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. 2013 Jan-Mar;17(1):12–16.

Vasoactive Intestinal Peptide Inhaled Agonists: Potential Role in Respiratory Therapeutics

AG Mathioudakis 1, V Chatzimavridou-Grigoriadou 1, E Evangelopoulou 2, GA Mathioudakis 3
PMCID: PMC3738270  PMID: 23935337

Abstract

Purpose of review: Vasoactive Intestinal Peptide (VIP) is a neuropeptide, expressed by lymphoid as well as neural cells, which has diverse effects on the cellular mediators of inflammation and immunity and is also a potent neurotransmitter. VIP seems to have a major role in the homeostasis of the respiratory system, while several studies, including clinical trials, suggest that VIP-inhaled agonists could be used in respiratory therapeutics. In this review, we provide an introduction to the field of VIP research geared to clinical and research pulmonologists.

Recent Findings: As a neurotransmitter, VIP exerts a potent bronchodilatory and vasodilatory effect and also is supposed to induce the house-keeping mucus secretion by submucosal glands. On the other hand, it has immunomodulatory functions which include humoral immune response suppression, inhibition of vascular and bronchial remodeling and inflammation and attenuation of the cigarette smoke extract-induced apoptotic death of alveolar L2 cells. Recent research on a wide spectrum of lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, and sarcoidosis indicates a potential therapeutic role of a VIP agonist. Simultaneously, novel stabilized inhaled VIP agonists and drug delivery systems have been proposed as a promising candidate alternative drug with minimized side effects. These data are supported by the results of certain, limited clinical trials which have already been conducted.

Conclusion: Ongoing research continues to clarify the immunomodulatory effects of VIP and to confirm animal findings with human studies. A major challenge for investigators will be to determine whether stabilized inhaled-VIP agonists could be used in respiratory therapeutics.

Keywords: VIP, Pulmonary Therapeutics, COPD, Asthma, Cystic Fibrosis, Sarcoidosis, Pulmonary Hypertension

Introduction

Since Vasoactive Intestinal Peptide (VIP) was discovered by Said and Mutt in 19701, it has been extensively studied, due to its broad range of physiological functions, as a neurotransmitter and also a Th-2 cytokine, and its participation in the pathophysiologic background of many diseases of several organ systems.It has positive inotropic and chronotropic effect in the cardiovascular system and also causes coronary vasodilation. VIP also has multiple functions in the gastrointestinal system, stimulating the secretion of water and electrolytes in the gastrointestinal lumen, the pancreatic juice and the bile, stimulating the secretion of pepsinogen and also increasing its motility. Furthermore, it regulates prolactin secretion and promotes vaginal lubrication2. Finally, as we will describe next, it has potent bronchodilatory and immunomodulatory effects in the respiratory system. As a result, VIP agonists have been proposed as possible pharmacologic agents for many different diseases, including several respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, sarcoidosis and also the inflammatory upper respiratory tract diseases.

Recent studies on VIP agonists have shown encouraging results indicating an increased likelihood of producing a new drug with wide therapeutic range and novel mechanisms of action. Inhaled VIP agonists are also expected to have very few systemic adverse effects because of their localized action. These hypotheses are supported by the results of certain, limited clinical trials. Consequently, the aim of this review is to assemble and integrate all these investigatory results in anticipation of the forthcoming conduct of additional clinical trials.

The Role of VIP in the Respiratory System

VIP is a peptide that contains 28 amino acid residues which belongs to the glucagon-secretin superfamily3. It is an inhibitory neurotransmitter of the nonadrenergic, noncholinergic autonomic nervous system4 and also a Th-2 cytokine5,6. Its action is mediated through VIP receptor type-1 (VPAC1) and VIP receptor type-2 (VPAC2), which are also activated by Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) that also belongs to the glucagon-secretin superfamily.

Being one of the most abundant neuropeptides of the human body, VIP is highly expressed in the lung and also in the nasal mucosa. Regarding its receptors, VPAC1 is more abundant in the lung tissue and T-lymphocytes, whereas VPAC2 is essentially found in the smooth muscle, mast cells and the basal parts of the lung mucosa. Both VPAC1 and VPAC2 are G-protein coupled receptors which increase intracellular cAMP by stimulating adenylate cyclase7. Stimulation of other intracellular messenger systems including calcium and phospholipase D has also been reported8.

