vasoactive-intestinal-peptide and Asthma

Vasoactive intestinal peptide (VIP) conveys various physiological effects in the digestive tract, nervous and cardiovascular system, airways, reproductive system, endocrine system, and more. A family of specific membrane bound receptors, termed VPAC1, VPAC2, and PAC1, bind VIP and trigger the effects. Many of them are of clinical interest. To date more than two thousand publications suggest the use of VIP in diseases like asthma, erectile dysfunction, blood pressure regulation, inflammation, endocrinology, tumours, etc. Despite this considerable potential, the peptide is not regularly used in clinical settings. A key problem is the short half life of inhaled or systemically administered VIP due to rapid enzymatic degradation. This shortcomings could be overcome with stable derivates or improved pharmacokinetics. A promising strategy is to use biocompatible and degradable depots, to protect the peptide from early degradation and allow for controlled release. This review focuses on aspects of clinical applications of VIP and the idea to use formulations based on biodegradable particles, to constitute a dispersible VIP-depot. Smart particle systems protect the peptide from early degradation, and assist the sustainable cell targeting with VIP for therapeutic or imaging purposes.

Topics: Administration, Inhalation; Animals; Asthma; Drug Carriers; Gastrointestinal Agents; Humans; Hypertension, Pulmonary; Liposomes; Nanoparticles; Neoplasms; Neuroprotective Agents; Protamines; Pulmonary Disease, Chronic Obstructive; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide; Vasodilator Agents

There is mounting evidence that pulmonary arterial hypertension (PAH), asthma and chronic obstructive pulmonary disease (COPD) share important pathological features, including inflammation, smooth muscle contraction and remodeling. No existing drug provides the combined potential advantages of reducing vascular- and bronchial-constriction, and anti-inflammation. Vasoactive intestinal peptide (VIP) is widely expressed throughout the cardiopulmonary system and exerts a variety of biological actions, including potent vascular and airway dilatory actions, potent anti-inflammatory actions, improving blood circulation to the heart and lung, and modulation of airway secretions. VIP has emerged as a promising drug candidate for the treatment of cardiopulmonary disorders such as PAH, asthma, and COPD. Clinical application of VIP has been limited in the past for a number of reasons, including its short plasma half-life and difficulty in administration routes. The development of long-acting VIP analogues, in combination with appropriate drug delivery systems, may provide clinically useful agents for the treatment of PAH, asthma, and COPD. This article reviews the physiological significance of VIP in cardiopulmonary system and the therapeutic potential of VIP-based agents in the treatment of pulmonary diseases.

Topics: Animals; Asthma; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Disease, Chronic Obstructive; Respiratory System Agents; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is one of the major peptide transmitters in the central and peripheral nervous systems, being involved in a wide range of biological functions. In an airway system where VIP-immunoreactive nerve fibers are present, VIP acts as neurotransmitter or neuromodulator of the inhibitory non-adrenergic and non-cholinergic airway nervous system and influences many aspects of pulmonary biology. A clinical application of VIP has been believed to offer potential benefits in the treatment of chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), however, its clinical application has been limited in the past for a number of reasons, including its extremely short plasma half-life after intravenous administration and difficulty in administration routes. The development of long-acting VIP analogues, in combination with appropriate drug delivery systems, may provide clinically useful agents for the treatment of asthma/COPD. In this review, development of efficacious VIP derivatives, drug delivery systems designed for VIPs and the potential application for asthma/COPD are discussed. We also include original data from our chemical modification experiments and formulation studies, which led to successful development of [R(15, 20, 21), L(17)]-VIP-GRR (IK312532), a potent VIP analogue, and a VIPs-based dry powder inhaler system.

Topics: Animals; Asthma; Binding, Competitive; Drug Delivery Systems; Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Pulmonary Disease, Chronic Obstructive; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Chronic inflammatory airway diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD) are major contributors to the global burden of disease. Although inflammatory cells play the central role in the pathogenesis of the diseases, recent observations indicate that also resident respiratory cells represent important targets for pulmonary drug development. Especially targeting airway neuromediators offers a possible mechanism by which respiratory diseases may be treated in the future. Among numerous peptide mediators such as tachykinins, calcitonin gene-related peptide, neurotrophins or opioids, vasoactive intestinal polypeptide (VIP) is one of the most abundant molecules found in the respiratory tract. In human airways, it influences many respiratory functions via the receptors VPAC1, VPAC2 and PAC1. VIP-expressing nerve fibers are present in the tracheobronchial smooth muscle layer, submucosal glands and in the walls of pulmonary and bronchial arteries and veins. Next to its strong bronchodilator effects, VIP potently relaxes pulmonary vessels, and plays a pivotal role in the mediation of immune mechanisms. A therapy utilizing the respiratory effects of VIP would offer potential benefits in the treatment of obstructive and inflammatory diseases and long acting VIP-based synthetic non-peptide compounds may represent a novel target for drug development.

Topics: Animals; Asthma; Bronchodilator Agents; Humans; Lung; Mucus; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Conformation; Randomized Controlled Trials as Topic; Receptors, Vasoactive Intestinal Peptide; Respiratory Mucosa; T-Lymphocytes; Vagus Nerve; Vasoactive Intestinal Peptide; Vasodilation

Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

Topics: Animals; Antibodies, Catalytic; Apoptosis; Asthma; Autoantibodies; Autoimmune Diseases; Biomarkers; Cytotoxicity, Immunologic; DNA; Humans; Hydrolysis; Mice; Multiple Sclerosis; Myelin Basic Protein; Prodrugs; Thyroglobulin; Thyroiditis, Autoimmune; Vasoactive Intestinal Peptide

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Autoantibodies; Colitis, Ulcerative; Fibroblasts; Humans; Lentivirus Infections; Nasal Polyps; Pulmonary Disease, Chronic Obstructive; Th2 Cells; Vasoactive Intestinal Peptide; Viral Envelope Proteins; Virus Latency

Vasoactive intestinal polypeptide (VIP) is one of the most abundant, biologically active peptides found in the human lung. VIP is a likely neurotransmitter or neuromodulator of the inhibitory non-adrenergic non-cholinergic airway nervous system and influences many aspects of pulmonary biology. In human airways VIP-immunoreactive nerve fibres are present in the tracheobronchial airway smooth muscle layer, the walls of pulmonary and bronchial vessels and around submucosal glands. Next to its prominent bronchodilatory effects, VIP potently relaxes pulmonary vessels. The precise role of VIP in the pathogenesis of asthma is still uncertain. Although a therapy using the strong bronchodilatory effects of VIP would offer potential benefits, the rapid inactivation of the peptide by airway peptidases has prevented effective VIP-based drugs so far and non-peptide VIP-agonists did not reach clinical use.

Topics: Airway Resistance; Asthma; Humans; Inflammation; Muscle, Smooth; Peptide Hydrolases; Receptors, Vasoactive Intestinal Peptide; Respiratory Physiological Phenomena; Respiratory System; Signal Transduction; Vasoactive Intestinal Peptide

Topics: Adrenergic beta-Agonists; Asthma; Atrial Natriuretic Factor; Bronchial Spasm; Bronchodilator Agents; Humans; Ion Channels; Muscle Relaxation; Muscle, Smooth; Phosphodiesterase Inhibitors; Respiratory Muscles; Vasoactive Intestinal Peptide

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Asthma; Atrial Natriuretic Factor; Bronchodilator Agents; Heart Failure; Humans; Lung; Molecular Sequence Data; Neuropeptides; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasodilator Agents

Analogs of vasoactive intestinal peptide (VIP) were synthesized and screened as bronchodilators with the ultimate goal of enhancing the potency and extending the duration of action of the native peptide. Several design approaches were applied to the problem. First, the amino acid residues required for receptor binding and activation were identified. A model of the active pharmacophore was developed. With knowledge of the secondary structure (NMR) of the peptide, various analogs were synthesized to stabilize alpha-helical conformations. Having achieved a level of enhanced bronchodilator potency, our approach then concentrated on identification of the sites of proteolytic degradation and synthesis of metabolically-stable analogs. Two primary cleavage sites on the VIP molecule were identified as the amide bonds between Ser25-Ile26 and Thr7-Asp8. This information was used to synthesize cyclic peptides which incorporated disulfide and lactam ring structures. Analog work combined the best multiple-substitution sites with potent cyclic compounds which resulted in identification of a cyclic lead peptide. This compound, Ro 25-1553, exhibited exceptionally high potency, metabolic stability, and a long duration of action and may be an effective therapeutic for the treatment of bronchospastic diseases.

Topics: Amino Acid Sequence; Animals; Asthma; Drug Design; Humans; Molecular Sequence Data; Protein Conformation; Structure-Activity Relationship; Vasoactive Intestinal Peptide

The physiopathological mechanisms underlying the multifactorial syndrome that is asthma are very complex and protean. Most probably, they are genetically determined, but they are largely modulated by the environment and by the inflammation of bronchi in which allergy occupies a special place. Chemical mediators of cellular origin interact with each other and with the cells that live or are recruited in the airways. Among these mediators histamine and arachidonic acid metabolites seem to play a predominant role, but the clinical use of antagonists has not confirmed the data obtained in vitro and in vivo in animals and even man. Cytotoxic mediators (cationic proteins, free oxygen radicals) are though to exert their noxious effect directly on the bronchial epithelium. No single neuromediator of the adrenergic and cholinergic system can explain the dysfunctions observed in asthma. Mediators of the non-adrenergic non-cholinergic system seem to be more interesting owing to their potential interaction with cells and with chemical mediators which contribute to the development of a true neurogenic inflammation.

