vasoactive-intestinal-peptide and Pulmonary-Disease--Chronic-Obstructive

Vasoactive intestinal peptide (VIP) is an abundant neurotransmitter in the lungs and other organs. Its discovery dates back to 1970. And VIP gains attention again due to the potential application in COVID-19 after a research wave in the 1980s and 1990s. The diverse biological impacts of VIP extend beyond its usage in COVID-19 treatment, encompassing its involvement in various pulmonary and systemic disorders. This review centers on the function of VIP in various lung diseases, such as pulmonary arterial hypertension, chronic obstructive pulmonary disease, asthma, cystic fibrosis, acute lung injury/acute respiratory distress syndrome, pulmonary fibrosis, and lung tumors. This review also outlines two main limitations of VIP as a potential medication and gathers information on extended-release formulations and VIP analogues.

Topics: Humans; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Vasoactive Intestinal Peptide

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

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

Chronic obstructive pulmonary disease (COPD) as an inflammatory respiratory system disease is caused by exposure to cigarette smoke and tobacco in long-term. Some anti-inflammatory peptides can control inflammation in COPD. N-acetyl-seryl-aspartyl-proline (Ac-SDKP) and vasoactive intestinal peptide (VIP) as peptide have anti-inflammatory effect, and, in this study, the effect of Ac-SDKP and VIP on COPD inflammation was studied. After producing cigarette smoke-induced COPD mice model, which were treated with VIP and Ac-SDKP, the levels of antioxidant-related factors (malondialdehyde (MDA) and superoxide dismutase (SOD)), fibrotic factors (hydroxyproline (HP) and TGF-β), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and inflammation in histopathological examination were studied. MDA, Remodeling factors, pro-inflammatory cytokines, and inflammation in lung tissue were controlled by VIP and Ac-SDKP treatment. These treatments could enhance SOD. VIP and Ac-SDKP as immuno-regulatory factors had benefit effect in treatment of COPD. The anti-inflammatory, anti-fibrosis, and anti-oxidant properties of VIP and Ac-SDKP may be effective therapy in COPD.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Fibrosis; Inflammation; Mice; Oligopeptides; Pulmonary Disease, Chronic Obstructive; Superoxide Dismutase; Vasoactive Intestinal Peptide

Introduction: Chronic obstructive pulmonary disease (COPD) with hypertension occupy a leading position in morbidity and mortality in the world. The question of studying a single pathological way of their development, the search for diagnostic markers and therapeutic targets in this comorbid pathology remains relevant. The aim of the study was to study cardiopulmonary parameters in patients with chronic obstructive pulmonary disease with concomitant hypertension, depending on the level of vasoactive intestinal peptide (VIP).. Materials and methods: 99 patients with COPD GOLD 2 were examined, 54 of whom had concomitant hypertension II stage, in which the dependence of lipid metabolism, spirometry and hemodynamic parameters, depending on the level of VIP in blood serum.. Results and conclusions: It was established that the smallest values of VIP and the greatest changes in cardiopulmonary parameters, lipid metabolism were found in the cohort of persons with concomitant hypertension. There was a significant decrease in spirometry values and an increase in hemodynamic parameters, respectively, a decrease in VIP levels in patients with COPD in combination with hypertension, which may indicate its role in the formation of these pathologies due to a decrease in its protective function, both in relation to apoptosis of alveolar cells and in relation to progression atherosclerosis and high blood pressure. It was also noted that in patients with the lowest VIP serum levels, a more rapid formation of COPD was observed. The data obtained make it possible to consider VIP as a diagnostic marker and a potential therapeutic target for the comorbid pathology examined.

Topics: Disease Progression; Humans; Hypertension; Pulmonary Disease, Chronic Obstructive; Vasoactive Intestinal Peptide

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

Topics: Aged; Aged, 80 and over; Animals; Cell Proliferation; Disease Models, Animal; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Male; Mice; Middle Aged; Myocytes, Smooth Muscle; NFATC Transcription Factors; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is the most abundant neuropeptide in the lung. VIP has been linked to pulmonary arterial hypertension and hypoxia.. We aimed to assess circulating VIP levels at exacerbation and at stable chronic obstructive pulmonary disease (COPD) and to evaluate the diagnostic performance in a well-characterized cohort of COPD patients.. The nested cohort study included patients with Global Initiative for Chronic Obstructive Lung Disease stage II-IV. Patients were examined at stable state and at acute exacerbation of COPD (AE-COPD), and dedicated serum was collected at both conditions. Serum VIP levels were determined by enzyme-linked immunosorbent assay. Diagnostic accuracy was analyzed by receiver operating characteristic curve and area under the curve (AUC).. Patients with acute exacerbation (n = 120) and stable COPD (n = 163) had similar characteristics at baseline. Serum VIP levels did not correlate with oxygen saturation at rest (p = 0.722) or at exercise (p = 0.168). Serum VIP levels were significantly higher at AE-COPD (130.25 pg/ml, 95% CI 112.19-151.83) as compared to stable COPD (40.07 pg/ml, 95% CI 37.13-43.96, p < 0.001). The association of increased serum VIP with AE-COPD remained significant after propensity score matching (p < 0.001). Analysis of the Youden index indicated the optimal serum VIP cutoff value as 56.6 pg/ml. The probability of AE-COPD was very low if serum VIP was ≤35 pg/ml (sensitivity >90%) and very high if serum VIP was ≥88 pg/ml (specificity >90%). Serum VIP levels presented a robust performance to diagnose AE-COPD (AUC 0.849, 95% CI 0.779-0.899).. Increased serum VIP levels are associated with AE-COPD.

