vasoactive-intestinal-peptide and Pneumonia

Pulmonary arterial hypertension is a progressive, fatal disease. Current treatments including prostanoids, endothelin-1 (ET-1) antagonists, and phosphodiesterase (PDE) inhibitors, have sought to address the pulmonary vascular endothelial dysfunction and vasoconstriction associated with the condition. These treatments may slow the progression of the disease but do not afford a cure. Future treatments must target more directly the structural vascular changes that impair blood flow through the pulmonary circulation. Several novel therapeutic targets have been proposed and are under active investigation, including soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-HT2B receptors, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, Rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. Tyrosine kinase inhibitors, statins, 5-HT2B receptor antagonists, EPCs and soluble guanylyl cyclase activators are among the most advanced, having produced encouraging results in animal models, and human trials are underway. This review summarises the current research in this area and speculates on their likely success.

Topics: Adrenomedullin; Animals; Bone Morphogenetic Protein Receptors; Cyclic GMP; Dichloroacetic Acid; Drug Discovery; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; NFATC Transcription Factors; Pancreatic Elastase; Pneumonia; Receptor Protein-Tyrosine Kinases; rho-Associated Kinases; Serotonin; Stem Cells; Vasoactive Intestinal Peptide

The pathogenesis of tissue injury in disease is a complex process that is only partially understood. We have investigated different models of acute lung injury, representing the clinical entity known as the acute respiratory distress syndrome, and tested their possible modulation by the neuropeptide vasoactive intestinal peptide (VIP). Three major mechanisms of injury appear to be involved in many of these models as common denominators: (1) activation of nuclear transcriptions factor NFkappaB; (2) apoptotic cell death; and (3) excitotoxic phenomena, due to activation of N-methyl-D-aspartate glutamate receptors. These pathogenetic mechanisms and pathways are logical targets of therapeutic intervention. Protection by VIP against lung injury, and against related forms of injury/cell death of neuronal cells and heart muscle, is attributable, in large measure, to the ability of VIP to suppress these mechanisms, and to additional anti-inflammatory and anti-oxidant actions. Finally, a hypothesis is presented for survival-promoting pathways that can be augmented by VIP and the related pituitary adenylyl cyclase-activating peptide.

Topics: Animals; Apoptosis; Cell Survival; Humans; Infant, Newborn; Lung; Lung Injury; Pneumonia; Respiratory Distress Syndrome, Newborn; Signal Transduction; Vasoactive Intestinal Peptide

Topics: Administration, Inhalation; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Drug Combinations; Humans; Immunotherapy; Lung; Male; Melanoma; Phentolamine; Pneumonia; Programmed Cell Death 1 Receptor; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

The present study aimed to design a PEGylated VIP derivative, [Arg(15, 20, 21), Leu(17)]-VIP-GRR (IK312532), with improved metabolic stability, and develop its respirable powder (RP) formulation for inhalation therapy. IK312532 was chemically conjugated with PEG (5 kDa, P5K), the physicochemical and biochemical properties of which were characterized by CD spectral analysis, binding assays, and metabolic stability. CD spectral analysis demonstrated that PEG conjugation had no impact on the conformational structure of IK312532. Although the receptor-binding activity of IK312532/P5K (IC₅₀: 82 nM) was estimated to be ca. 30-fold less than that of IK312532 (IC₅₀: 2.8 nM), the metabolic stability of IK312532/P5K was highly improved. The IK312532/P5K was jet-milled and blended with lactose carrier particles to provide RP formulation of IK312532/P5K (IK312532/P5K-RP). In vitro inhalation performance and in vivo pharmacological effects of the IK312532/P5K-RP in antigen-sensitized rats were also evaluated. In cascade impactor analyses, fine particle fraction of IK312532/P5K-RP was calculated to be ca. 37%. Insufflation of IK312532/P5K-RP (150 μg of IK312532/P5K) in antigen-sensitized rats resulted in marked attenuation of inflammatory events, as evidenced by significant decreases in inflammatory biomarkers and granulocyte recruitment in pulmonary tissue 24h after the antigen challenge. From these findings, PEGylation of a VIP derivative, as well as its strategic application to the RP formulation, may be a viable approach to improve its therapeutic potential for the treatment of airway inflammatory diseases.

Topics: Administration, Inhalation; Allergens; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cell Count; L-Lactate Dehydrogenase; Lung; Male; Ovalbumin; Particle Size; Peroxidase; Pneumonia; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; 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

Pulmonary vascular remodeling and inflammation often coexist in clinical and experimentally induced pulmonary arterial hypertension (PAH). In some instances, the pulmonary hypertension may be the primary, or at least the initial, problem, while inflammatory or autoimmune responses appear to initiate or dominate the picture in other cases. Based on studies in a model of PAH resulting from targeted deletion of the neuropeptide vasoactive intestinal peptide (VIP) gene, we propose that, at least in this experimental model, but possibly also in other situations, both vascular remodeling and inflammation may be mediated by one and the same mechanism: uncontrolled activation of calcineurin-NFAT (nuclear factor of activated T cells) signaling. If this hypothesis is validated, VIP would emerge as an endogenous modulator of pulmonary vascular remodeling and inflammation, through its suppression of NFAT activation.