Topics: Asthma; Atrial Natriuretic Factor; Cytokines; Histamine; Humans; Leukotrienes; Parasympathetic Nervous System; Platelet Activating Factor; Prostaglandins; Substance P; Sympathetic Nervous System; Sympathomimetics; Vasoactive Intestinal Peptide

Topics: Administration, Inhalation; Asthma; Bronchial Hyperreactivity; Calcitonin Gene-Related Peptide; Endothelins; Humans; Neuropeptides; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Asthma; Humans; Lung; Muscle, Smooth; Neuropeptides; Neurotransmitter Agents; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Second Messenger Systems; Vasoactive Intestinal Peptide

Many neuropeptides have recently been identified in human and animal airways. These peptides have potent effects on airway caliber, blood vessels, and secretions, raising the possibility that they may be involved in airway diseases such as asthma. Vasoactive intestinal peptide and peptide histidine methionine are potent bronchodilators and may be neurotransmitters of nonadrenergic bronchodilator nerves. In asthma, if these peptides are broken down more rapidly by enzymes from inflammatory cells, this might contribute to exaggerated bronchial responsiveness. Neuropeptides that are found in sensory nerves, such as substance P, neurokinin A, and calcitonin gene-related peptide, have inflammatory effects and might also contribute to the pathology of asthma if released from sensory nerve endings by an axon reflex. These findings may have important therapeutic implications for the future.

Topics: Animals; Asthma; Axons; Bronchi; Calcitonin Gene-Related Peptide; Epithelium; Humans; Nervous System Physiological Phenomena; Neuropeptides; Reflex; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Topics: Asthma; Humans; Neuropeptides; Neurotransmitter Agents; Protein Precursors; Tachykinins; Vasoactive Intestinal Peptide

Topics: Animals; Asthma; Calcitonin Gene-Related Peptide; Humans; Muscle, Smooth; Neuropeptides; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Respiratory Physiological Phenomena; Respiratory System; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Topics: Asthma; Humans; Neuropeptides; Respiratory System; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Asthma; Autonomic Nervous System; Capsaicin; Humans; Neuropeptides; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Asthma; Humans; Lung; Substance P; Vasoactive Intestinal Peptide

An understanding of the non adrenergic non cholinergic nervous system and its implication in the pathogenesis of asthma would benefit by the identification and localisation of the numerous natural bioactive peptides at the pulmonary level. In the past few years two components of the non adrenergic non cholinergic nervous system have been characterised. A bronchodilator component which would be mediated by "vaso-active intestinal peptide" (VIP) and the "peptide histidine methionine" (PHM). A broncho-constrictor component which would be mediated by the neurokinins (substance P (SP), neurokinin A (NKA) and the "calcitonin gene related peptide" (CGRP)). These neuropeptides, in vitro as well as in vivo, have effects which are not limited to the regulation of bronchial smooth muscle tone. In effect, they may intervene in the regulation of vascular tone, in the production of mucous and in the expression of immediate hypersensitivity reactions at pulmonary level. Several neuropeptides are present or co-exist with classical neurotransmitter in the afferent nerve endings of the pulmonary efferents. This co-existence of several neurotransmitters in the same nervous fibres raised the questions as to their interactions at the pre or post synaptic level. The implication of these neuropeptides in the pathogenesis of asthma rests on numerous experimental arguments. This recent aspect in the pathophysiology of asthma allows us to hope for new therapeutic approaches.

Topics: Asthma; Autonomic Nervous System; Bronchi; Humans; Muscle, Smooth; Neuropeptides; Neurotransmitter Agents; Peptide Fragments; Peptide PHI; Protein Precursors; Respiratory Hypersensitivity; Vasoactive Intestinal Peptide

In addition to classical cholinergic and adrenergic neural mechanisms, a third division of autonomic control has been recognised in human airways. Non-adrenergic inhibitory nerves are the dominant inhibitory neural pathway in human airway smooth muscle and there is increasing evidence that VIP and a related peptide, PHM, may be the neurotransmitters. These peptides are probably cotransmitters of acetylcholine in the airways and may modulate cholinergic effects. A defect in this system could occur in asthma because inflammation may more rapidly inactivate these neurotransmitter peptides. Non-cholinergic excitatory nerves have also been described in animal airways, although their existence in human airways is less certain. The neurotransmitter may be substance P or a related peptide neurokinin A, which could be released by axon reflex. Another peptide, calcitonin gene-related peptide, is colocalized with substance P and appears to be much more potent in human airways. Non-adrenergic non-cholinergic mechanisms may also regulate mucus secretion and the bronchial microvasculature. The role of this nervous system in health and disease is still uncertain as there are no specific blockers available.

Topics: Acetylcholine; Asthma; Autonomic Nervous System; Calcitonin Gene-Related Peptide; Humans; Lung; Muscle, Smooth; Nerve Tissue Proteins; Neurons; Neurotransmitter Agents; Peptide PHI; Peptides; Respiratory Physiological Phenomena; Respiratory System; Substance P; Vasoactive Intestinal Peptide

Several peptides have been localised to pulmonary nerves and endocrine cells. The neuropeptides vasoactive intestinal polypeptide (VIP) and substance P have potent effects on the airway smooth muscle, bronchial glands and blood vessels. There is increasing evidence that VIP and substance P are neurotransmitters of the non-adrenergic, non-cholinergic nervous (NANC) system. Non-adrenergic inhibitory nerves are the predominant inhibitory nervous system of the human airways. The presence of VIP in the innervation of the airways and the demonstration that it can mimick the effect of NANC nerve stimulation supports the hypothesis that it could be a mediator of the NANC system in the lungs. Sensory nerve fibers containing substance P can contribute to the smooth muscle contraction and mucosal oedema seen in asthma, by local axon reflexes that are initiated by noxious stimuli, such as for example cigarette smoke. A rat model for study of the bronchial reaction to substance P and related tachykinins, is described. In addition to a direct effect on airway smooth muscle, a large part of the broncho-constrictory actions of tachykinins in the rat is mediated by interaction with cholinergic nerves.

Topics: Airway Resistance; Animals; Asthma; Bronchi; Humans; Inflammation; Kinins; Lung; Nerve Tissue Proteins; Substance P; Vasoactive Intestinal Peptide; Vasodilation

Topics: Acetylcholine; Animals; Asthma; Bronchi; Humans; Lung; Nervous System; Neural Inhibition; Neurotransmitter Agents; Peptide PHI; Peptides; Protein Precursors; Purines; Respiratory System; Tissue Distribution; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), first isolated from the gut, was originally considered a candidate gastrointestinal hormone. Since about 1975, however, it has become increasingly clear that it is primarily a neurotransmitter or neuromodulator and that it exerts its functions mainly by local release from nerve endings. VIP plays a hormonal role only when it is released in large amounts from a tumor, with a consequent overflow into the circulation and grossly elevated plasma concentrations of the peptide. Moderately increased VIP plasma and tissue concentrations that cause mainly local effects are found in intestinal ischemia. Crohn's disease and some other chronic inflammatory diseases of the bowel. VIP is also measured in increased amounts in the normal fetus and neonate, where it may play an important physiological role. Such an increase of VIP levels in the circulation could enhance perfusion and metabolic activity of tissues during their rapid-growth period. On the other hand, disorders with a disturbed VIP function such as achalasia and Hirschsprung's disease and possibly also asthma and cystic fibrosis seem to be characterized mainly by a derangement of smooth muscle activity and/or exocrine secretion. Considering this list of disorders where VIP has either a proven or suspected role, it is easy to imagine the significance of this peptide in pediatric pathophysiology.

Topics: Asthma; Bronchodilator Agents; Celiac Disease; Child; Child, Preschool; Crohn Disease; Cystic Fibrosis; Digestive System; Esophageal Achalasia; Hirschsprung Disease; Humans; Hypoxia; Infant; Infant, Newborn; Placenta; Vasoactive Intestinal Peptide; Vipoma

The synthetic vasoactive intestinal peptide (VIP) analogue Ro 25-1553 is a selective VIP-PACAP type 2 (VPAC(2)) receptor agonist that causes a bronchodilatory effect in guinea pigs in vivo. The effect of Ro 25-1553 given by inhalation to patients with asthma was studied and compared with that of a long acting beta(2) adrenoceptor agonist.. Twenty four patients with moderate stable asthma participated in a double blind, randomised, placebo controlled, crossover study. The primary variable was bronchodilatory effect (increase in forced expiratory volume in 1 second, FEV(1)) after inhalation of Ro 25-1553 (100 microg or 600 microg) and formoterol (4.5 microg), respectively. Putative side effects were characterised by monitoring sitting blood pressure, serum potassium, electrocardiography and echocardiography.. Inhalation of 600 microg Ro 25-1553 caused a rapid bronchodilatory effect (geometric mean increase in FEV(1) compared with placebo) within 3 minutes of 6% (95% CI 4 to 9), as did inhalation of formoterol (8% (95% CI 5 to 10)). The corresponding maximum bronchodilatory effect during 24 hours was similar for 600 microg Ro 25-1553 (7% (95% CI 4 to 10)) and the reference bronchodilator formoterol (10% (95% CI 7 to 12)). However, for both doses of Ro 25-1553 the bronchodilatory effect was attenuated 5 hours after inhalation whereas formoterol still had a bronchodilatory effect 12 hours after inhalation. Neither Ro 25-1553 nor formoterol produced any clinically relevant side effects. No drug related difference in adverse events was observed.. Inhalation of a synthetic selective VPAC(2) receptor agonist constitutes a promising approach for bronchodilation in patients with asthma.

