neuropeptide-y and Asthma

Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin or β-defensin 2. Interacting with peptide receptors located in the lungs or on immune cells opens up new therapeutic possibilities for the treatment of asthma, especially when it is resistant to available therapies. This article provides a concise review of the most important and current findings regarding the involvement of regulatory peptides in asthma pathology.

Topics: Animals; Asthma; beta-Defensins; Gene Expression Regulation; Humans; Neuropeptide Y; Neurotensin; Peptides; Receptors, Peptide; Tachykinins

The Flinders Sensitive Line (FSL) rats were originally selectively bred for increased responses to an anticholinesterase agent. The FSL rat partially resembles depressed individuals because it exhibits reduced appetite and psychomotor function but exhibits normal hedonic responses and cognitive function. The FSL rat also exhibits sleep and immune abnormalities that are observed in depressed individuals. Neurochemical and/or pharmacological evidence suggests that the FSL rat exhibits changes consistent with the cholinergic, serotonergic, dopaminergic, NPY, and circadian rhythm models but not the noradrenergic, HPA axis or GABAergic models of depression. However, evidence for the genetic basis of these changes is lacking and it remains to be determined which, if any, of the neurochemical changes are primary to the behavioral alterations. The FSL rat model has been very useful as a screen for antidepressants because known antidepressants reduced swim test immobility when given chronically and psychomotor stimulants did not. Furthermore, rolipram and a melatonin agonist were shown to have anti-immobility effects in the FSL rats and later to have antidepressant effects in humans. Thus, the FSL rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed individuals and has been very effective in detecting antidepressants.

Topics: Animals; Antidepressive Agents; Anxiety; Asthma; Behavioral Symptoms; Breeding; Circadian Rhythm; Depression; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Immune System Diseases; Irritable Bowel Syndrome; Nerve Growth Factors; Neuropeptide Y; Neurotransmitter Agents; Pituitary-Adrenal System; Rats; Rats, Inbred Strains

Neuropeptides such as neuropeptide Y (NPY) have long been proposed to play a role in the pathogenesis of inflammatory diseases. NPY is a 36 amino acid neuropeptide which participates in the regulation of a large number of physiological and pathophysiological processes in the cardiorespiratory system, immune system, nervous system and endocrine system. Serum levels of NPY are increased during exacerbations of asthma, whereas the number of NPY-immunoreactive nerves in the airways remains constant in the airways of patients with inflammatory airway diseases such asthma or rhinitis. Next to a role in the regulation of glandular activity, NPY exerts a major influence on humoral and cellular immune functions. In this respect, NPY is known to modulate potent immunological effects such as immune cell distribution, T helper cell differentiation, mediator release, or natural killer cell activation. In addition to these direct effects, NPY also acts as an immunomodulator by influencing the effects of a variety of other neurotransmitters. Whereas the peptide has been focused for therapeutic options in the central nervous system, a potential use in the treatment of pulmonary inflammatory disorders has not been revealed so far due to the complex pulmonary effects of NPY. However, since selective antagonists and agonists and gene-depleted animals for the different receptors are now available, NPY may be of value for future strategies in airway nerve modulation.

Topics: Animals; Asthma; Cytokines; Humans; Muscle, Smooth, Vascular; Neuropeptide Y; Respiratory System; Sympathetic Nervous System; Th1 Cells; Th2 Cells

Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the receptor for NPY, Y1 receptor. NPY modulates these cells via its Y1 receptor, and involvement of NPY in the pathophysiology of bronchial asthma, has been reported. Increased plasma levels of NPY in asthmatic patients have been reported. NPY polymorphisms are associated with an increased risk for asthma in overweight subjects and young adults. We and other researchers have reported that using murine models of allergic airway responses, NPY and Y1 receptor play critical roles for the development of allergic airway inflammation and airway hyperresponsiveness. Therefore, manipulating NPY-Y1 pathway represents a novel therapeutic target to control allergic airway responses, and might be beneficial for treatment of bronchial asthma.