Topics: Age Factors; Aged; Area Under Curve; Biomarkers; Case-Control Studies; Cohort Studies; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Prognosis; Propensity Score; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Assessment; ROC Curve; Sensitivity and Specificity; Severity of Illness Index; Sex Factors; Statistics, Nonparametric; Vasoactive Intestinal Peptide

The aim of this study was to define the involvement of some biomarkers in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH), with particular attention to sub-groups with a PH that is "out of proportion" (OP).. Patients with COPD without PH, with PH and marked airways obstruction, and with PH and mild airways obstruction were compared. Assays for human interleukin-6 (IL-6), leukotriene B4 (LTB4), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1) were performed on the blood samples taken during right heart catheterization (RHC) in a pulmonary artery.. In all, 83 patients were enrolled and divided into three groups: 37 simple COPD (mean pulmonary artery pressure [mPAP] <25 mmHg) and 46 COPD with PH (mPAP ≥25 mmHg). Among the latter, those who had a mPAP ≥35 mmHg and forced expiratory volume in 1 sec [FEV1] ≥50% were classified as OP (7 patients). Patients with PH were older and had a body mass index (BMI) higher than the other groups; moreover, they had lower FEV1 and carbon monoxide diffusion (DLCO) values. A lower level of partial pressure of oxygen in arterial blood (PaO2) was observed in the group of OP patients. The levels of ET-1, IL-6, and LTB4 were similar in each group; VIP was higher in the OP patients than in simple COPD and was related to PAP.. In the patients with COPD and PH and in particular in the group of OP PH, VIP is significantly increased, probably to correct the imbalance between vasoconstrictor and vasodilatator mediators.

Topics: Aged; Biomarkers; Cardiac Catheterization; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Vasoactive Intestinal Peptide

To observe the influence of electroacupuncture (EA) of "Chize" (LU 5, He-sea acupoint) and "Shangjuxu" (ST 37, lower He-sea acupoint) on mesenteric microcirculation, vasoactive intestinal peptide (VIP) levels in the lung, colon and hypothalamus tissues in rats with chronic obstructive pulmonary disease (COPD), so as to investigate its mechanism underlying improvement of lung derived intestinal disorders in clinical practice.. Thirty-two male Wistar rats were randomly divided into normal control, model, EA-Chize (LU 5, EA-LU 5) and EA-Shangjuxu (ST 37, EA-ST 37) groups, with 8 rats being in each group. COPD model was established by intratracheal infusion of Lipopolysaccharide (LPS, 1 mg/mL, 0.2 mL/rat) and forced inhaling smoke, once daily for 28 days. EA was applied to bilateral LU 5 and ST 37 for 20 min, once every other day for 12 sessions. The state of mesenteric microcirculation was observed under microscope and divided into grade 0 (stagnation of blood flow), I (slow flowing and silt-like state), II (faster flowing with slight or obvious grainy feeling) and III (fast flowing without grainy feeling). The contents of VIP in the lung, colon and hypothalamus were detected using radioimmunoassay (RIA).. Following modeling, the microvascular calibers were increased slightly in the model, EA-LU 5 and EA-ST 37 groups. Compared with the normal group, the blood flow velocity was increased significantly in model group (P < 0.05). In comparison with the model group, the blood flow velocity was reduced significantly in EA-LU 5 and EA-ST 37 groups (P < 0.01). There were no significant differences between EA-LU 5 and EA-ST 37 groups in blood flow velocity, among the four groups in VIP contents of the lung tissue (P > 0.05). The content of VIP in the colon was markedly higher in the model group than in the normal group, and that in the hypothalamus was obviously lower in the EA-LU 5 group than in the model group (all P < 0.05).. EA stimulation of "Chize" (LU 5) can notably reduce hypothalamic VIP content and slow down blood flow velocity of the mesenteric microvessels in COPD rats.

Topics: Acupuncture Points; Animals; Colon; Electroacupuncture; Humans; Hypothalamus; Lung; Male; Microcirculation; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; 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

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

Chronic obstructive pulmonary disease is a major clinical disorder usually associated with cigarette smoking. A central feature of chronic obstructive pulmonary disease is inflammation coexisting with an abnormal protease/antiprotease balance, leading to apoptosis and elastolysis. In an in vitro study of rat lung alveolar L2 cells, cigarette smoke extract (CSE) induced apoptotic cell death. Exposure of L2 cells to CSE at a concentration of 0.25% resulted in a 50% increase of caspase-3 and matrix metalloproteinase (MMP) activities. Specific inhibitors for caspases and MMPs attenuated the cytotoxicity of CSE. RT-PCR amplification identified VPAC2 receptors in L2 cells. A radioligand-binding assay with (125)I-labeled vasoactive intestinal peptide (VIP) found high affinity and saturable (125)I-labeled VIP-binding sites in L2 cells. VIP and pituitary adenylate cyclase-activating polypeptide (PACAP27) were approximately equipotent for both VIP receptor binding and stimulation of cAMP production in L2 cells. Both neuropeptides, at concentrations higher than 10(-13) m, produced a concentration-dependent inhibition of CSE-induced cell death in L2 cells. VIP, at 10(-7) m, reduced CSE-stimulated MMP activity and caspase-3 activation. The present study has shown that VIP and PACAP27 significantly attenuate the cytotoxicity of CSE through the activation of VPAC2 receptor, and the protective effect of VIP may partly be the result of a reduction in the CSE-induced stimulation of MMPs and caspases.

Topics: Animals; Apoptosis; Caspase 3; Caspases; Cell Survival; Cells, Cultured; Matrix Metalloproteinases; Neuropeptides; Nicotiana; Pituitary Adenylate Cyclase-Activating Polypeptide; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Rats; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Hormone; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Smoke; 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