Topics: Administration, Inhalation; Adult; Aged; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Forced Expiratory Volume; Humans; Male; Middle Aged; Peptides, Cyclic; Vasoactive Intestinal Peptide

There is now considerable evidence in favor of vasoactive intestinal peptide (VIP) as a neurotransmitter of nonadrenergic noncholinergic nerves in the airways. The purpose of our study was to evaluate the influence of inhaled VIP on bronchomotor tone after a beta-adrenergic- and cholinergic-receptor blockage. The study was performed in six patients with asthma in 4 days. On the first day, a propranolol provocative dose producing a 20% change in FEV1 (PD20) was determined from the individual semilogarithmic dose-response curve. On the other days, the propranolol challenge was performed after inhalation of ipratropium bromide (40 micrograms), VIP (70 micrograms), and both drugs in randomized double-blind order. Statistical analysis was performed by two-way analysis of variance. The results demonstrated that mean propranolol PD20 was 0.14 mg (geometric mean + SD = 1.22). Ipratropium bromide administration, like VIP administration, significantly raised the PD20 value. The administration of both drugs elicited a further remarkable increase of mean propranolol PD20. The results demonstrated that inhaled VIP influences bronchomotor tone and that this effect is independent of the cholinergic blockage.

Topics: Adult; Aerosols; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Propranolol; Vasoactive Intestinal Peptide

In two studies vasoactive intestinal peptide (VIP) was administered intravenously to two groups of eight in-patient volunteers recovering from severe acute asthma. VIP (6 pmol/kg/min) infusion caused significant (p less than 0.01) increase in peak expiratory flow rate (PEFR) of 26 +/- 9 (SEM) l/min after 30 minutes infusion compared with a bronchodilation of 39 +/- 19 l/min seen with salbutamol (5 mcg/min). Following pretreatment with nebulized ipratropium bromide, VIP infusion caused a significant (p less than 0.02) bronchodilation of 25 l/min. VIP is a bronchodilator in severe asthma, although its effects are less than conventional medication. Reflex mechanisms are unlikely to explain the bronchodilatory effect of intravenous VIP.

Topics: Adult; Aged; Asthma; Bronchodilator Agents; Clinical Trials as Topic; Humans; Infusions, Parenteral; Middle Aged; Peak Expiratory Flow Rate; Vasoactive Intestinal Peptide

Topics: Asthma; Bronchodilator Agents; Humans; Vasoactive Intestinal Peptide

Nonadrenergic, noncholinergic nerves are the predominant inhibitory nervous pathway in human airway smooth muscle, and there is evidence in animals that the major neurotransmitter of this system is vasoactive intestinal peptide (VIP). We have investigated the effect of VIP on bronchomotor tone and bronchial responsiveness to inhaled histamine in 6 atopic asthmatic subjects. The VIP was given by inhalation to avoid any indirect effects on the airways that might arise from the potent cardiovascular actions of this peptide when given systemically. The VIP (100 micrograms) was compared with control solution (diluent: 1% human serum albumin in 2 ml 0.9% saline) and with beta 2-agonist (salbutamol, 200 micrograms) given double blind in random order on separate days. Specific airway conductance (SGaw) did not change after control or VIP inhalations, but it significantly increased after salbutamol inhalation. The provocation concentration of histamine causing a 35% fall in SGaw (PC35) did not change after control inhalation, but significantly increased after VIP (from 2.18 +/- 1.04 to 5.00 +/- 2.31 mg/ml histamine, mean +/- SE; p less than 0.05), and after salbutamol (from 1.71 +/- 0.83 to 15.6 +/- 4.2 mg/ml, p less than 0.01), the increase after salbutamol being significantly greater than after VIP. No changes in heart rate or blood pressure were found after any inhalation. We conclude that VIP protects against histamine-induced bronchoconstriction in human airways in vivo, and therefore has the capacity to be the neurotransmitter of nonadrenergic, noncholinergic inhibitory nerves in human airway smooth muscle.

Topics: Adult; Aerosols; Airway Resistance; Asthma; Bronchi; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Histamine; Humans; Male; Spirometry; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) caused significant bronchodilatation in seven asthmatic volunteers when given intravenously at the rate of 6 pmol/kg/min for 15 min during a double-blind study. Tachycardia and cutaneous flushing were observed during the infusion. VIP also ameliorated histamine-induced bronchoconstriction in all subjects. VIP may be an important natural bronchodilator in man and this has implications for the pharmacotherapy of asthma.

Topics: Adult; Asthma; Bronchi; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Histamine; Humans; Male; Vasoactive Intestinal Peptide

Modified BuShenYiQi formula (M-BYF) is derived from BuShenYiQi formula, used for the treatment of allergic asthma. The exact effect and mechanism of M-BYF on the improvement of asthma remain unclear.. We investigated the mechanism underlying the therapeutic effect of M-BYF on allergic asthma.. The asthma model was established in female BALB/c mice that were sensitized and challenged with ovalbumin (OVA). Mice in the treated groups were orally treated once a day with M-BYF (7, 14 and 28 g/kg/d) or dexamethasone before OVA challenge. Control and Model group received saline. Pathophysiological abnormalities and percentages of lung type 2 innate lymphoid cells (ILC2s) and Th9 cells were measured. Expression levels of type 2 cytokines and transcription factors required for these cells function and differentiation were analysed. Expression of vasoactive intestinal polypeptide (VIP)-VPAC2 signalling pathway-related proteins, and percentages of VIP expressing (VIP. M-BYF alleviated experimental asthma by negatively regulating ILC2s and Th9 cells and the VIP-VPAC2 signalling pathway. These findings provide the theoretical basis for future research of M-BYF in asthma patient population.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Immunity, Innate; Lymphocytes; Mice; Mice, Inbred BALB C; Receptors, Vasoactive Intestinal Peptide, Type II; Respiratory Hypersensitivity; Signal Transduction; Thy-1 Antigens; Vasoactive Intestinal Peptide

To observe the effect of moxibustion on respiratory function and contents of histamine and neuropeptides in skin tissue of "Feishu" (BL13) in asthmatic rats, so as to explore its mechanisms underlying improvement of asthma.. Thirty-six SD rats were randomly divided into normal control, model and moxibustion groups, with 12 rats in each group. The asthma model was established by subcutaneous injection (at the back and groin, 0.5 mL) and i．p. injection (1 mL)of mixture solution of ovalbumin (OVA), Aluminium Hydroxide gel and 0.9% sodium chloride solution, and repeated nasal drip of 1% OVA. Moxibustion was applied to bilateral BL13 for 15 min, once daily for 14 days. The inspiratory and expiratory resistance, and pulmonary ventilation compliance were detected by using a small animal pulmonary function tester under anesthesia. The contents of histamine, vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) in the local skin tissue of the left BL13 were assayed by using enzyme-linked immunosorbent assay (ELISA).. After modeling, the inspiratory and expiratory resistance were significantly increased (. Moxibustion of BL13 can improve pulmonary function in asthma rats, which may be related to changes of levels of histamine and neuropeptides as VIP, SP and CGRP in the local skin tissues of BL13.

Topics: Animals; Asthma; Histamine; Moxibustion; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

Bronchomotor tone is regulated by contraction and relaxation of airway smooth muscle (ASM). A weakened ASM relaxation might be a cause of airway hyperresponsiveness (AHR), a characteristic feature of bronchial asthma. Pituitary adenylyl cyclase-activating polypeptide (PACAP) is known as a mediator that causes ASM relaxation. To date, whether or not the PACAP responsiveness is changed in asthmatic ASM is unknown. The current study examined the hypothesis that relaxation induced by PACAP is reduced in bronchial smooth muscle (BSM) of allergic asthma. The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated. Tension study showed a BSM hyperresponsiveness to acetylcholine in the OA-challenged mice. Both quantitative RT-PCR and immunoblot analyses revealed a significant decrease in PAC

Topics: Animals; Asthma; Bronchi; Bronchial Hyperreactivity; Mice; Muscle Relaxation; Muscle, Smooth; Pituitary Adenylate Cyclase-Activating Polypeptide; Respiratory Hypersensitivity; Surface-Active Agents; Vasoactive Intestinal Peptide

This research was set up to explore the neural mechanisms of acupuncture in the treatment of bronchial asthma in rats by detecting the content of substance P(SP), vasoactive intestinal peptide (VIP), neurokinin A(NKA), neurokinin B (NKB), cyclic adenosine monophosphate/cyclic guanosine monophosphate ratio (cAMP/cGMP) and hematoxylin-eosin (HE) staining for the pathological changes of lung tissue, in order to Institute Certain Experimental and Theoretical Foundation for Traditional Chinese Medicine (TCM) Prevention and Treatment of Bronchial Asthma. For this purpose, fifty healthy adult Wistar male rats, weighing 200-250 g, were randomly divided into 5 groups: normal control group A, asthma control group B, asthma acupuncture group C, adrenalectomy (ADX)-asthma  group D, adrenalectomy (ADX)-asthma acupuncture group E. Group A was raised with other groups at the same period; Group B was induced asthma by ovalbumin; Group C was induced asthma as Group B and then acupunctured five acupoints (bilateral Feishu, bilateral Fengmen, and Dazhui); Group D was induced asthma after adrenalectomy; group E was treated with acupuncture on the basis of group D. HE staining was performed in the lung tissue of rats from each group, and histopathologic changes were observed. SP, VIP, NKA, NKB in each rat lung tissue were measured by immunohistochemistry. cAMP/cGMP was measured with ELISA to speculate the neural mechanisms of acupuncture in the treatment of bronchial asthma. The results were as: decrease of cAMP/cGMP and VIP and increase of SP, NKA, NKB in the lung tissue are the neural mechanisms of an asthma attack. The increase of cAMP/cGMP and decrease of NKA, NKB, SP and VIP in the lung tissue of group C indicated the improvement of bronchial asthma symptoms. It is possible that the decrease of NKA and NKB, increase of cAMP/cGMP and a slight change of SP and VIP in group E were related to the reduction of glucocorticoid after ADX which influenced the effect of acupuncture. The neural regulation mechanisms of acupuncture in the treatment of bronchial asthma were related to bronchiectasis caused by stimulation of adrenergic nerve and inhibition of the vagus nerve function by acupuncture, and related to the release of inflammatory mediators.