As a neurotransmitter, VIP is expressed in the tracheobronchial tree by a dense branched neuronal network, which is more dense in the central airways and almost vanishes in the alveolar spaces. These neurons are distributed to the smooth muscle cells of the airways, the pulmonary and bronchial vessel walls and the submucosal layer9.

Among its functions as a neurotransmitter, VIP exerts potent bronchodilatory effects, which are independent of the adrenergic and cholinergic receptors and cyclooxygenase, quantitatively 100-fold more potent compared to the adrenergic bronchodilation induced by isoproterenol10. Furthermore it causes a 50-fold more potent vasodilation than prostacyclin to both pulmonary and systemic arteries11. Its vasodilatory action is independent of the endothelium12. Finally, VIP is implicated in the regulatory mechanism of mucous secretion13 by increasing the total cystic fibrosis transmembrane receptor (CFTR) levels, with a resulting three-fold increase in Cl- efflux in bronchial epithelial cells14. According to a noteworthy but not yet well-documented hypothesis, VIP regulates housekeeping mucous secretion, whereas cholinergic system accounts for the increased secretion during stress15,16.

VIP also exerts elaborate immunomodulatory effects17, mostly anti-inflammatory18. It is secreted by polymorphonuclear cells (PMN) and T-lymphocytes19. VIP acts on T-lymphocytes and inhibits their proliferation20. It also acts as a differentiation factor of the T-lymphocytes and promotes T-helper 2 lymphocytes (Th2) differentiation against T-helper lympocytes (Th1)21. It also promotes regulatory T-cells (Tregs) induction17. There are contradictory data regarding its impact on mast cell degranulation and chemokine production and more studies are necessary22,23. Moreover, VIP inhibits humoral immunity24 and also neutrophil chemotaxis25. Studies have shown that VIP acts directly to type 2 lung cells, which express VIP receptors, inhibiting their apoptosis26,27. Moreover, recent data show that VIP, through its anti-inflammatory action inhibits pulmonary vascular remodeling in patients with pulmonary arterial hypertension28. Finally, there are certain indications showing that VIP suppresses toll-like receptor 4 receptor (TLR-4)29,30.

VIP agonists

VIP has been thoroughly studied because of the potential pharmacologic uses of its agonists with a multitude of diseases concerning several organs, including the respiratory system. Major obstacles against the development of a functional VIP-agonist were its short half-life and also the wide range of its physiological functions, which can be translated into an increased possibility for adverse effects. Initially, efforts were focused on the creation of more stable VIP agonists31-33. Other studies were focused on the creation of either VPAC134 or VPAC235 selective agonists. Briefly, all these early studies have been inconclusive because of troublesome side effects, which appeared due to the action of these molecules on a major signal transduction pathway. From the respiratory physician’s points of view, these results necessitate the drug delivery by inhalation. So during the last decade, several studies, including clinical trials, have been conducted, concerning the administration of inhaled VIP agonists for respiratory diseases.

Firstly, in 2003, Linden A et al36 studied the FEV1 improvement after the administration of inhaled Ro25-1553, which is a selective VPAC2 agonist, to 24 patients with moderate stable asthma. Twenty four patients were studied in a double blind placebo controlled trial and a rapid-onset, but short-duration potent bronchodilatory effect, without adverse effects, was documented. Ro25-1553 is also hypothesized to exert anti-inflammatory activity, since it has been proven to inhibit allergen induced thromboxane A2 release. Briefly, this study showed that more stable VPAC2 agonists could be used for the treatment of moderate stable asthma.

In 2008, Leuchte HH et al37 demonstrated that aviptadil, which is another inhaled VIP analogue, when it was administered to 20 patients with pulmonary hypertension, caused temporary, intermediate vasodilatation of the pulmonary vessels and a decrease of the right heart load. No adverse effects were observed.

Moreover, in 2010, Prasse A et al38 administered nebulized VIP to patients with sarcoidosis. They have showed that VIP can induce regulatory T-cells and downregulate the inflammatory status of these patients, whereas they did not detect any obvious side effects or systemic immunosuppression.

Although these studies are limited by the temporary pharmacologic effect of the utilized VIP-agonists, they indisputably provide evidence of the potential significant role of long-acting agonists in respiratory therapeutics. The half-life issue has been thoroughly studied by two other research groups. They have both created non-selective (agonists of both VPAC1 and VPAC2) VIP-agonists with prolonged half-life.