Topics: Animals; Asthma; Humans; Hypersensitivity; Inflammation; Mice; Neuropeptide Y; Receptors, Neuropeptide Y

Neuropeptide Y (NPY) was recently proposed to be associated with stress and airway inflammation; however, this has rarely been studied in animal models of asthma. Twenty-four C57BL/6 mice were randomly divided into 3 groups of 8 each: naive control group, asthma group (with an established asthma model), and stressed asthma group (with established asthma and stress models). Bronchoalveolar lavage (BAL) fluid was collected for total cell counts using a hemocytometer and for cytological examinations by Wright stain. Differential inflammatory cell counts were performed to identify eosinophils, macrophages, neutrophils, and lymphocytes. NPY and corticosterone serum levels were determined with enzyme immunoassay kits. Stress was associated with increased airway inflammatory response, which was manifested by the accumulation of total leukocytes and eosinophils in the BAL fluid in comparison with the asthma and the control groups. The levels of NPY (p<0.05) and corticosterone (p<0.01) were elevated in the stressed asthma group in comparison with the control and asthma groups. The concentration of NPY and corticosterone positively correlated with the total leukocyte count (r=0.892, p<0.05 and r=0.937, p<0.01 respectively) and eosinophil numbers (r=0.806, p=0.053 and r=0.885, p<0.01 respectively). Stress may be associated with elevated peripheral NPY level, which was observed to be associated with exacerbated airway inflammation in asthmatic mice.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Corticosterone; Disease Models, Animal; Inflammation; Leukocyte Count; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Stress, Psychological

Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.

Topics: Animals; Asthma; Forkhead Transcription Factors; Humans; Mice; Mice, Knockout; Muscle Contraction; Muscle, Smooth; Myosin Light Chains; Neuropeptide Y; Repressor Proteins; Respiratory Mucosa; rho-Associated Kinases

Neuropeptide Y, a widely circulating neurotransmitter, plays a pivotal role in energy balance, immunomodulation and asthma, and several NPY polymorphisms are promising genetic risk factors for asthma and obesity. We explored the associations of candidate NPY gene polymorphisms with prevalent asthma and its relationship with obesity in young adult asthma patients free of other chronic medical morbidity.. Five common gene variants of NPY (rs16147 (-399T/C), rs17149106 (-602G/T), rs16140 (+1000C/G), rs5573 (+1201A/G), rs5574 (+5327C/T)) previously validated to account for most of the NPY expression in vitro and in vivo were investigated in 126 physician-diagnosed asthma patients without other chronic medical morbidity and 182 healthy controls (21-35years). Plasma levels of NPY, adiponectin, and CRP were determined using ELISA, and IL-6 was measured by Luminex in a subgroup of 70 patients and 69 age- and sex-matched healthy controls.. In logistic regression models controlling for gender and obesity, the CT genotype of rs5574 (OR=0.54, 95%CI: 0.30-0.89) and the GT genotype of rs17149106 (OR=5.58, 95%CI: 1.09-28.54) were significantly associated with asthma. No significant interaction between NPY SNP polymorphisms and obesity were detected. Plasma NPY level was correlated with adiponectin levels (p<0.05). Compared with the healthy controls, patients with asthma had higher BMI (p<0.001), adiponectin (p<0.05), IL-6 (p=0.001) and CRP (p<0.001), and lower NPY levels (p<0.01).. The CT genotype of rs5574 and the GT genotype of rs17149106 are significantly associated with prevalent asthma.

Topics: Adiponectin; Adiposity; Adult; Asthma; C-Reactive Protein; Comorbidity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prevalence; Young Adult

Topics: Asthma; Humans; Neuropeptide Y; Stress, Psychological; Th2 Cells

Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association.. We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-α, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data.. Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-α (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-α (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up.. The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes.

Topics: Adiponectin; Adult; Asthma; Biomarkers; Body Mass Index; Case-Control Studies; Chi-Square Distribution; Cross-Sectional Studies; Female; Humans; Inflammation Mediators; Interleukin-4; Linear Models; Logistic Models; Longitudinal Studies; Male; Neuropeptide Y; Obesity; Prevalence; Risk Factors; Singapore; Time Factors; Young Adult

