Grode TL, Cox CP, Kimmel G, Said SI. Differential responses of human asthmatics to inhaled vasoactive intestinal peptide (VIP) (abstract). Am Rev Respir Dis 1985; 131:281A. 38. Krco Cl, Gores A, Go VLW.Gastrointestinal regulatory peptides modulate in vitro immune reactions of mouse lymphoid cells. Clin Immunol Immunopathol 1986; 39:308-18. 39. Ottaway CA. Selective effects of vasoactive intestinal peptide on the mitogenic response of murine T cells. Immunology 1987; 62:291-7. 40. Rola-Pleszczynski M, Bolduc D, St-Pierre S. The effects of vasoactive intestinal peptide on hu-
524 man natural killer cell function. J Immunol 1985; 135:2569-73. 41. Moore TC, Spruck CH, Said SI. Depression of lymphocyte traffic in sheep by vasoactive intestinal peptide (VIP). Immunology 1988;64:475-8. 42. Wiik P. Vasoactive intestinal peptide inhibits the respiratory burst in human monocytes by a cyclic AMP-mediated mechanism. Regul Pept 1989; 25:187-97. 43. Litwin DK, Claypool WD, Onal E, Foda HD, Said SI. Vasoactive intestinal polypeptide inhibits rat alveolar macrophage phagocytosis (abstract). Am Rev Respir Dis 1989; 139:AI58. 44. Undem BJ, Dick EC, Buckner CK. Inhibition
SAMII. SAID
by vasoactive intestinal peptide of antigen-induced histamine release from guinea-pig minced lung. Eur J Pharmacol 1983; 88:247-9. 45. Foda HD, Iwanaga T, Liu L-W, Said SI. Vasoactive intestinal peptide protects against HCIinduced pulmonary edema in rats. Ann N Y Acad Sci 1988; 527:633-6. 46. Pakbaz H, Liu L-W, Foda HD, Berisha H, Said SI. Vasoactive intestinal peptide (VIP) as a modulator of PAF-induced lung injury (abstract). Clin Res 1988; 36:626A. 47. Berisha H, Foda H, Sakakibara H, Trotz M, Pakbaz H, Said SI. Vasoactive intestinal peptide prevents lung injury due to xanthine/xanthine oxi-
dase. Am J Physiol 1990; 259:L151-5. 48. Berisha HI, Foda HD, Pakbaz H, Said SI. VIP protects the lung against injury and edema caused by prolonged perfusion ex vivo (abstract). Clin Res 1988; 36:855A. 49. Pakbaz H, Foda HD, Berisha HI, Said SI. Vasoactive intestinal peptide (VIP) modulates injury caused by paraquat in guinea pig lungs (abstract). Clin Res 1990; 38:440A. 50. Matsuzaki Y, Hamasaki Y, Said SI. Vasoactive intestinal peptide: a possible transmitter of nonadrenergic relaxation of guinea pig airways. Science 1980; 210:1252-3.