Stark B et al investigated the interactions between VIP and polymerized liposomes39 and developed unilamellarnano-sized VIP-loaded liposomes (VLL)40,41, to prolong VIP half-life. Their hypothesis was based on the observation that both VPAC1 and VPAC2 are internalized upon ligand binding and rapidly recycled to the cell surface. After the saturation of VIP receptors, VIP should remain for a recycled receptor. During this period of time, VIP is mostly degraded. The inhalable liposomal formulation developed, carries large quantities of VIP, protects it from degradation and gradually releases it. According to their data, this analogue could be also administered in a nebulized form with a consequent decrease of the adverse effects and also an increase in its half-life.

Finally, Yamada S et al conducted a series of studies and developed two stable, long-acting VIP agonists: [R15,20,21,L17 ]-VIP-GRR(IK312532)42 and [R15,20,21, L17, A24,25, des-N28]-VIP-GRR43 and also a dry powder inhalation system for their agonists, namely IK312532-DPI44. Both VIP-agonists are characterized by increased stability and potent VIP-analogue effect. The second one was developed more recently and is even more stable.

Potential Impact on Certain Respiratory Diseases

Due to its physiological actions described above, VIP is essential for pulmonary homeostasis. Decreased levels are implicated in the pathophysiology of several respiratory diseases. Furthermore, VIP receptors are potential pharmacological targets for even more diseases. The pathophysiogical and immunological pathways participating in each disease are described below.

Asthma

Asthma is a chronic inflammatory disease mediated by Th2 cells, Tregs, mast cells, eosinophils, neutrophils and also mesenchymal such as epithelial and endothelial cells, fibroblasts and smooth muscle cells. VIP affects all these cell-types and causes bronchodilation and anti-inflammatory effect45,46. A pharmacologic agonist of VIP may represent a new targeted therapeutic approach, suitable for both maintenance and exacerbation treatment of asthmatic patients47. Although current therapy of asthma, especially corticosteroids and β2-agonists, is very effective, a VIP agonist could meet the needs of patients with refractory asthma who have side effects with systemic corticosteroids.

COPD

The bronchodilation caused by VIP is predominantly located in the large airways48, so its bronchodilatory effects cannot be used in COPD patients since their major airflow obstruction is detected in the small, more peripheral airways. Furthermore COPD is mediated by Th1, which are not affected by VIP. But on the other hand Th2, which are downregulated by VIP, play an important role during the exacerbations49. Last but not least, VIP has been documented to inhibit the apoptosis of alveolar L2 cells caused by the cigarette smoke-induced cytotoxicity and consequently to inhibit the progress of the disease26,49.

Cystic Fibrosis

Mucous secretion in the lung is induced by acetylcholine and VIP, which physiologically acts synergistically, property that is absent in cystic fibrosis14. VIP secretion and submucosal glands response to VIP are both reduced in patients with cystic fibrosis50. VIP causes an increase in the total CFTR levels51, with a resulting three-fold increase in Cl- efflux in bronchial epithelial cells12. Wine JJ15 highlights some remarkable but not well-documented assumptions which are in accordance with current data and reasonably explain the pathophysiological background of the disease. Mucous secretion is supposed to be mediated by different but partially overlapping neural pathways. Housekeeping mucous secretion, contributing to the innate defense is mediated by the intrinsic nervous system and VIP, whereas the excessive mucous secretion as part of an acute airway defense reflex is controlled by the parasympathetic system. Indicative of this assumption is that lung transplant patients maintain housekeeping but not the reflexive mucous secretion. On the contrary, patients with cystic fibrosis maintain only the reflexive and not the housekeeping secretion. The use of hypertonic saline to induce mucous secretion in these patients is supportive of this assumption. Unfortunately, VIP agonists could not be used for the treatment of cystic fibrosis, because of the mutation of CFTR, but these findings are substantial in the understanding of respiratory physiology and the role of the nonadrenergicnoncholinergic autonomic nervous system.