Topics: Acupuncture Therapy; Animals; Asthma; Cyclic AMP; Cyclic GMP; Immunohistochemistry; Inflammation Mediators; Lung; Male; Neurokinin B; Rats; Rats, Wistar; Substance P; Vasoactive Intestinal Peptide

Asthma is a heterogeneous clinical syndrome characterized by airway inflammation, hyper-responsiveness and remodeling. Airway remodeling is irreversible by current antiasthmatic drugs, and it is the main cause of severe asthma. Airway smooth muscle cells (ASMCs) act as the main effector cells for airway remodeling; the proliferation and hypertrophy of which are involved in airway remodeling. Caveolin (Cav)- 1 is present on the surface of ASMCs, which is involved in cell cycle and signal transduction regulation, allowing ASMCs to change from proliferation to apoptosis. The extracellular signal-regulated kinase (ERK)1/2 signaling pathway is a common pathway regulated by various proliferative factors, which demonstrates a regulatory role in airway remodeling of asthma. There have been many studies on the correlation between vasoactive intestinal peptide (VIP) and airway reactivity and inflammation in asthma, but the functions and related mechanisms of ASMCs remain unclear. In this study, we established an airway remodeling model in asthmatic mice, and concluded that VIP inhibits airway remodeling in vivo. The in vitro effect of VIP on interleukin-13-induced proliferation of ASMCs was studied by examining the effects of VIP on expression of ERK1/2, phospho-ERK1/2 and Cav-1 in ASMCs, as well as changes in cell cycle distribution. VIP inhibited phosphorylation of the ERK1/2 signaling pathway and expression of Cav-1 on ASMCs and decreased the proportion of S phase cells in the cell cycle, thus inhibiting the proliferation of ASMCs. This study provides a novel therapeutic mechanism for the treatment of asthma.

Topics: Airway Remodeling; Animals; Asthma; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Female; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Smooth Muscle; Vasoactive Intestinal Peptide

To investigate the effects of vasoactive intestinal peptide (VIP) on the airway inflammation and its regulatory effect on Th17/Treg imbalance in asthmatic mice.. A total of 30 BALB/c mice were equally and randomly divided into three groups: control, asthma, and VIP. An acute asthmatic mouse model was established by sensitization and challenge with ovalbumin (OVA). The control group received normal saline instead of OVA. Before the challenge with OVA, the VIP group was administered VIP (20 μg/mL) by aerosol inhalation for 30 minutes. The bronchoalveolar lavage fluid (BALF) and the lung tissue were collected from mice. The pathological changes in the lung tissue were observed by hematoxylin and eosin staining. The levels of Th17/Treg-related cytokines in BALF were measured by enzyme-linked immunosorbent assay. The expression of retinoid-related orphan receptor gamma t (RORγt) and forkhead box P3 (Foxp3) were measured by real-time fluorescence quantitative PCR and immunohistochemistry.. The histopathological results showed that the VIP group had milder symptoms of airway inflammation than the asthma group. The level of IL-17 in BALF in the asthma group was significantly higher than that in the control group and the VIP group (P<0.01), but the level of IL-17 in the control group was significantly lower than that in the VIP group (P<0.01). The level of IL-10 in BALF in the asthma group was significantly lower than that in the control group and the VIP group (P<0.01, but the level of IL-10 in the VIP group was significantly higher than that in the control group (P<0.01). The asthma group showed significantly higher expression levels of RORγt mRNA and protein in the lung tissue and significantly lower expression levels of Foxp3 mRNA and protein than the control group (P<0.01). The VIP group had significantly lower expression levels of RORγt mRNA and protein in the lung tissue and significantly higher expression levels of Foxp3 mRNA and protein than the asthma group (P<0.05).. The Th17/Treg imbalance may be closely related to the airway inflammation in asthmatic mice. VIP can improve airway inflammation by regulating the Th17/Treg imbalance in asthmatic mice.

Topics: Animals; Asthma; Forkhead Transcription Factors; Interleukin-10; Interleukin-17; Male; Mice; Mice, Inbred BALB C; Nuclear Receptor Subfamily 1, Group F, Member 3; T-Lymphocytes, Regulatory; Th17 Cells; Vasoactive Intestinal Peptide

Asthma is a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, airway hyperresponsiveness and recurring attacks of impaired breathing. Vasoactive intestinal peptide (VIP) has been proposed as a novel anti-asthma drug due to its effects on airway smooth muscle relaxation, bronchodilation and vasodilation along with its immunomodulatory and anti-inflammatory properties. In the current study, we investigated the therapeutic effects of VIP when conjugated with α-alumina nanoparticle (α-AN) to prevent enzymatic degradation of VIP in the respiratory tract. VIP was conjugated with α-AN. Balb/c mice were sensitized and challenges with ovalbumin (OVA) or PBS and were divided in four groups; VIP-treated, α-AN-treated, α-AN-VIP-treated and beclomethasone-treated as a positive control group. Specific and total IgE level, airway hyperresponsiveness (AHR), bronchial cytokine expression and lung histology were measured. α-AN-VIP significantly reduced the number of eosinophils (Eos), serum IgE level, Th2 cytokines and AHR. These effects of α-AN-VIP were more pronounced than that seen with beclomethasone or VIP alone (P<0.05). The current data indicate that α-AN-VIP can be considered as an effective nano-drug for the treatment of asthma.

Topics: Aluminum Oxide; Animals; Anti-Asthmatic Agents; Asthma; Drug Carriers; Drug Stability; Eosinophilia; Female; Immunoglobulin E; Lung; Mice; Nanoparticles; Vasoactive Intestinal Peptide

To investigate and analyze the correlation between the c-fos protein expression and neuropeptide content in the lung of bronchial asthmatic rats.. Thirty-two (32) SD rats were randomly allocated into 4 groups of the normal control, the non-acute asthma, the acute asthma and the dexamethasone intervention. Immunohistochemistry was performed for histological observation, and substance P (SP) and vasoactive intestinal peptide (VIP) concentrations in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay (ELISA).. SP concentration in the alveolar lavage of asthmatic rat was significantly higher than that in the normal control group (P < 0.0001), whereas VIP concentration was significantly lower (P < 0.0001). The optical density of c-fos protein in the lung tissues of groups of the non-acute asthma, the acute asthma and the dexamethasone intervention was positively correlated with SP concentration in the bronchoalveolar lavage fluid (r = 0.908, r = 0.967, r = 0.865), and negatively correlated with the VIP concentration in the alveolar lavage (r = -0.974, r = -0.949, r = -0.962).. The c-fos protein expression and neuropeptide content in the lungs of asthmatic rats are related with asthma attacks.

Topics: Animals; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Male; Neuropeptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Substance P; Vasoactive Intestinal Peptide

To observe changes of cholecystokinin octapeptide (CCK-8), calcitonin gene related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) in each tissue of the digestive system of allergic asthma (AA) model rats.. The pulmonary disease (AA) rat model was duplicated by 1% ovalbumin. Its effect on the pathological morphology of the six main parts of the digestive system (stomach, duodenum, jejunum, ileum, colon and rectum) and related regulating factors such as CCK8, CGRP, SP, and VIP were observed.. The pathological morphology of the lung was synchronously changed as that of the colon of model rats. But there was no obvious change in the stomach, duodenum, jejunum, ileum, or rectum. Significant changes occurred in CCK8 (79 961.4 +/- 12 577.9, 48 519.5 +/- 12 240.7), CGRP (41 950.1 +/- 12 600.1, 38 059.8 +/- 11 942.4), and SP (88 243.9 +/- 32 177.2, 47 417.8 +/- 16 462.4), and VIP (20 711.4 +/- 7 334.6, 43 208.1 +/- 13 433.8) of the lung tissue and the colon tissue of model rats (P < 0. 05, P < 0.01). But there was no significant change in the aforesaid substances of the stomach, duodenum, jejunum, ileum and rectum (P > 0.05).. Pulmonary disease might affect the colon, inducing pathological changes of the colon tissue and changes of related regulating factors such as CCK8, CGRP, SP, and VIP. It showed no significant effect on the stomach, duodenum, jejunum, ileum and rectum.

Topics: Animals; Asthma; Calcitonin Gene-Related Peptide; Colon; Disease Models, Animal; Lung; Male; Rats; Rats, Wistar; Sincalide; Substance P; Vasoactive Intestinal Peptide

The present study was undertaken to develop a respirable sustained-release powder (RP) formulation of long-acting VIP derivative, [Arg(15, 20, 21), Leu(17)]-VIP-GRR (IK312532), using PLGA nanospheres (NS) with the aim of improving the duration of action. NS formulation of IK312532 (IK312532/NS) was prepared by an emulsion solvent diffusion method in oil, and a mixture of the IK312532/NS and erythritol was jet-milled and mixed with lactose carrier to obtain the IK312532/NS-RP. Physicochemical properties were characterized focusing on appearance, particle size, and drug release, and in vivo pharmacological effects were assessed in antigen-sensitized rats. The IK312532/NS with a diameter of 140 nm showed a biphasic release pattern in distilled water with ca. 20% initial burst for 30 min and a sustained slow release up to ca. 55% for 24h. Laser diffraction analysis demonstrated that IK312532/NS-RP had fine dispersibility and suitable particle size for inhalation. In antigen-sensitized rats, insufflated IK312532/NS-RP (10 μg of IK312532/rat) could suppress increases of granulocyte recruitment and myeloperoxidase in pulmonary tissue for up to 24h after antigen challenge, although IK312532-RP at the same dose was less effective with limited duration of action. From these findings, newly prepared IK312532/NS-RP might be of clinical importance in improving duration of action and medication compliance for treatment of airway inflammatory diseases.