Introduction Since its discovery and characterization, the vasoactive intestinal peptide (VIP) has been known to occur in the lung and to have tracheobronchial relaxant activity (1, 2). More recent data suggest that this peptide also has anti-inflammatory effects, and that it may have a physiologic role as an endogenous modulator of both bronchoconstriction and pulmonary inflammation. Evidence for these conclusions is summarized in this review. The evidence is based on the presence of VIP in key structures in the lung and in inflammatory cells, the presence of receptor sites for VIP in the lung and in inflammatory cells, the antispasmodic and anti-inflammatory effects of VIP, the ability of this peptide to reduce or prevent experimental lung injury, and its release in response to this injury. VIP in the Lung Immunohistochemical studies have localized immunoreactive VIP in nerve fibers and nerve terminals within airway smooth muscle, surrounding tracheobronchial mucous and serous glands, and in the walls of pulmonary and bronchial arteries (1-6). VIP-immunoreactive neuronal cell bodies have also been demonstrated in microganglia within the lungs (1-6), and probably serve as a source of intrinsic innervation of pulmonary structures. No VIP-containing nerve fibers have been observed in airway epithelium. VIP in Inflammatory Cells Immunoreactive VIP has been localized, either by radioimmunoassay or by immunohistochemistry or both, in three types of leukocytes: neutrophils, eosinophils, and mononuclear cells (7-9), as well as in pulmonary and peritoneal mast cells (10). Of the human leukocytes, eosinophils contain the highest levels of this peptide (9). The VIP produced by mast cells is a mixture of several structurally related but different peptides (11), and it is released by mast-cell degranulators such as Ca 2 + ionophore A23187 and compound 48/80 (10). Receptor Sites in the Lung Specific, high-affinity receptors for VIP have been identified in membrane preparations of rat, mouse, guinea pig, and human lungs (1), in rat alveolar macrophages (12), and in human lung tumor cells (13, 14). The cellular sites of these receptors have been localized immunocytochemicallyby detection of the increased cellular cyclic AMP content result822
ing from the binding of VIP to its receptors (15). These sites include the submucosal serous and mucous glands of the ferret and the ciliated and basal cells of canine tracheal epithelium (15).The use of autoradiography has demonstrated the presence of extensive VIP uptake sites (and, presumably, receptors) in bronchial epithelium, submucosal glands, smooth muscle, and alveolar cells (16-18). As in most other cells and tissues, the binding of VIP to airway sites is coupled to an adenylate cyclase (19, 20). The VIP-induced accumulation of cyclicAMP levels may be an important mediator of airway relaxation and other biologic effects of the peptide. VIP receptors in human and other mammalian lungs have recently been characterized by covalent cross-linkingand solubilization techniques (21-24). The binding of VIP to its highaffinity receptors in the lung is rapid, reversible, and sensitive to the guanine nucleotide OTP. Receptor Sites on Inflammatory Cells In addition to its presence in cells that mediate and modulate inflammation, VIP binds to specific receptor sites on these cells. Such receptors have been described on murine and human Tdymphocytes (25, 26), MOLT 4b lymphoblasts (27), human blood monocytes (28-30), rat alveolar macrophages, and rabbit platelets (31). Antispasmodic Action of VIP in the Lung VIP relaxes airway smooth muscle both in vitro and in vivo. Thus, it relaxes isolated tracheal or bronchial segments from guinea pigs, rabbits, dogs, and humans and prevents or attenuates their contraction by constrictors, including histamine, POF2 U , kallikrein, leukotriene D4 , neurokinin A and B (1), and endothelin (32). This relaxant action is relatively long-lasting and is independent of adrenergic and cholinergic receptors and of cyclooxygenase activity (1). Inhaled VIP protects against the bronchoconstriction induced by histamine or POF 2U in dogs and by histamine in guinea pigs (33), and infused VIP reverses serotonin-induced bronchoconstriction in cats (34). In human subjects, however, the protective effect of aerosolized VIP against asthmatic or histamine-induced bronchoconstriction has been generally less pronounced than in animal experiments (35-37). The latter discrepancymay be caused by the rapid degradation of VIP by peptidases in asthmatic airways.
Anti-inflammatory Actions of VIP A considerable body of recent data suggest that VIP has potent anti-inflammatory activity in the lung. These data are based on the ability of the peptide to (1) inhibit inflammatory cell function, (2) antagonize major humoral mediators of inflammation, and (3) attenuate acute edematous lung injury in several experimental models.