Pulmonary Arterial Hypertension (PAH)

It has been proven that VIP is a key mediator in the pathway leading to PAH28. Frequent VIP gene alterations have also been identified in patients with PAH52. Decreased serum and pulmonary tissue levels have been demonstrated in mice with PAH53 while VIP gene deletion caused intermediate level PAH54,55. Furthermore, its vasodilatory effects have already been presented. In the clinical trial mentioned earlier35, aviptadil induced a mean pulmonary artery pressure reduction with a concomitant increase in the cardiac output and the mixed venous blood oxygenation. Additionally, recent studies show that via its immunomodulatory effects, VIP downregulates the calcineurin-nuclear factor of activated T cells (NFAT) pathway, inhibiting pulmonary artery remodelling50. Finally, bronchial hyperreactivity secondary to precapillary pulmonary hypertension is also prevented by VIP.

Sarcoidosis

Despite the shortage of studies regarding the role of VIP and the impact of its agonists in sarcoidosis, a clinical trial was conducted, with positive results36. In this study, the anti-inflammatory effects of VIP, the induction of Tregs and the reduction of TNF-a were verified56. Its potential therapeutic role in sarcoidosis is supported by these results.

Conclusion

Although the investigatory material concerning the physiologic actions of VIP and the potential use of its agonists in respiratory therapeutics are indicative, additional research is essential. In particular, more human studies need to be conducted, to confirm the results of several animal studies and also to further illuminate the exact VIP pathways and properties. Furthermore, new clinical trials should be conducted with larger enrollment, longer administration and more organized follow-up.

Undoubtedly, the likelihood of a newly developed potential therapeutic agent to reach clinical practice, even after a successful clinical trial, is relatively low. On the other hand, there are only a few agents providing so many necessary characteristics and simultaneously lacking adverse effects. All these, combined with the encouraging outcomes of several clinical trials, could indicate an increased likelihood towards a successful path.

Conflict of Interest

Nothing to declare.