Topics: Administration, Inhalation; Animals; Asthma; Bronchoalveolar Lavage Fluid; Delayed-Action Preparations; Disease Models, Animal; Granulocytes; Lung; Lung Diseases; Male; Nanospheres; Peroxidase; Pneumonia; Rats; Rats, Sprague-Dawley; Respiratory System; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has been considered as a promising drug candidate for asthma and COPD because of its potent immunomodulating and anti-inflammatory activities. Recently, our group developed a new VIP derivative, [R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR (IK312548), with improved chemical and metabolic stability. In the present study, a dry powder inhaler system of IK312548 was designed for inhalation therapy with minimal systemic side effects, the physicochemical properties of which were also evaluated with a focus on morphology, particle size distribution, inhalation performance, and peptide stability. Laser diffraction and cascade impactor analysis suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 31.2%. According to UPLC/ESI-MS and circular dichroic spectral analyses, no significant changes in the purity and structure of VIP derivative were observed during preparation of respirable formulation. Anti-inflammatory properties of IK312548 respirable powder (RP) were characterized in antigen-sensitized asthma/COPD-model rats. There were marked inflammatory cells infiltrated into the lung tissues of experimental asthma/COPD-model rats; however, intratracheal administration of IK312548-RP led to significant reductions of recruited inflammatory cells in lung tissues and BALF by 72 and 78%, respectively. Thus, respirable powder formulation of IK312548 might be a promising medication for asthma, COPD, and other airway inflammatory diseases.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Disease Models, Animal; Drug Stability; Dry Powder Inhalers; Inflammation; Lung; Male; Particle Size; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Tissue Distribution; Vasoactive Intestinal Peptide

We earlier reported spontaneous features of asthma in Vasoactive Intestinal Peptide knockout mice (VIP KO): 1) peribronchiolar airway inflammation, with accumulation of lymphocytes and eosinophils, 2) pro-inflammatory cytokine production of IL-5, IL-6, with IFN-γ, and 3) airway hyper-responsiveness to inhaled methacholine. In human asthma, a phenotype with sulfite sensitivity leads to airway inflammation and hyper-responsiveness to inhaled sulfites, and is associated with upregulation of anti-oxidant protein lung carbonyl reductase. For the present experiments, we examined the role of VIP in modulating anti-oxidant genes and their proteins, including lung carbonyl reductase.. Four male VIP KO mice and four wild-type age- and gender matched mice had lungs examined for whole genome microarray and a proteomics approach using mass spectrometry. The proteomics analysis revealed that a novel variant of anti-oxidant protein lung carbonyl reductase (car3) was uniquely and markedly elevated in the VIP KO mice. RT-PCR indicated that carbonic anhydrase 3, which is an anti-oxidant protein, was elevated in the VIP KO mice.. These data support the concept that VIP influences the endogenous oxidant/antioxidant balance. One potential implication is that VIP and its analogues may be used to treat inflammatory diseases, including asthma.

Topics: Alcohol Oxidoreductases; Animals; Asthma; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteome; Proteomics; Sulfites; Up-Regulation; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) exerts immunomodulating and anti-inflammatory activities through its specific receptors, such as VPAC1 and 2 receptors. Previously, a stabilized VIP derivative, [R(15,20,21), L(17)]-VIP-GRR (IK312532), was proposed as a candidate of anti-asthma drug, and a dry powder inhaler system of IK312532 was also developed for inhalation therapy with minimal systemic side-effects. In the present study, the anti-inflammatory properties of IK312532 respirable powder (RP) were characterized in an asthma/COPD-like animal model, with the use of newly developed ovalbumin (OVA)-RP for lung inflammation. Marked inflammatory events in the lung were observed after OVA-RP challenge in rats as evidenced by significant increase of inflammatory biomarkers such as eosinophil peroxidase (EPO), myeloperoxidase (MPO) and lactate dehydrogenase (LDH). However, intratracheal administration of IK312532-RP led to significant attenuation of plasma EPO, MPO and LDH activities, as well as significant reduction of recruited inflammatory cells in BALF, especially macrophages and eosinophils. In the rats pretreated with IK312532-RP, histochemical examinations revealed that the inflammatory cells infiltrating to the lung and the epithelial wall thickness decreased significantly by 85% and 58%, respectively. Thus, inhalable powder formulation of IK312532 exerts its anti-inflammatory activity by suppressing granulocyte recruitment to the lung and epithelial hyperplasia, followed by the reduction of cytotoxic peroxidases.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; L-Lactate Dehydrogenase; Male; Peroxidase; Powders; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

Human airway smooth muscle cells (HASMC) secrete fractalkine (FKN), a chemokine the concentration of which is increased in asthmatic patients. HASMC also induce mast cell chemotaxis, as a component of asthma inflammation. We therefore evaluated the role of smooth muscle-derived FKN in mast cell migration. We assessed the capacity of recombinant FKN to induce human mast cell chemotaxis. This effect implicates a calcium-independent pathway involving actin reorganization and protein kinase C-delta. We found that HASMC constitutively produce FKN, the synthesis of which is reinforced upon proinflammatory stimulation. Under basal experimental conditions, FKN production by HASMC is not sufficient to induce mast cell chemotaxis. However, pretreatment of mast cells with the neuropeptide vasoactive intestinal peptide (VIP) increases FKN potency to attract mast cells. Since we observed, in asthmatic patients, an increase in both FKN and VIP expression by airway smooth muscle and a positive correlation between VIP staining and mast cell infiltration of the smooth muscle layer, we conclude that HASMC-derived FKN may contribute to mast cell recruitment in asthma.

Topics: Asthma; Bronchi; Cell Line; Cells, Cultured; Chemokine CX3CL1; Chemokines, CX3C; Chemotaxis, Leukocyte; Humans; Mast Cells; Membrane Proteins; Myocytes, Smooth Muscle; Protein Kinase C; Vasoactive Intestinal Peptide

The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Female; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Hydrolases; Pneumonia; Severity of Illness Index; Vasoactive Intestinal Peptide

The neuropeptide vasoactive intestinal peptide (VIP) is one of the physiologic mediators of non-adrenergic, non-cholinergic smooth muscle relaxation of the airway and an important modulator of innate and adaptive immune responses. VIP catalytic autoantibodies are increased in asthma and serum VIP level is decreased during acute exacerbation of asthma. The effect of pregnancy on asthma is variable and depends in part on the severity of pre-existing asthma, along with other physiological and pathophysiological changes. We hypothesized that hydrolysis of VIP by circulating catalytic VIP antibodies will be increased in pregnancy in patients with asthma.. To determine the level of catalytic autoantibodies to VIP in pregnant asthmatics compared to non-pregnant asthmatics and control pregnant women without asthma.. We prospectively enrolled eight pregnant asthmatics (age, 26.5 +/- 2.6 years; mean +/- SEM), nine pregnant women without asthma (32.0 +/- 3.0 years), seven non-pregnant women with asthma (25.0 +/-1.9 years), and seven non-pregnant women without asthma (34.4 +/- 2 years) into the study. VIP hydrolysis was performed in all subjects.. Immunoglobulin G (IgG) autoantibodies that catalyze the hydrolysis of vasoactive intestinal peptide (VIP) were present at greater levels in the blood of pregnant women with asthma (7.6 +/- 1.1 pM VIP/6 h) compared to pregnant women without asthma (4.0 +/- 0.5; p < 0.001), non-pregnant asthmatics (4.9 +/- 0.9; p < 0.05) or non-pregnant women without asthma (1.9 +/- 0.7; p < 0.05).. An increase in the VIP hydrolyzing activity of IgG is independently associated with asthma and pregnancy. The autoantibodies hold the potential of affecting the pathophysiology of the airways in pregnant asthmatics.

Topics: Adult; Asthma; Autoantibodies; Catalysis; Female; Humans; Hydrolysis; Immunoglobulin G; Pregnancy; Pregnancy Complications; Prospective Studies; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act as neurotransmitters in numerous biological responses. We previously reported that the replacement of Lys by Arg, and Met by Leu in VIP (IK312532; [Arg15, 20, 21, Leu17]-VIP) resulted in a significant improvement in metabolic stability and biological activity. In the present study, we investigated the effect of VIP and its related peptides including long-acting VIP derivative (IK312532) and PACAP27 on the cytotoxicity of cigarette smoke extract (CSE), a causative factor of chronic obstructive pulmonary disease (COPD), in rat alveolar L2 cells. RT-PCR displayed the dominant expression of mRNA for the VIP-specific VPAC2 receptor in L2 cells, and VIP and the related peptides showed the specific binding activity and potent stimulation of adenylate cyclase. CSE at a concentration of 0.1% or higher induced significant apoptotic death of L2 cells. Interestingly, the addition of neuropeptides at a concentration of 10(-11) M or higher in L2 cells with CSE (0.25%) resulted in significant attenuation of cell death with the deactivation of CSE-evoked caspase-3 activity. IK312532 was much stable against the enzymatic digestion compared to VIP, and the protective effect of IK312532 was 1.6-fold higher than that of VIP. Taken together with our previous report showing that IK312532 has long-acting relaxant activity in the lung, IK312532 may be a potential candidate for drug treatment of asthma and COPD.