Neuropeptide Y (NPY) level is elevated in allergic asthmatic airways and activation of NPY receptor-1 (NPY-Y1) on antigen-presenting cells (APCs) is essential for T cell priming. Paradoxically, NPY-Y1 modulates hyper-responsiveness in T cells, suggesting a bimodal role for NPY in APCs and T cells. Therefore, determination of the temporal and spatial expression pattern of NPY and its receptors in asthmatic airways is essential to further understand the role of NPY in allergic asthma.. Lungs were isolated from control and acute and chronic stages of OVA-sensitized and challenged mice (OVA). Stains, including H&E, PAS, and trichrome, were used to determine the severity of lung pathology. The expression patterns of NPY and NPY-Y receptors in the airways were determined using ELISA and immunofluorescence. Cytokine levels in the BALF were also measured.. NPY levels were undetectable in the BALF of control mice, but significantly increased in the OVA group at day 80. Levels of IL-4, TGF-β1 and TGF-β2, significantly increased and peaked on day 45 and decreased on day 80 in the OVA group, exhibiting an inverse correlation with NPY levels. NPY expression was localized to macrophage-like cells in the peri-bronchial and peri-vascular areas in the lung tissue. NPY-Y1 and -Y5 receptors were constitutively expressed by both structural and inflammatory cells in the lung tissue.. NPY produced by activated macrophage-like cells may be involved in regulating cytokine production and cellular activities of immune cells in asthma. However, it remains unclear whether such an increase in NPY is a defensive/compensatory mechanism to modulate the effects of inflammatory cytokines.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Enzyme Activation; Inflammation; Interleukin-4; Lung; Macrophages; Mice; Mice, Inbred BALB C; Neuropeptide Y; Ovalbumin; Receptors, Neuropeptide Y; Respiratory System; Transforming Growth Factor beta1; Transforming Growth Factor beta2

Our recent study showed that prenatal and early postnatal exposure of mice to side-steam tobacco smoke (SS), a surrogate to environmental tobacco smoke (ETS), leads to increased airway responsiveness and sensory innervation later in life. However, the underlying mechanism initiated in early life that affects airway responses later in life remains undefined. The concomitant increase in nerve growth factor (NGF) after exposures suggests that NGF may be involved the regulation of airway innervation. Since NGF regulates sympathetic nerve responses, as well as sensory nerves, we extended previous studies by examining neuropeptide Y (NPY), a neuropeptide associated with sympathetic nerves. Different age groups of mice, postnatal day (PD) 2 and PD21, were exposed to either SS or filtered air (FA) for 10 consecutive days. The level of NPY protein in lung and the density of NPY nerve fibers in tracheal smooth muscle were significantly increased in the PD2-11SS exposure group compared with PD2-11FA exposure. At the same time, the level of NGF in lung tissue was significantly elevated in the PD2-11SS exposure groups. However, neither NPY (protein or nerves) nor NGF levels were significantly altered in PD21-30SS exposure group compared with the PD21-30FA exposure group. Furthermore, pretreatment with NGF antibody or K252a, which inhibits a key enzyme (tyrosine kinase) in the transduction pathway for NGF receptor binding, significantly diminished SS-enhanced NPY tracheal smooth muscle innervation and the increase in methacholine-induced airway resistance. These findings show that SS exposure in early life increases NPY tracheal innervation and alters pulmonary function and that these changes are mediated through the NGF.

Topics: Age Factors; Airway Resistance; Animals; Animals, Newborn; Asthma; Carbazoles; Indole Alkaloids; Methacholine Chloride; Mice; Mice, Inbred ICR; Muscle, Smooth; Nerve Fibers; Nerve Growth Factor; Neuropeptide Y; Protein-Tyrosine Kinases; Tobacco Smoke Pollution; Trachea