References

  • 1.Said SI, Mutt V. Potent peripheral and splanchnic vasodilator peptide from normal gut. Nature. 1970;225:863–864. doi: 10.1038/225863a0. [DOI] [PubMed] [Google Scholar]
  • 2.Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H. Pituitary adenylatecyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev. 2000;52:269–324. [PubMed] [Google Scholar]
  • 3.Said SI, Mutt V. Polypeptide with broad biological activity: Isolation from small intestine. Science. 1970;169:1217–1218. doi: 10.1126/science.169.3951.1217. [DOI] [PubMed] [Google Scholar]
  • 4.Berisha HI, Bratut M, Bangale Y, Colasurdo G, Paul S, Said SI. New evidence for transmitter role of VIP in the airways: Impaired relaxation by a catalytic antibody. Pulm Pharmacol Ther. 2002;15:121–127. doi: 10.1006/pupt.2001.0337. [DOI] [PubMed] [Google Scholar]
  • 5.Martinez C, Delgado M, Abad C, Gomariz RP, Ganea D, Leceta J. Regulation of VIP production and secretion by murine lymphocytes. J Neuroimmunol. 1999;93:126–138. doi: 10.1016/s0165-5728(98)00216-1. [DOI] [PubMed] [Google Scholar]
  • 6.Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. 2001;7:563–568. doi: 10.1038/87887. [DOI] [PubMed] [Google Scholar]
  • 7.Couvineau A, Laburthe M. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol. 2012;166:42–50. doi: 10.1111/j.1476-5381.2011.01676.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Dickson L, Finlayson K. VPAC and PAC receptors: From ligands to function. Pharmacol Ther. 2009;121:294–316. doi: 10.1016/j.pharmthera.2008.11.006. [DOI] [PubMed] [Google Scholar]
  • 9.Lundberg JM, Fahrenkrug J, Hökfelt T, Martling CR, Larsson O, Tatemoto K, et al. 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. doi: 10.1016/0196-9781(84)90090-1. [DOI] [PubMed] [Google Scholar]
  • 10.Hasaneen NA, Foda HD, Said SI. Nitric oxide and vasoactive intestinal peptide as co-transmitters of airway smooth-muscle relaxation: analysis in neuronal nitric oxide synthase knockout mice. Chest. 2003;124:1067–1072. doi: 10.1378/chest.124.3.1067. [DOI] [PubMed] [Google Scholar]
  • 11.Saga T, Said SI. Vasoactive intestinal peptide relaxes isolated strips of human bronchus, pulmonary artery, and lung parenchyma. Trans Assoc Am Physicians. 1984;97:304–310. [PubMed] [Google Scholar]
  • 12.Greenberg B, Rhoden K, Barnes PJ. Relaxant effects of vasoactive intestinal peptide and peptide histidine isoleucine in human and bovine pulmonary arteries. Blood Vessels. 1987;24:45–50. doi: 10.1159/000158670. [DOI] [PubMed] [Google Scholar]
  • 13.Coles SJ, Said SI, Reid LM. Inhibition by vasoactive intestinal peptide of glycoconjugate and lysozyme secretion by human airways in vitro. Am Rev Respir Dis. 1981;124:531–536. doi: 10.1164/arrd.1981.124.5.531. [DOI] [PubMed] [Google Scholar]
  • 14.Qu F, Liu HJ, Xiang Y, Tan YR, Liu C, Zhu XL, et al. Activation of CFTR trafficking and gating by vasoactive intestinal peptide in human bronchial epithelial cells. J Cell Biochem. 2011;112:902–908. doi: 10.1002/jcb.22999. [DOI] [PubMed] [Google Scholar]
  • 15.Wine JJ. Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system. Auton Neurosci. 2007;133:35–54. doi: 10.1016/j.autneu.2007.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Choi JY, Joo NS, Krouse ME, Wu JV, Robbins RC, Ianowski JP, et al. Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis. J Clin Invest. 2007;117:3118–3127. doi: 10.1172/JCI31992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Gonzalez-Rey E, Delgado M. Vasoactive intestinal peptide and regulatory T-cell induction: a new mechanism and therapeutic potential for immune homeostasis. Trends Mol Med. 2007;13:241–251. doi: 10.1016/j.molmed.2007.04.003. [DOI] [PubMed] [Google Scholar]
  • 18.Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol. 2010;30:2537–2551. doi: 10.1128/MCB.01282-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Lygren I, Revhaug A, Burhol PG, Giercksky KE, Jenssen TG. Vasoactive intestinal polypeptide and somatostatin in leucocytes. Scand J Clin Lab Invest. 1984;44:347–351. doi: 10.3109/00365518409083818. [DOI] [PubMed] [Google Scholar]
  • 20.Tang H, Welton A, Ganea D. Neuropeptide regulation of cytokine expression: Effects of VIP and RO 25-1553. J Interferon Cytokine Res. 1995;15:993–1003. doi: 10.1089/jir.1995.15.993. [DOI] [PubMed] [Google Scholar]