Topics: Animals; Hypertension, Pulmonary; Lung; Mice; Models, Animal; Models, Biological; NFATC Transcription Factors; Pneumonia; Pulmonary Artery; Rats; 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 lung is richly supplied with peptidergic nerves that store and secrete substance P (SP), vasoactive intestinal peptide (VIP), and other neuropeptides known to potently modulate leukocyte function in vitro and airway inflammation in vivo. To investigate and characterize neuromodulation of immune responses compartmentalized in lung parenchyma, neuropeptide release and expression of neuropeptide receptors were studied in lungs of antigen-primed C57BL/6 mice after intratracheal challenge with sheep erythrocytes. The concentrations of cytokines in bronchoalveolar lavage (BAL) fluid rose early and peaked on day 1 for interleukin (IL)-2, interferon gamma, and IL-10; days 1 to 2 for IL-6; and day 3 for IL-4, whereas the total number and different types of leukocytes in BAL fluid peaked subsequently on days 4 to 6 after i.t. antigen challenge. Immunoreactive SP and VIP in BAL fluid increased maximally to nanomolar concentrations on days 1 to 3 and 2 to 7, respectively in lungs undergoing immune responses. The high-affinity SP receptor (NK-1 R), and VIP types I (VIPR1) and II (VIPR2) receptors were localized by immunohistochemistry to surface membranes of mononuclear leukocytes and granulocytes in perivascular, peribronchiolar, and alveolar inflammatory infiltrates during immune responses. As quantified by reverse transcription-polymerase chain reaction, significant increases were observed in levels of BAL lymphocyte mRNA encoding NK-1 R (days 2 to 4), VIPR1 (days 2 to 4), and VIPR2 (days 4 to 6), and in alveolar macrophage mRNA encoding NK-1 R (days 2 to 6) and VIPR1 (days 2 to 4), but not VIPR2. Systemic treatment of mice with a selective, nonpeptide NK-1 R antagonist reduced significantly the total numbers of leukocytes, lymphocytes, and granulocytes retrieved by BAL on day 5 of the pulmonary immune response. The results indicate that SP and VIP are secreted locally during pulmonary immune responses, and are recognized by leukocytes infiltrating lung tissue, and thus their interaction may regulate the recruitment and functions of immune cells in lung parenchyma.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Immunohistochemistry; Inflammation Mediators; Leukocytes; Mice; Mice, Inbred C57BL; Pneumonia; Receptors, Neurokinin-1; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Substance P; Vasoactive Intestinal Peptide

The effects of airway inflammation induced by chronic antigen exposure on substance P (SP)-induced increases and vasoactive intestinal peptide (VIP)-induced decreases in airway opening pressure (Pao), and the recovery of intact and hydrolyzed radiopeptide were studied in tracheally perfused guinea pig lungs. SP (10(-6) mol/kg) induced a significantly greater increase in Pao in lungs from antigen-exposed (30 +/- 5 cm H2O) than saline-exposed animals (15 +/- 1 cm H2O, P < 0.05). Significantly more intact 3H-SP and significantly less 3H-SP 1-7, a neutral endopeptidase (NEP) hydrolysis product, were recovered from the lung effluent of antigen-exposed than saline-exposed animals (P < 0.05). Injection of VIP (10(-9) mol/kg) induced significantly more pulmonary relaxation in saline-exposed compared with antigen-exposed lungs (62 +/- 4%, P < 0.001). In contrast to effluent from saline-exposed animals, lung effluent from antigen-exposed lungs contained less intact VIP, increased amounts of a tryptic hydrolysis product, and no products consistent with the degradation of VIP by NEP. These data indicate that inflamed lungs are more sensitive to the contractile effects of SP because it is less efficiently degraded by NEP and are less sensitive to the relaxant effects of VIP because it is more efficiently degraded by a tryptic enzyme. Changes in airway protease activity occur with allergic inflammation and may contribute to airway hyperresponsiveness.

Topics: Animals; Guinea Pigs; Hydrolysis; Lung; Male; Neprilysin; Perfusion; Pneumonia; Protease Inhibitors; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Basophils; Humans; Inflammation; Lung; Mast Cells; Neuropeptides; Pneumonia; Respiratory Tract Diseases; Vasoactive Intestinal Peptide