Inhibition of Inflammatory Cells Lymphocytes. VIP inhibits mitogen-induced 'f-lymphocyte proliferation and other aspects of TIymphocyte function, including the releaseof cytokines, especiallyinterleukin-2 (38, 39). VIP also modulates natural killer cell activity (40). Infusions of VIP into afferent lymphatics cause prompt and marked reduction of both recirculating and blast lymphocyte traffic in efferent lymph (41). Mononuclear cells. VIP inhibits the respiratory burst in human monocytes (42) and inhibits phagocytosis and superoxide radical production by rat alveolar macrophages (43). Both of these effects are associated with stimulated cyclic AMP production. Mast cells. VIP moderately inhibits antigeninduced release of histamine (and possibly other mast-cell mediators) from guinea pig lung (44). Platelets. VIP elevatescylicAMP levelsand inhibits rabbit platelet aggregation and serotonin secretion induced by platelet-activating factor (PAF) (31). Antagonism of Inflammatory Mediators As mentioned above, VIP inhibits the bronchoconstrictor effects of histamine, POF2U , leukotrienes C4 and D4 , neurokinins A and B, and endothelin. VIP also counteracts the pulmonary vasoconstrictor action of these compounds. Further, as described below,VIP reducesPAF-induced injury and edema in isolated rat lungs.
1 From the University of Illinois at Chicago College of Medicine and the Westside VeteransAffairs Medical Center, Chicago, Illinois. 2 Supported in part by Grants HL-30450and HL35656 from the National Institutes of Health and by the Department of Veterans Affairs. 3 Correspondence and requests for reprints should be addressed to Sami I. Said, M.D., University of Illinois at Chicago, 1940West Taylor, M/C 789, Chicago, IL 60612. 4 Medical Investigator of the Veterans Administration.
AM REV RESPIR DIS 1991; 143:522-524
523
VIP AS MODULATOR OF WNG INFLAMMATION AND AIRWAY CONSTRICTION
Attenuation of Inflammatory Injury In recent experiments on isolated, perfused rat lungs, VIP (l to 10 ug-kgv-rnin') dosedependently reduced all signs of acute lung injury produced by intratracheal instillation of H'Cl and infusion of PAF or of xanthine and xanthine oxidase (45-47). Signs of injury that were attenuated or prevented by VIP treatment were:peak airway pressure, pulmonary artery perfusion pressure, wet/dry lung weight ratio, and protein content in bronchoalveolar lavage. VIP also protected rat lungs against edematous injury caused by prolonged perfusion ex vivo (48) and protected guinea pig lungs from paraquatinduced injury (100 mg/kg) (49). Possible mechanisms by which VIP may reduce or prevent acute lung injury include (1) inhibition of inflammatory cell function and release of cytokines (see above); (2) inhibition of the generation of other inflammatory mediators, including arachidonic acid metabolites and PAP; (3)neutralization of the actions of inflammatory mediators (see above); (4) the antioxidant activity demonstrated in the xanthine-xanthine oxidase model of injury cited previously. Is VIP an Endogenous Modulator of Airway Constriction and Lung Inflammation?
The foregoing observations, together with the presence of VIP and of its specific receptors in all key pulmonary structures as well as in the cells that mediate and modulate inflammation, suggest that VIP may be a physiologic modulator of inflammation in the lung. For this hypothesis to be validated, at least three criteria must be fulfilled: (1) VIP should be capable of preventing or reducing inflammatory injury; (2) VIP should be released in response to injury; (3) inhibition of VIP release or actions should aggravate the inflammatory response.The first criterion has clearly been fulfilled, as outlined above. For the second, there is now evidencethat VIP is released both in vivo and by isolated lungs in response to injury by PAF (46) and oxidant stress (47), respectively. The third requirement must await the availability of specific and potent antagonists of VIP release or action. As a likely transmitter of nonadrenergic relaxation of airways (50), VIP probably also servesas a modulator of bronchoconstriction. Conclusions
The airway relaxant action of VIP is well known and its likely role as a transmitter of nonadrenergic relaxation is widely accepted. In this report, evidence has been briefly presented to support the view that VIP also has anti-inflammatory properties and may be a physiologicmodulator of acute inflammatory injury in the lung.
Acknowledgment The writer thanks Dianna Dichtl and lane Guttman for their invaluable help with the preparation of the manuscript.