  • 21.Voice JK, Grinninger C, Kong Y, Bangale Y, Paul S, Goetzl EJ. Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J Immunol. 2003;170:308–314. doi: 10.4049/jimmunol.170.1.308. [DOI] [PubMed] [Google Scholar]
  • 22.Undem BJ, Dick EC, Buckner CK. Inhibition by vasoactive intestinal peptide of antigen-induced histamine release from guinea-pig minced lung. Eur J Pharmacol. 1983;88:247–250. doi: 10.1016/0014-2999(83)90012-2. [DOI] [PubMed] [Google Scholar]
  • 23.Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123:398–410. doi: 10.1111/j.1365-2567.2007.02705.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kimata H. Vasoactive intestinal peptide differentially modulates human immunoglobulin production. Adv Neuroimmunol. 1996;6:107–115. doi: 10.1016/s0960-5428(96)00004-6. [DOI] [PubMed] [Google Scholar]
  • 25.Sergejeva S, Hoshino H, Yoshihara S, Kashimoto K, Lötvall J, Lindén A. A synthetic VIP peptide analogue inhibits neutrophil recruitment in rat airways in vivo. RegulPept. 2004;117:149–154. doi: 10.1016/j.regpep.2003.10.002. [DOI] [PubMed] [Google Scholar]
  • 26.Onoue S, Ohmori Y, Endo K, Yamada S, Kimura R, Yajima T. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide attenuate the cigarette smoke extract-induced apoptotic death of rat alveolar L2 cells. Eur J Biochem. 2004;271:1757–1767. doi: 10.1111/j.1432-1033.2004.04086.x. [DOI] [PubMed] [Google Scholar]
  • 27.Filippatos GS, Gangopadhyay N, Lalude O, Parameswaran N, Said SI, Spielman W, et al. Regulation of apoptosis by vasoactive peptides. Am J Physiol Lung Cell Mol Physiol. 2001;281:L749–L761. doi: 10.1152/ajplung.2001.281.4.L749. [DOI] [PubMed] [Google Scholar]
  • 28.Said SI. The vasoactive intestinal peptide gene is a key modulator of pulmonary vascular remodeling and inflammation. Ann N Y Acad Sci. 2008;1144:148–153. doi: 10.1196/annals.1418.014. [DOI] [PubMed] [Google Scholar]
  • 29.Jiang W, Tang W, Geng Q, Xu X. Inhibition of toll-like receptor 4 with vasoactive intestinal peptide attenuates liver ischemia-reperfusion injury. Transplant Proc. 2011;43:1462–1467. doi: 10.1016/j.transproceed.2011.01.191. [DOI] [PubMed] [Google Scholar]
  • 30.Arranz A, Androulidaki A, Zacharioudaki V, Martinez C, Margioris AN, Gomariz RP, et al. Vasoactive intestinal peptide suppresses toll-like receptor 4 expression in macrophages via Akt1 reducing their responsiveness to lipopolysaccharide. Mol Immunol. 2008;45:2970–2980. doi: 10.1016/j.molimm.2008.01.023. [DOI] [PubMed] [Google Scholar]
  • 31.Bolin DR, Michalewsky J, Wasserman MA, O’Donnell M. Design and development of a vasoactive intestinal peptide analog as a novel therapeutic for bronchial asthma. Biopolymers. 1995;37:57–66. doi: 10.1002/bip.360370203. [DOI] [PubMed] [Google Scholar]
  • 32.Gozes I, Bardea A, Reshef A, Zamostiano R, Zhukovsky S, Rubinraut S, et al. Neuroprotective strategy for alzheimer disease: Intranasal administration of a fatty neuropeptide. Proc Natl Acad Sci U S A. 1996;93:427–432. doi: 10.1073/pnas.93.1.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Sethi V, Onyüksel H, Rubinstein I. Liposomal vasoactive intestinal peptide. Methods Enzymol. 2005;391:377–395. doi: 10.1016/S0076-6879(05)91021-5. [DOI] [PubMed] [Google Scholar]
  • 34.Yu RJ, Zhang L, Yi TH, Xie SS, Dai Y. In vivo anti-obesity effect of the agonist for receptor VPAC1. Sheng Li Xue Bao. 2008;60:751–758. [PubMed] [Google Scholar]
  • 35.Yu RJ, Xie QL, Dai Y, Gao Y, Zhou TH, Hong A. Intein-mediated rapid purification and characterization of a novel recombinant agonist for VPAC2. Peptides. 2006;27:1359–1366. doi: 10.1016/j.peptides.2005.11.026. [DOI] [PubMed] [Google Scholar]
  • 36.Lindén A, Hansson L, Andersson A, Palmqvist M, Arvidsson P, Löfdahl CG, et al. Bronchodilation by an inhaled VPAC(2) receptor agonist in patients with stable asthma. Thorax. 2003;58:217–221. doi: 10.1136/thorax.58.3.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Leuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32:1289–1294. doi: 10.1183/09031936.00050008. [DOI] [PubMed] [Google Scholar]
  • 38.Prasse A, Zissel G, Lützen N, Schupp J, Schmiedlin R, Gonzalez-Rey E, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med. 2010;182:540–548. doi: 10.1164/rccm.200909-1451OC. [DOI] [PubMed] [Google Scholar]