The role of neuropeptide Y (NPY) and its gene polymorphisms in the development of atherosclerosis has become increasingly evident. In asthma, NPY has been shown to be involved as immunomodulator. In this study, we investigated the role of two functional NPY polymorphisms, NPY-Leu7Pro (rs16139) and NPY-399C/T (rs16147) and obesity for the development of asthma as well as atherosclerosis in asthmatic and non-asthmatic subjects. Also, we measured heart rate variability (HRV) and NPY in serum since these might contribute through these polymorphisms to both diseases.. Thousand hundred and seventy six Finnish young adults were genotyped and three groups (G1-G3) were formed based on the observed diplotypes. The NPY-Pro7 allele always co-existed with the NPY-399T allele indicating complete linkage disequilibrium. Here we show that overweight (BMI≥25kg/m2) was associated with 2.5-fold increased risk for asthma in subjects with the NPY-399T allele without NPY-Pro7 allele (G2, n=716). Overweight was also associated with increased atherosclerosis determined by carotid intima media thickness (cIMT), but asthma seemed to be more significant determinant than overweight in determing cIMT having a decreasing effect. NPY concentration in serum was diplotype-driven (G1=792.2(29.5), G2=849.0(18.9), G3=873.9(45.2) pg/ml) and correlated positively with cIMT in the group having NPY-Pro7 allele (G3, n=142). However, the subjects with asthma had a negative NPY-cIMT relationship. Total HRV was increased in asthma and correlated negatively with cIMT irrespective of the NPY genotype.. Overweight together with the NPY-399T allele without NPY-Pro7 allele was associated with increased risk for asthma. Atherosclerosis was decreased in subjects with asthma depending on the NPY genotype. The results reveal novel insights into the genetics and biology of the relationship of atherosclerosis and asthma.

Topics: Adolescent; Alleles; Anthropometry; Asthma; Atherosclerosis; Body Height; Body Weight; Carotid Intima-Media Thickness; Child; Child, Preschool; Cohort Studies; Data Interpretation, Statistical; DNA; Endothelium, Vascular; Female; Finland; Gene Frequency; Genotype; Heart Rate; Humans; Lipids; Male; Neuropeptide Y; Overweight; Polymorphism, Genetic; Risk

Asthma affects 300 million people worldwide, yet the mechanism behind this pathology has only been partially elucidated. The documented connection between psychological stress and airway inflammation strongly suggests the involvement of the nervous system and its secreted mediators, including neuropeptides, on allergic respiratory disease. In this study, we show that neuropeptide Y (NPY), a prominent neurotransmitter, which release is strongly upregulated during stress, exacerbates allergic airway inflammation (AAI) in mice, via its Y1 receptor. Our data indicate that the development of AAI was associated with elevated NPY expression in the lung and that lack of NPY-mediated signalling in NPYKO mice or its Y1 receptor in Y1KO mice significantly improved AAI. In vivo, eosinophilia in the bronchoalveolar fluid as well as circulating immunoglobulin E in response to AAI, were significantly reduced in NPY- and Y1-deficient compared with wild-type mice. These changes correlated with a blunting of the Th2 immune profile that is characteristic for AAI, as shown by the decreased release of interleukin-5 during ex vivo re-stimulation of T cells isolated from the thoracic draining lymph nodes of NPY- or Y1-deficient mice subjected to AAI. Taken together this study demonstrates that signalling through Y1-receptors emerges as a critical pathway for the development of airway inflammation and as such potentially opens novel avenues for therapeutic intervention in asthma.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Eosinophilia; Immunoglobulin E; Interleukin-5; Lung; Mice; Mice, Knockout; Neuropeptide Y; Receptors, Neuropeptide Y; Respiratory Hypersensitivity; Respiratory System; Signal Transduction

Leptin (LEP) and neuropeptide Y (NPY) are involved in the maintenance of energy balance and create regulatory loops on central and peripheral stage between neuropeptides and hormones, additionally regulated by other physiological stimuli. According to data confirming tendency to overweight and obesity in asthmatic children we have examined the influence of mild asthma on neurohormonal balance. 43 children, aged 7-17 years, including 27 steroid naive mild asthmatic children aged (mean+/-SD) 12.3+/-2.6 years and 16 age matched healthy children participated in the study. Serum LEP and NPY levels were measured radioimmunologically (RIA). Serum leptin level in asthmatic children was 2.84+/-2.1 ng/ml and did not differ to that of healthy children -3.49+/-1.65 ng/ml, both in boys (p=0.85) and girls (0.49). Similarly, we did not observe any differences between NPY levels in asthmatic (113.5+/-31.1 micromol/ml) and healthy (98.5+/-21.9 micromol/ml (p=0.17)), irrespective to sex. Significant correlations between leptin levels and body mass index (BMI) in asthmatics (r=0.62, p=0.01) and healthy children (r=0.56, p=0.02) were observed. We conclude, that mild asthma in children seems not to affect neurohormonal regulation of energy balance.