References 1. Said SI. Influence of neuropeptides on airway smooth muscle. Am Rev Respir Dis 1987; 136 (Suppl:525-8). 2. Said SI. Vasoactiveintestinal peptide in the lung. Ann N Y Acad Sci 1988; 527:450-64. 3. Dey RD, Shannon WA, Said SI. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats and human subjects. Cell Tissue Res 1981; 220:231-8. 4. Dey RD, Said SI. Lung pep tides and the pulmonary circulation. In: Said SI, ed. The pulmonary circulation and acute lung injury. New York: Futura Publishing Co., 1985; 101-22. 5. Uddman R, Sundler F. VIP nerves in human upper respiratory tract. Otorhinolaryngology 1979; 41:221-6. 6. Laitinen A, Partanen M, Hernonen A, PeltoHuikko M, Laitinen LA. VIP-likeimmunoreactive nerves in human respiratory tract. Histochemistry 1985; 82:313-9. 7. O'Dorisio MS, O'Dorisio TM, Cataland S, Balcerzak SP. Vasoactive intestinal polypeptide as a biochemical marker for polymorphonuclear leukocytes. 1 Lab Clin Med 1980; 96:666-72. 8. Lygren I, Revhaug A, Burhol PG, Giercksky K-E, lenssen TG. Vasoactiveintestinal polypeptide and somatostatin in leukocytes. Scand lClin Lab Invest 1984; 44:347-51. 9. Aliakbari 1, Sreedharan SP, Turck CW, Goetzl El. Selective localization of vasoactive intestinal peptide and substance P in human eosinophils. Biochern Biophys Res Commun 1987; 148:1440-5. 10. Cutz E, Chan W, Track NS, Goth A, Said SI. Releaseof vasoactive intestinal polypeptide in mast cellsby histamine liberators. Nature 1978;275:661-2. 11. Goetzl El, Sreedharan SP, Turck CWo Structurally distinctive vasoactiveintestinal peptides from rat basophilic leukemia cells. 1 BioI Chern 1988; 263:9083-6. 12. Sakakibara H, Luis 1, Lin Y,Berisha HI, Foda HD, Said SI. Binding of vasoactive intestinal polypeptide (VIP) to rat alveolar macrophages: demonstration of specific binding sites coupled with adenylate cyclase (abstract). Clin Res 1989; 37:949A. 13. Laburthe M, Boissard C, Chevalier G, Zweibaum A, Rosselin G. Peptide receptors in human lung tumor cellsin culture: vasoactiveintestinal peptide (VIP) and secretin interaction with CALU-l and SW-9OO cell lines. Regul Pept 1981; 2:219-30. 14. Shaffer MM, Carney DN, Korman LY, Lebovic GS, Moody TW. High-affinity binding of VIP to human lung cancer cell lines. Peptides 1987; 8: 1101-6. 15. Lazarus SC, Basbaum CB, Barnes Pl, Gold WM. Mapping of VIP receptors by use of an immunocytochemical probe for the intracellular mediator cyclic AMP. Am 1 Physiol1986; 251:C115-9. 16. Carstairs lR, Barnes Pl. Visualization of vasoactive intestinal peptide receptors in human and guinea pig lung. 1 Pharmacol Exp Ther 1986; 239:249-55. 17. Leroux P, Vaundry H, Fournier A, St-Pierre S, Pelletier G. Characterization and localization of vasoactive intestinal peptide receptors in the rat lung. Endocrinology 1984; 114:1506-12. 18. Leys K, Morice A, Hughes A, Schachter M, Sever P. Autoradiographic visualization of VIP receptors in human lung. FEBS Lett 1986; 199: 198-202. 19. Frandsen EK, Krishna GA, Said SI. Vasoactive intestinal polypeptide promotes cyclic adenosine 3',5'-monophosphate accumulation in guinea pig trachea. Br 1 Pharmacol 1978; 62:367-9. 20. Robberecht P, Chatelain P, De Neef P, Camus 1-C, Waelbroeck M, Christophe 1. Presence of vasoactive intestinal peptide receptors coupled
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