Topics: Animals; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Caspase 3; Caspases; Cell Death; Cell Line; DNA, Complementary; Gene Expression; Humans; Nerve Growth Factors; Neuropeptides; Neurotransmitter Agents; Nicotiana; Pituitary Adenylate Cyclase-Activating Polypeptide; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Rats; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Smoke; Vasoactive Intestinal Peptide

Both vasoactive intestinal peptide (VIP) and nitric oxide (NO) relax airway smooth muscle and are potential co-transmitters of neurogenic airway relaxation. The availability of neuronal NO synthase (nNOS) knockout mice (nNOS-/-) provides a unique opportunity for evaluating NO.. To evaluate the relative importance of NO, especially that generated by nNOS, and VIP as transmitters of the inhibitory nonadrenergic, noncholinergic (NANC) system.. In this study, we compared the neurogenic (tetrodotoxin-sensitive) NANC relaxation of tracheal segments from nNOS-/- mice and control wild-type mice (nNOS(+/+)), induced by electrical field stimulation (EFS). We also examined the tracheal contractile response to methacholine and its relaxant response to VIP.. EFS (at 60 V for 2 ms, at 10, 15, or 20 Hz) dose-dependently reduced tracheal tension, and the relaxations were consistently smaller (approximately 40%) in trachea from nNOS-/- mice than from control wild-type mice (p < 0.001). VIP (10(- 8) to 10(-6) mol/L) induced concentration-dependent relaxations that were approximately 50% smaller in nNOS-/- tracheas than in control tracheas. Methacholine induced concentration-dependent contractions that were consistently higher in the nNOS-/- tracheas relative to wild-type mice tracheas (p > 0.05).. Our data suggest that, in mouse trachea, NO is probably responsible for mediating a large (approximately 60%) component of neurogenic NANC relaxation, and a similar (approximately 50%) component of the relaxant effect of VIP. The results imply that NO contributes significantly to neurogenic relaxation of mouse airway smooth muscle, whether due to neurogenic stimulation or to the neuropeptide VIP.

Topics: Airway Resistance; Animals; Asthma; Culture Techniques; Dose-Response Relationship, Drug; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscle, Smooth; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Reference Values; Trachea; Vasoactive Intestinal Peptide

The identity of the transmitter(s) of nonadrenergic, noncholinergic airway smooth muscle relaxation has long been investigated. Recently, nitric oxide (NO) has been proposed as the main, if not the only transmitter. We earlier suggested vasoactive intestinal peptide (VIP) as a candidate transmitter and target for pathogenic catalytic autoantibodies (VIPases) found in certain humans. To re-examine the role of VIP, we studied the airway transport and effects of a model monoclonal antibody (Ab) capable of binding and cleaving VIP. In vitro receptor binding assays indicated the catalytic light chain subunit of the VIPase Ab to inhibit the saturable binding of (Tyr(10-125)I) VIP by guinea pig lung membranes, whereas a catalytically deficient mutant of the Ab light chain was without significant inhibitory activity. Systemically administered IgG preparations of the VIPase Ab accumulated in the airway lavage fluid of guinea pigs at levels close to those in blood, suggesting that the Ab reaches the airways freely. Electrical field stimulation (EFS)-induced relaxations of tracheal strips were weaker and shorter in VIPase-treated animals than in control nonimmune IgG-treated animals. The inhibitory effect of the VIPase was dose-dependent. VIPase-mediated inhibition of EFS-induced relaxation was evident both in the absence and presence of blockade of beta-adrenergic and cholinergic receptors. Thus, circulating VIP binding and cleaving antibodies can reach the airways and attenuate the neurogenic relaxation of guinea pig tracheal smooth muscle, probably by neutralizing endogenously released VIP. The findings support a role for VIP as a major mediator of neurogenic relaxation of guinea pig tracheal smooth muscle. Lack of complete abrogation of relaxation is consistent with a co-transmitter role for NO.

Topics: Animals; Antibodies, Catalytic; Asthma; Bronchoalveolar Lavage Fluid; Electric Stimulation; Guinea Pigs; Humans; Muscle Relaxation; Muscle, Smooth; Trachea; Vasoactive Intestinal Peptide; Vasodilator Agents

The characteristic feature of asthma is bronchial hyperresponsiveness (BHR). It is due predominately to inflammation of airways. Pathologically, there are inflammatory infiltration, epithelial sloughing and mucosal edema in the bronchi. The objective of this study is to investigate the relationship between BHR and airway inflammation.. 57 cases of asthma and 22 normal subjects were tested with bronchial reactivity examination and P-selectin, substance P (SP) and vasoactive intestinal peptide (VIP) in plasma.. It was found that the bronchial reactivity to inhaled methacholine was positive in 53 of the 57 asthmatic patients (92.98%), while the remaining four were negative (7.02%). Twenty-two normal subjects were all negative with the test of bronchial reactivity. The levels of P-selectin and SP in asthmatics with corticosteroids treatment (n = 27) were higher than those in the control group (P < 0.05), but lower than those in asthmatics treated with aminophylline and salbutamol sulfate (n = 30), (P < 0.01). The concentration of VIP in asthmatics with corticosteroids treatment was significantly higher than that of asthmatics with out corticosteroids treatment (P < 0.01) but lower than that in the control group (P < 0.01). There was positive relationship between bronchial reactivity and P-selectin (r = 0.328, P < 0.05), as well as SP (r = 0.529, P < 0.01) in asthmatics, but negative relationship between bronchial reactivity and VIP (r = -0.419, P < 0.05).. The increase of P-selectin and SP and decrease of VIP can induce BHR, corticosteroids can reduce levels of P-selectin, SP and enhance the level of VIP, therefore it can improve the reactivity of airway and relieve symptoms.

Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Glucocorticoids; Humans; Male; Middle Aged; P-Selectin; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Ragweed (Ambrosia artemisiifolia) is clinically the most important source of seasonal aeroallergens, as it is responsible for the majority and most severe cases of hay fever (allergic rhinitis). Extracts from pollen grains have been shown to contain numerous proteins with various functions, including a novel serine proteolytic enzyme with chymotrypsin-like specificity that has been previously described (J. Biol. Chem. 1996; 271:26227-26232). We now report the isolation and properties of a second, trypsin-like enzyme with a molecular mass near 80 kD, from ragweed pollen extracts. This enzyme has a blocked N-terminus, a pH optimum near 9.0, and requires Ca2+ for stability and activity, but not reducing agents. The enzyme is inhibited by diisopropyl fluorophosphate, a general serine class proteinase inhibitor, and more specifically by N-p-tosyl-L-lysine chloromethyl ketone. Activity toward protein substrates was not detected, but various synthetic substrates and small biologically active peptides were efficiently cleaved, with a strong preference for Arg in the P1 position and either Arg or Gly in the P2 position. This specificity was confirmed through inhibition studies with both peptidyl chloromethyl ketone and organophosphate inhibitors. Significantly, atrial natriuretic peptide and angiotensin 2, whose degradation would amplify kinin activity and influence inflammatory diseases of the respiratory tract and nasal passages, were also rapidly hydrolyzed. Thus, the ragweed pollen endopeptidase may be involved in the inactivation of regulatory neuropeptides during pollen-initiated allergic reactions.

Topics: Amino Acid Sequence; Arginine; Asthma; Endopeptidases; Hypersensitivity; Molecular Sequence Data; Neuropeptides; Pollen; Protease Inhibitors; Serine Endopeptidases; Substance P; Substrate Specificity; Vasoactive Intestinal Peptide

Neuropeptides act on most of the components of the bronchial environment. They influence bronchomotor tone and bronchial vascular caliber and permeability. To investigate the nonadrenergic, noncholinergic system within the airways in asthma and chronic bronchitis, we performed endobronchial biopsies in 16 normal human volunteers, 49 patients with asthma of varying severity, including 16 patients treated with oral corticosteroids, and 13 patients with chronic bronchitis. Frozen sections of biopsies stained with specific antibodies against the neural marker PGP 9.5, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were analyzed for the presence of nerves through indirect immunofluorescence. Nerves were present in most of the biopsies and were found within and below the epithelium and adjacent to smooth muscle, glands, and blood vessels. By comparison with those in normal subjects, the numbers of VIP-immunoreactive nerves were not significantly decreased in patients with asthma and chronic bronchitis, but NPY-immunoreactive nerves were significantly decreased in the smooth muscle of these latter two groups of patients (p < 0.005). There was no correlation between disease severity and the number of nerves found in the biopsies. This study does not confirm previous findings in autopsy material of some defects in sensory and VIP-containing nerves in severe asthma.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Beclomethasone; Biomarkers; Biopsy; Bronchi; Bronchitis; Bronchoconstriction; Calcitonin Gene-Related Peptide; Capillary Permeability; Chronic Disease; Epithelium; Female; Fluorescent Antibody Technique, Direct; Glucocorticoids; Humans; Male; Middle Aged; Mucous Membrane; Muscle, Smooth; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Prednisone; Substance P; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide; Vasomotor System

Asthma is a chronic inflammatory disorder of the airways in which many cells participate. This inflammation causes recurrent episodes and symptoms that are associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. Therefore, an investigation of useful remedies for the treatment of bronchial asthma is proposed. In this study, we determined whether both forms of pituitary adenylate cyclase activating polypeptide (PACAP 38 and PACAP 27) belonging to the vasoactive intestinal peptide (VIP) family of peptides could inhibit the effects of histamine-induced respiratory resistance (Rr) in anesthetized guinea pigs, when compared with VIP. The order for 50% suppression (ED50) of Rr induced by peptides was VIP > PACAP 27 > PACAP 38. The inhibitory effects induced by PACAP 38 on histamine-induced Rr in guinea pigs were more prolonged than with the other two peptides. Moreover, adding the endopeptidase inhibitor phosphoramidon prolonged the inhibitory effects of PACAPs. These results suggested that the exogenous peptides of the inhibitory nonadrenergic noncholinergic nervous (i-NANC) peptides could become a useful remedy for treatment of bronchial asthma, because these belong to an important intrinsic hormone.