Topics: Adolescent; Asthma; Body Mass Index; Case-Control Studies; Child; Female; Humans; Leptin; Male; Neuropeptide Y; Radioimmunoassay

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

1. Bronchoconstriction does not seem to be a stimulus for sympathoadrenal activation, as judged by venous plasma concentrations of noradrenaline, adrenaline or neuropeptide Y-like immunoreactivity. However, venous measurements have methodological drawbacks. In the present study arterial and mixed venous (pulmonary arterial) levels of these variables were determined before and after histamine-induced bronchoconstriction in non-medicated asthmatic subjects. In addition, noradrenaline kinetics in plasma (isotope dilution) and the pulmonary overflows of noradrenaline and neuropeptide Y-like immunoreactivity were determined. 2. Histamine inhalation induced bronchoconstriction; forced expiratory volume in ls decreased by 38.7% +/- 4.1% (SE) and arterial PO2 by 3.0 +/- 0.9 kPa. This acute bronchoconstriction induced significant elevations of arterial and mixed venous plasma noradrenaline from < or = 1.18 nmol/l to > or = 1.40 nmol/l. The clearance of NA from plasma increased marginally. Thus, the arterial plasma NA response was due to increased spillover of noradrenaline to plasma (from 1.80 +/- 0.18 to 2.52 +/- 0.36 mmol min-1/m2 at maximal bronchoconstriction, with a subsequent further increase). There were no elevations of adrenaline or neuropeptide Y-like immunoreactivity in arterial plasma. 3. No sympathetic activation could be demonstrated in the lungs (pulmonary noradrenaline or neuropeptide Y-like immunoreactivity overflow), and no alterations in pulmonary vascular resistance or cardiac output were observed. Neither arterial nor mixed venous plasma concentrations of adrenaline were influenced by bronchoconstriction. 4. Acute bronchoconstriction thus leads to peripheral sympathetic activation (possibly due to the increased work of breathing) which does not involve the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchoconstriction; Catecholamines; Epinephrine; Female; Histamine; Humans; Kinetics; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Sympathetic Nervous System

The interaction between the nervous system, immune system and bronchial reactivity was studied in rats by using the neurotoxin capsaicin. Rats were treated with capsaicin at 1-2 days of age or at adult age, before or after sensitization by subcutaneous injections with ovalbumin (OA). The levels of the neuropeptides neurokinin A and calcitonin gene-related peptide were decreased in the lung after capsaicin treatment, as determined with radioimmunoassay, whereas the levels of neuropeptide Y were unaffected. The levels of IgA, IgE and IgG in bronchial lavage were also affected by capsaicin treatment; however, the results were heterogeneous. Capsaicin treatment after sensitization reduced the bronchial reactivity to challenge with OA aerosol and serotonin iv. The results demonstrated that reduction of neuropeptide levels with capsaicin affected both bronchial reactivity and the levels of antibodies in bronchial lavage fluid. However, no correlation between these two parameters was seen, demonstrating the complexity of the system.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Calcitonin Gene-Related Peptide; Capsaicin; Female; Injections, Subcutaneous; Lung; Male; Neurokinin A; Neuropeptide Y; Radioimmunoassay; Rats; Rats, Inbred BN

Bronchoconstriction has been found to cause little sympathoadrenal activation in asthmatic patients. It has been questioned whether this is due to blunted sympatho-adrenal reactivity in asthmatics or if bronchoconstriction is a stimulus for sympatho-adrenal activation at all. We therefore compared sympatho-adrenal responses in eight asthmatic patients and 12 healthy subjects by measurements of plasma adrenaline and noradrenaline concentrations before, during and after methacholine-induced bronchoconstriction. Significant bronchoconstriction was obtained in eight of the healthy subjects and in all of the asthmatics. Considerably higher concentrations of methacholine were required to evoke bronchoconstriction in the healthy subjects but the relative magnitudes of bronchoconstriction were similar in the two groups: peak expiratory flow (PEF) decreased by approximately 24 and approximately 28% and specific airway conductance (sGaw) decreased by approximately 68 and approximately 70% in asthmatics and controls, respectively). Methacholine-induced bronchoconstriction did not alter plasma catecholamine levels significantly in either group. In addition, plasma concentrations of catecholamines and neuropeptide Y-like immunoreactivity (NPY-LI) were measured before and during bronchoconstriction induced by histamine or allergen in 8 and 5 asthmatic subjects, respectively. Plasma noradrenaline, adrenaline and NPY-LI remained unchanged up to 30 min after bronchoconstriction induced by histamine or allergen. We, therefore, conclude that bronchoconstriction is not a stimulus for sympatho-adrenal activation and that the lack of an adrenaline response to bronchoconstriction is not likely to be related to NPY release.