  • 39.Stark B, Debbage P, Andreae F, Mosgoeller W, Prassl R. Association of vasoactive intestinal peptide with polymer-grafted liposomes: Structural aspects for pulmonary delivery. Biochim Biophys Acta. 2007;1768:705–714. doi: 10.1016/j.bbamem.2006.11.017. [DOI] [PubMed] [Google Scholar]
  • 40.Hajos F, Stark B, Hensler S, Prassl R, Mosgoeller W. Inhalable liposomal formulation for vasoactive intestinal peptide. Int J Pharm. 2008;357:286–294. doi: 10.1016/j.ijpharm.2008.01.046. [DOI] [PubMed] [Google Scholar]
  • 41.Stark B, Andreae F, Mosgoeller W, Edetsberger M, Gaubitzer E, Koehler G, et al. Liposomal vasoactive intestinal peptide for lung application: protection from proteolytic degradation. Eur J Pharm Biopharm. 2008;70:153–164. doi: 10.1016/j.ejpb.2008.04.015. [DOI] [PubMed] [Google Scholar]
  • 42.Ohmori Y, Maruyama S, Kimura R, Onoue S, Matsumoto A, Endo K, et al. Pharmacological effects and lung-binding characteristics of a novel VIP analogue, [R15, 20, 21, L17]-VIP-GRR (IK312532) Regul Pept. 2004;123:201–207. doi: 10.1016/j.regpep.2004.04.029. [DOI] [PubMed] [Google Scholar]
  • 43.Onoue S, Misaka S, Ohmori Y, Sato H, Mizumoto T, Hirose M, et al. Physicochemical and pharmacological characterization of novel vasoactive intestinal peptide derivatives with improved stability. Eur J Pharm Biopharm. 2009;73:95–101. doi: 10.1016/j.ejpb.2009.05.013. [DOI] [PubMed] [Google Scholar]
  • 44.Ohmori Y, Onoue S, Endo K, Matsumoto A, Uchida S, Yamada S. Development of dry powder inhalation system of novel vasoactive intestinal peptide (VIP) analogue for pulmonary administration. Life Sci. 2006;79:138–143. doi: 10.1016/j.lfs.2005.12.049. [DOI] [PubMed] [Google Scholar]
  • 45.Szema AM, Hamidi SA, Lyubsky S, Dickman KG, Mathew S, Abdel-Razek T, et al. Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP. Am J Physiol Lung Cell Mol Physiol. 2006;291:L880–L886. doi: 10.1152/ajplung.00499.2005. [DOI] [PubMed] [Google Scholar]
  • 46.Groneberg DA, Springer J, Fischer A. Vasoactive intestinal polypeptide as mediator of asthma. Pulm Pharmacol Ther. 2001;14:391–401. doi: 10.1006/pupt.2001.0306. [DOI] [PubMed] [Google Scholar]
  • 47.Onoue S, Yamada S, Yajima T. Bioactive analogues and drug delivery systems of vasoactive intestinal peptide (VIP) for the treatment of asthma/COPD. Peptides. 2007;28:1640–1650. doi: 10.1016/j.peptides.2007.04.009. [DOI] [PubMed] [Google Scholar]
  • 48.Altiere RJ, Diamond L. Comparison of vasoactive intestinal peptide and isoproterenol relaxant effects in isolated cat airways. J Appl Physiol. 1984;56:986–992. doi: 10.1152/jappl.1984.56.4.986. [DOI] [PubMed] [Google Scholar]
  • 49.Misaka S, Sato H, Aoki Y, Mizumoto T, Onoue S, Yamada S. Novel vasoactive intestinal peptide derivatives with improved stability protect rat alveolar L2 cells from cigarette smoke-induced cytotoxicity and apoptosis. Peptides. 2011;32:401–407. doi: 10.1016/j.peptides.2010.10.021. [DOI] [PubMed] [Google Scholar]
  • 50.Joo NS, Irokawa T, Wu JV, Robbins RC, Whyte RI, Wine JJ. Absent secretion to vasoactive intestinal peptide in cystic fibrosis airway glands. J Biol Chem. 2002;277:50710–50715. doi: 10.1074/jbc.M208826200. [DOI] [PubMed] [Google Scholar]
  • 51.Dérand R, Montoni A, Bulteau-Pignoux L, Janet T, Moreau B, Muller JM, et al. Activation of VPAC1 receptors by VIP and PACAP-27 in human bronchial epithelial cells induces CFTR-dependent chloride secretion. Br J Pharmacol. 2004;141:698–708. doi: 10.1038/sj.bjp.0705597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111:1339–1346. doi: 10.1172/JCI17500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;31:135–139. doi: 10.1183/09031936.00105807. [DOI] [PubMed] [Google Scholar]
  • 54.Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115:1260–1268. doi: 10.1161/CIRCULATIONAHA.106.681718. [DOI] [PubMed] [Google Scholar]
  • 55.Habre W, Albu G, Janosi TZ, Fontao F, von Ungern-Sternberg BS, Beghetti M, et al. Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension. Respir Res. 2011;12:58. doi: 10.1186/1465-9921-12-58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Prasse A, Schmiedlin R, Bacher G, Bevec D, Zissel G, Muller- Quernheim J. Inhaled vasoactive intestinal peptide (VIP) reduces TNF-a production by BAL-cells and increases BAL regulatory T-cell counts in patients with sarcoidosis. American Thoracic Society, Toronto International Conference. 2008;A953802 [Google Scholar]

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