Topics: Airway Resistance; Animals; Asthma; Bronchoconstriction; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Time Factors; Trachea; Vasoactive Intestinal Peptide

An immunoglobulin light chain (L chain) library derived from the peripheral blood lymphocytes of a patient with asthma was cloned into a phagemid vector. Phage particles displaying L chains capable of binding vasoactive intestinal polypeptide (VIP) were isolated by affinity chromatography. Two VIP binding L chains were expressed in Escherichia coli in soluble form and purified to electrophoretic homogeneity by metal chelating and protein L affinity chromatography. Both L chains catalyzed the hydrolysis of [tyr10-125I]VIP substrate. The catalytic activity eluted at the molecular mass of the monomer form of the L chain (28 kDa) from a gel filtration column. The activity was bound by immobilized anti-kappa-chain antibody. A control recombinant L chain displayed no catalytic activity. Hydrolysis of VIP by the catalytic L chains was saturable and consistent with Michaelis-Menten kinetics. The turnover of the L chains was moderate (0.22 and 2.21/min) and their Km values indicated comparatively high affinity recognition of VIP[111 and 202 nM), producing catalytic efficiencies comparable to or greater than trypsin. Unlike trypsin, the L chains did not display detectable cleavage of casein, suggesting a catalytic activity specialized for VIP. Comparisons of the nucleotide sequences of the L chain cDNA with their putative germ-line counterparts suggested the presence of several replacement mutations in the complementarity determining regions (CDRs). These observations suggest: (a) Retention or acquisition of catalytic activity by the L chains is compatible with affinity maturation of antibodies; and (b) The autoimmune L chain repertoire can serve as a source of substrate-specific and efficient catalysts.

Topics: Amino Acid Sequence; Antibodies, Catalytic; Asthma; Autoantibodies; Base Sequence; DNA Primers; Genes, Immunoglobulin; Humans; Immunoglobulin kappa-Chains; Kinetics; Molecular Sequence Data; Recombinant Proteins; Vasoactive Intestinal Peptide

Tracheal and lung parenchymal SP-LI (substance P-like immunoreactivity) and VIP-LI (vasoactive intestinal peptide-like immunoreactivity) content was measured in HPLC-purified tissue extracts from patients with and without asthma. We detected significantly less SP-LI in tracheal tissue from asthmatic than from nonasthmatic patients, whereas parenchymal SP-LI content was not significantly different between these groups. This finding does not support the concept that asthmatic lungs contain excessive amounts of SP. Indeed, lower SP-LI content of tracheal tissues from asthmatic patients may reflect augmented SP release followed by degradation. We detected greater quantities of VIP-LI in tracheal than in parenchymal tissue in both groups, but did not detect significant differences in VIP-LI content in tracheal or parenchymal tissues from asthmatic and nonasthmatic patients. These findings indicate that asthmatic and nonasthmatic lungs contain similar levels of VIP.

Topics: Adolescent; Adult; Aged; Asthma; Female; Humans; Immunohistochemistry; Lung; Male; Middle Aged; Substance P; Vasoactive Intestinal Peptide

Topics: Asthma; Autoantibodies; Humans; Vasoactive Intestinal Peptide

Neuropeptides in the lung occur in neurons, neuroendocrine and inflammatory cells. Their widespread distribution and physiological effects suggest that they may play important roles in asthma. We investigated whether, during an exacerbation of asthma, patients displayed changes in plasma levels of the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY). Venous blood from 25 adult patients attending the emergency ward with an exacerbation of asthma was sampled before and after treatment. Plasma levels of VIP-, SP-, CGRP- and NPY-like immunoreactivity (-LI) were determined by immunoassay, and the results obtained were compared with findings in 21 healthy controls. The mean plasma levels of VIP-LI were lower in patients (3.4 +/- 0.4 pmol.l-1) than in controls (10.4 +/- 0.7 pmol.l-1), whereas the levels of CGRP-LI (43.7 +/- 3.4 pmol.l-1), SP-LI (4.6 +/- 0.4 pmol.l-1) and NPY-LI levels (159 +/- 6 pmol.l-1) were higher in patients than in controls (21.1 +/- 3.4; 2.2 +/- 0.2 and 105 +/- 8 pmol.l-1, respectively). A relationship was seen between the reversibility of obstruction, expressed as improvement of peak expiratory flow upon treatment, and the neuropeptide levels, such that lower VIP-LI levels and higher CGRP-LI levels correlated with less reversibility. Plasma levels of neuropeptides, VIP-LI and CGRP-LI in particular, may therefore be employed as predictors of responsiveness to bronchodilatory therapy.

Topics: Acute Disease; Asthma; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Neuropeptides; Radioimmunoassay; Vasoactive Intestinal Peptide

Studies were conducted to compare the effect of native vasoactive intestinal peptide (VIP), Ro 25-1553 (a cyclic peptide analog of VIP) and salbutamol (a beta2-adrenoceptor agonist) on antigen-induced pathophysiological effects in the guinea pig. Ro 25-1553 and salbutamol (0.01-1.0 microM) prevented antigen-induced contractions of the guinea pig trachea in vitro with IC50 values of 0.07 and 0.05 microM, respectively. VIP (0.01-1.0 microM) had no effect on antigen-induced tracheal contractions. Aerosolized Ro 25-1553 and salbutamol were equipotent in preventing antigen-induced increases in guinea pig lung resistance (IC50 value = 0.0001%), whereas aerosolized VIP (0.1%) was ineffective. Ro 25-1553 (0.1-100 micrograms), instilled intratracheally 2 min before the antigen challenge of buffer-perfused lungs from sensitized guinea pigs, produced a dose-dependent inhibition of bronchoconstrictor, vasoconstrictor and edemagenic responses, whereas intratracheal VIP (100 micrograms) had no effect. Intratracheal salbutamol (0.1-100 micrograms) inhibited antigen-induced responses in a manner comparable to Ro 25-1553. Lung inflammation was assessed as leukocyte accumulation in bronchoalveolar lavage fluid after the antigen provocation. Aerosolized antigen-induced bronchoalveolar lavage eosinophilia (13-fold increase over saline controls) at 6 hr after challenge was prevented in a concentration-dependent manner by pretreatment with nebulized Ro 25-1553 and salbutamol, but not by pretreatment with native VIP. These results indicate that Ro 25-1553 suppresses various pathophysiological features associated with pulmonary anaphylaxis and asthma, including airway reactivity, edema formation and granulocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuterol; Anaphylaxis; Animals; Antigens; Asthma; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Disease Models, Animal; Guinea Pigs; In Vitro Techniques; Lung Diseases; Male; Muscle Contraction; Muscle, Smooth; Peptides, Cyclic; Perfusion; Vasoactive Intestinal Peptide

Non-adrenergic non-cholinergic (NANC) nerves are the third nervous system in the lung. There are increasing evidences that the main transmitters of NANC inhibitory (NANC-i) nerves and NANC excitatory (NANC-e) nerves are vasoactive intestinal peptide (VIP) and substance P (SP) respectively. We measured the levels of plasma VIP. SP and bronchial responsiveness in the patients with asthma. Chronic bronchitis and healthy subjects. The results showed that VIP level is decreased and negatively correlated with airway resistance, whereas SP level is increased and positively correlated with bronchial hyperresponsiveness (BHR) in asthma. It is suggested that overexcitation of NANC-e nerves and deficiency of NANC-i nerves are closely related with asthma attack and BHR.

Topics: Adult; Airway Resistance; Asthma; Bronchitis; Female; Humans; Lung; Male; Middle Aged; Substance P; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), which is localized in normal human lung, may play an important role in regulating bronchial tone, pulmonary blood flow and mucus secretion. The level of plasma VIP and bronchial responsiveness were studied in patients with asthma, chronic bronchitis and the healthy subjects. The results showed that the level of plasma VIP in asthmatic patients during acute attack and symptom-free period was significantly lower than that in the patients with bronchitis and the healthy subjects and it is negatively correlated with the bronchial hyperresponsiveness. It is suggested that both asthmatic attack and bronchial tone are related with the decrease of VIP.

Topics: Adult; Aged; Airway Resistance; Asthma; Bronchial Hyperreactivity; Bronchitis; Female; Humans; Male; Middle Aged; Vasoactive Intestinal Peptide

It was recently shown that peptide NTM (RSANFTDNAKTIIVQLNESV), corresponding to residues 280-299 in the second conserved domain of HIV-1 envelope glycoprotein gp120, has spectral and sequence similarity with human vasoactive intestinal peptide, VIP (Veljkovic et al., Biochem. Biophys. Res. Commun., 189, 705-710, 1992). We found that natural autoantibodies cross-reactive with this peptide can be detected in sera from HIV-negative asthma patients and healthy blood donors. The level of these antibodies is significantly higher in asthma patients than in healthy individuals, suggesting that these antibodies can in fact be at least partly identical to natural anti-VIP antibodies previously described (Paul et al., Biochem. Biophys. Res. Commun., 130, 479-483, 1985; Paul et al., Science, 244, 158-1162, 1989). Possible origin and role of these antibodies in AIDS pathogenesis and therapy are discussed.

Topics: Adult; Amino Acid Sequence; Asthma; Autoantibodies; Conserved Sequence; Cross Reactions; Enzyme-Linked Immunosorbent Assay; HIV Envelope Protein gp120; HIV-1; Humans; Kinetics; Molecular Sequence Data; Peptide Fragments; Peptides; Vasoactive Intestinal Peptide

Responses of plasma vasoactive intestinal polypeptide (VIP) to methacholine inhalation and to exercise loading were studied in asthmatic patients to clarify a significant role of the peptide. The mean of basal VIP in asthmatics was not significantly different from the normals. The levels were increased after FEV (1.0) (forced expiratory volume in a second) decreased to 80% of the baseline following methacholine inhalation and were returned to values similar to the baseline when FEV (1.0) recovered to 100%. Thirty minutes after the exercise, mean VIP was significantly lower in patients with the lowest FEV (1.0). These results suggest that VIPergic system contributes, at least partly, to relax constricted bronchioles in some patients with bronchial asthma.