Topics: Acute Disease; Adolescent; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Bronchial Spasm; Epinephrine; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Neuropeptide Y; Norepinephrine; Reference Values; Respiratory Function Tests

I. Based on experiments on the rat portal vein, it is suggested that NPY is capable of inhibiting TNS-induced release of 3H-NA from the sympathetic nerves via a prejunctional site of action, and that NPY enhances the spontaneous contractility and the vasoconstrictor response to TNS via a postjunctionally mediated mechanism. II. Based on experiments in the pithed rat, it is suggested that NPY inhibits the PNS-induced enhancement of plasma NA and A levels, and that this reflects an inhibitory effect of NPY on the release of NA from sympathetic nerve terminals and the secretion of A from the adrenal medulla. III. Based on experiments in the pithed rat, it is suggested that infusion of NPY, at subthreshold doses, potentiates the blood-pressure response to PNS and to injection of the alpha-agonist phenylephrine and that NPY in higher doses induces pressor responses, which are resistant to alpha- and beta-adrenoceptor blockade but sensitive to the calcium antagonist nifedipine. IV. Based on experiments in the pithed rat, it is suggested that A is secreted from the adrenal medulla directly into the circulating blood, since the peak plasma A level occurred immediately (0-20 s) after the initiation of PNS, and that NA and NPY are released from sympathetic nerve terminals from where the transmitters have to diffuse into the systemic circulation, since the maximal levels of circulating NA and NPY-LI were reached later (20-40 s) than A. V. Based on experiments in the pithed guinea-pig, it is suggested that the PNS-induced increase of the plasma NPY-LI level is modulated by a prejunctional alpha 2-adrenoceptor mediated inhibitory control mechanism, since the alpha 2-agonist clonidine was found to reduce and the alpha 2-antagonist yohimbine to markedly enhance the PNS-induced increase in plasma NPY-LI, whereas the alpha 1-antagonist prazosin had no effect. Furthermore, guanethidine reduced this parameter, lending further support to the assumption that circulating NPY is of sympathetic neuronal origin. VI. Based on experiments in the pithed guinea-pig, it is suggested that prejunctional facilitatory beta-adrenoceptors may also be involved in the regulation of the NPY release, since infusion of isoprenaline elicited a facilitation of the PNS-induced increase of plasma NPY-LI levels which could be antagonised by propranolol.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Angiotensin II; Animals; Asthma; Electric Stimulation; Epinephrine; Female; Guinea Pigs; Humans; Male; Neuropeptide Y; Norepinephrine; Peripheral Nerves; Portal Vein; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; Synaptic Transmission

Twenty-five elderly asthmatic patients attending the internal medicine emergency ward because of an acute exacerbation of asthma were sampled, prior to acute treatment, for determination of systemic venous plasma levels of noradrenaline (NA), adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY-LI). Whereas NA and NPY-LI were about two-fold higher than control values, plasma A levels were not significantly increased. Twelve of the asthmatic patients were also tested at resting stable conditions and were essentially asymptomatic. All values were then similar to those of control subjects (n = 28) except for a significantly higher NPY-LI plasma level in asthmatics. In seven of these patients a near maximal physical exercise test caused significantly increased NA, A and NPY-LI plasma levels. It is concluded that the acute asthma attack is associated with elevated NA and NPY-LI plasma levels, but an impaired A response. Furthermore, that circulating NPY under these conditions has a nervous rather than adrenal origin.

Topics: Acute Disease; Aged; Aged, 80 and over; Asthma; Epinephrine; Female; Humans; Male; Middle Aged; Neuropeptide Y; Rest