Topics: Adolescent; Asthma; Bronchial Provocation Tests; Child; Exercise; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Vasoactive Intestinal Peptide

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Cyclic AMP; Humans; Lung; Neuropeptides; Neurotransmitter Agents; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Second Messenger Systems; Vasoactive Intestinal Peptide

To investigate neural events within the airways in asthma, endobronchial biopsies were obtained by fibre-optic bronchoscopy from 8 atopic asthmatic subjects and 8 non-atopic healthy controls. The biopsies were immediately fixed on sampling and subsequently analysed for nerves using specific indirect immunofluorescence with antisera to the neural marker PGP 9.5 and to the neuropeptides vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Nerves were present in all the biopsies from both subject groups, with no significant difference between the asthmatic and non-asthmatics. VIP-immunoreactive nerves were equally present in both subject groups, being localized to smooth muscle and glandular sites. No immunoreactive nerves to SP or CGRP could be identified in any biopsy at any location. These in vivo findings do not identify an anatomical neuronal imbalance in asthma.

Topics: Adult; Asthma; Biopsy; Bronchi; Calcitonin Gene-Related Peptide; Female; Humans; Male; Mucous Membrane; Substance P; Vasoactive Intestinal Peptide

Human blood polymorphonuclear neutrophils (PMN) are thought to be involved in the pathogenesis of asthma through their recruitment into the bronchoalveolar lumen and the lung by local release of chemotactic factors. Therefore chemotactic activities of several mediators (PAF, histamine and three neuropeptides substance P, VIP and a somatostatin analog) were compared on blood PMN from both healthy subjects (HS) and asthmatic patients (AP). The maximal response to PAF was significantly different (P less than 0.05) with cells from both groups. Moreover activity for the HS peaked at 10(-6) M, whereas the AP showed peak chemotactic activity at 10(-8) M. Histamine had no chemoattractant effect on PMN. Substance P did not induce PMN locomotion, whereas VIP induced a chemotactic response in a dose-dependent manner, particularly with cells from HS as compared to those from AP. BIM 23014 (a somatostatin analog) exhibited chemotactic activity which was also more pronounced with PMN from HS as compared to those from AP. Our findings showed that blood PMN could be involved in asthma through their heightened locomotor reactions to mediators which are known to be released locally by activated cells in bronchoalveolar lumen.

Topics: Adolescent; Adult; Asthma; Chemotaxis, Leukocyte; Histamine; Humans; Middle Aged; Neuropeptides; Neutrophils; Platelet Activating Factor; Somatostatin; Substance P; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide (VIP) concentrations in the pulmonary and systemic arterial blood were evaluated in 11 asthmatic patients in symptom-free period and during methacholin induced broncospasm. The basal venous and arterial mean values do not significantly differ. A significant difference was observed after bronchial challenge. This could be caused by an increased VIP pulmonary production as a defensive mechanism. No correlation was found between bronchial reactivity (as PD20-FEV1 Methacholin) and VIP concentrations.

Topics: Adult; Aged; Asthma; Female; Humans; Lung; Male; Middle Aged; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a potent relaxant of the airway smooth muscle. In this study, VIP-binding autoantibodies were observed in the plasma of 18% asthma patients and 16% healthy subjects. Immunoprecipitation studies and chromatography on DEAE-cellulose and immobilized protein G indicated that the plasma VIP-binding activity was largely due to IgG antibodies. Saturation analysis of VIP binding by the plasmas suggested the presence of one or two classes of autoantibodies, distinguished by their apparent equilibrium affinity constants (Ka). The autoantibodies from asthma patients exhibited a larger VIP-binding affinity compared to those from healthy subjects (Ka 7.8 x 10(9) M-1 and 0.13 x 10(9) M-1, respectively; P less than 0.005). The antibodies were specific for VIP, judged by their poor reaction with peptides bearing partial sequence homology with VIP (peptide histidine isoleucine, growth hormone releasing factor and secretin). IgG prepared from the plasma of an antibody-positive asthma patient inhibited the saturable binding of 125I-VIP by receptors in guinea pig lung membranes (by 39-59%; P less than 0.001). These observations are consistent with a role for the VIP autoantibodies in the airway hyperresponsiveness of asthma.

Topics: Adult; Antibody Specificity; Asthma; Autoantibodies; Chromatography; Female; Humans; Male; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

The autonomic nervous system includes, side by side with the sympathetic and parasymathetic systems, a third, non-adrenergic and non-cholinergic system called NANC. The mediators in this system are peptides acting as neurotransmitters, i.e. neuropeptides. The NANC system has two components: bronchodilator and bronchoconstrictor. The bronchial relaxant system, called non-adrenergic inhibitory system, has several neurotransmitters, viz.: vasoactive intestinal peptide (VIP), isoleucine histidine peptide (IHP) and methionine histidine peptide (MPH), all derived from a common precursor: pre-pro VIP. MHP has been described in man and IHP in some animal species. VIP relaxes the bronchial smooth muscle, is vasodilator and exerts cellular effects in phagocytes, lymphocytes and mast cells. VIP receptors are present on cells. The other component, called non-cholinergic excitatory system, has tachykinins as neuromediators, including substance P, neurokinins A and B, neuropeptide K and calcitonin gene related peptide (CGRP). Substance P contracts the bronchi, increases mucus secretion, dilates vessels and also exerts cellular effects in lymphocytes and phagocytes. Tachykinins act through receptors 3 types of which are now known: NK 1, NK 2 and NK 3. Other neuropeptides have been isolated, including galanin, neuropeptide Y, bombesin, gastrin releasing peptide, enkephalins and katacalcin. The coexistence, in pre- and post-synaptic positions, of the conventional mediators (noradrenaline, acetylcholine) and neuropeptides leads to the concept of co-transmission and makes the notion of nerve impulse transmission more complex. The development of neuropeptide agonists and antagonists opens new therapeutic prospects in the management of asthma.

Topics: Asthma; Bronchi; Calcitonin Gene-Related Peptide; Humans; Neuropeptides; Neurotransmitter Agents; Peptide PHI; Receptors, Neurotransmitter; Tachykinins; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) is a neuropeptide present in the nerve fibers of normal lungs, where it acts to relax bronchial smooth muscle. To determine its presence or absence in the lungs of patients with asthma, we examined lung tissue obtained at autopsy or lobectomy from five patients with asthma and nine without asthma. The avidin-biotin-peroxidase complex technique was used to stain tissue for immunoreactivity to VIP. At least 80 tissue sections from each patient were examined microscopically; the airway diameter ranged from 100 microns to 1.2 cm. Immunoreactive VIP was seen within nerves in more than 92 percent of the sections from the lungs of patients without asthma. No VIP was seen in any of 468 sections we could evaluate that were obtained from the lungs of patients with asthma. As a control for the nonspecific destruction of neuropeptides, immunostaining for substance P was also carried out. Abundant amounts of this neuropeptide were seen within nerves in tissue from the lungs of all patients. We conclude that in patients with asthma there is a loss of VIP from the pulmonary nerve fibers that may diminish neurogenically mediated bronchodilation. Whether this loss is a cause or a result of asthma is unclear.

Topics: Adolescent; Adult; Asthma; Humans; Immunohistochemistry; Lung; Middle Aged; Vasoactive Intestinal Peptide

Topics: Asthma; Humans; Lung; Vasoactive Intestinal Peptide

Topics: Asthma; Humans; Respiratory System; Vasoactive Intestinal Peptide

Topics: Afferent Pathways; Animals; Asthma; Autonomic Nervous System; Bronchi; Efferent Pathways; Humans; Muscle Contraction; Muscle, Smooth; Vasoactive Intestinal Peptide

To determine the role of gastrointestinal regulatory peptides in exercise-induced asthma (EIA), we studied plasma levels of various gastrointestinal regulatory peptides before and after a 6-min exercise test in seven subjects with EIA and five normal and three asthmatic subjects without EIA. In the EIA group, plasma vasoactive intestinal polypeptide (VIP) rose significantly 5 min and plasma cholecystokinin (CCK) 0 and 20 min after the test compared with the controls. The changes in plasma somatostatin, secretin, pancreatic polypeptide (PP), motilin and insulin showed no significant differences between the two groups. VIP may play an ameliorating role in bronchial asthma, but the relation of CCK to the lung is speculative and awaits further studies.

Topics: Adolescent; Asthma; Asthma, Exercise-Induced; Child; Cholecystokinin; Female; Gastrointestinal Hormones; Humans; Insulin; Male; Motilin; Pancreatic Polypeptide; Physical Exertion; Secretin; Somatostatin; Time Factors; Vasoactive Intestinal Peptide

Bronchial release appears to be regulated by the nonadrenergic noncholinergic system whose transmitter is very probably VIP. In vivo and in vitro studies were conducted to discover whether peptide modifies basic function and/or bronchial spasm provoked by histamine. The data collected show that VIP failed to cause bronchodilation but protects against histamine induced bronchoconstriction both in vivo and in vitro.

Topics: Adult; Asthma; Bronchi; Bronchial Spasm; Histamine; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Tonus; Spirometry; Vasoactive Intestinal Peptide

Topics: Asthma; Bronchi; Histamine Antagonists; Humans; Respiratory Therapy; Vasoactive Intestinal Peptide

Topics: Adult; Asthma; Bronchi; Histamine Release; Humans; Isoproterenol; Male; Vasoactive Intestinal Peptide

Topics: Adult; Aerosols; Asthma; Asthma, Exercise-Induced; Blood Pressure; Heart Rate; Humans; Reference Values; Respiration; Vasoactive Intestinal Peptide