Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of substance P in the pathogenesis of asthma is unclear. Animal studies suggest that it may be important, whereas human studies do not confirm this. Alveolar macrophages can be recovered easily by bronchoalveolar lavage (BAL) and stimulated in vitro. To assess the role of substance P in humans, we tested its ability to stimulate alveolar macrophages from six normal subjects and seven asthmatic patients. BAL cells were separated by adherence and alveolar macrophages constituted 95% of the adherent cell population. Four concentrations of substance P were used (10(-7), 10(-6), 10(-5), 10(-4) M). To assess the non-specific activation of alveolar macrophages we used three concentrations of lipopolysaccharides (LPS) (5, 10, 20 micrograms/ml). The stimulation of alveolar macrophages was assessed by the release of thromboxane B2 by radioimmunoassay. This study indicates that alveolar macrophages are stimulated by LPS but are poorly activated or not at all by substance P.
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PMID:Substance P activation of bronchoalveolar macrophages from asthmatic patients and normal subjects. 248 Aug 40

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.
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PMID:The effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in subjects with asthma. 253 99

Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.
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PMID:Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. 254 62

In a double-blind, crossover study we have investigated the effect of nedocromil sodium on neurokinin A (NKA)-induced bronchoconstriction in asthmatics. 12 patients with mild asthma inhaled either nedocromil sodium 4mg or placebo, on 2 separate days, as 2 puffs from a metered-dose aerosol 30 minutes before challenge with NKA. On the placebo treatment day, NKA produced a concentration-dependent decrease in basal specific airway conductance (sGaw) and forced expiratory volume in 1 second (FEV1). The inhalation of nedocromil sodium 4mg inhibited the decrease in both sGaw and FEV1. The maximal percentage decrease in sGaw on the nedocromil sodium day was 27.0 +/- 5.2 (vs placebo, 53.3 +/- 5.4; p less than 0.05) and the maximal percentage decrease in FEV1 5.5 +/- 1.4 (vs placebo, 12.4 +/- 2.3; p less than 0.05). We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in asthmatics.
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PMID:Effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in asthmatics. 254 60

Capsaicin, which induces release of neuropeptides such as substance P from sensory nerves, stimulated mucus secretion in surgically resected human bronchi in vitro. Pretreatment of the tissue with the opioid antagonist naloxone significantly enhanced secretion, possibly by blocking the inhibitory effect of opiate premedication before surgery. Capsaicin-induced mucus secretion was completely blocked by morphine, and this effect was reversed by naloxone. Thus, sensory nerve stimulation increases mucus secretion in human airways, which might contribute to the mucus hypersecretion seen after inhalation of irritants such as cigarette smoke. Secretion can be completely inhibited by opioid drugs, so they may represent a new therapeutic approach to airway hypersecretion in chronic bronchitis and asthma, in which axon reflex mechanisms have been implicated.
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PMID:Opioid inhibition of neurally mediated mucus secretion in human bronchi. 256 21

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.
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PMID:[Neuropeptides and respiratory diseases: prospects in the treatment of asthma]. 257 26

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.
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PMID:Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. 279 74

Many agents are capable of mast cell activation (MCA). In the lung, exposure to allergens induces IgE-mediated mast cell degranulation. By this process, chemical mediators are released and attract inflammatory cells that infiltrate the airway wall. This immune response is a potent stimulus for the pathologic changes seen in asthma (e.g., bronchospasm, mucosal edema, airway hyperreactivity, and mucus secretion). One neglected component of the asthmatic response is vascular permeability--the hallmark of mast cell degranulation. Like muscle contraction, vascular permeability occurs rapidly in response to an antigen challenge and is prevented by classic antiasthmatic therapy. Studies with antidromic nerve stimulation have indicated a relationship between MCA and the histamine-induced release of the sensory neuropeptide substance P, which causes vasodilation. Mediators released during the immediate hypersensitivity reaction may attract neutrophils and other chemotactic factors involved in the late allergic response, which includes a recrudescence of MCA caused by the release of histamine-releasing factors. Understanding these pathophysiologic events in asthma will be useful in formulating therapy.
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PMID:Asthma and mast cell activation. 264 47

Recent studies have suggested that inflammation may play an important role in the characteristic bronchial hyperresponsiveness and symptoms of chronic asthma. The mechanisms by which inflammatory cells, mediators, and nerves interact to produce the features of asthma are still uncertain, however. Although mast cells play an important role in the immediate response to allergen (and probably exercise), pharmacologic evidence argues against a critical role in the late response or bronchial hyperresponsiveness in which other cells, such as macrophages and eosinophils, may play a more important role. Many mediators have been implicated in asthma, but only PAF causes a prolonged increase in bronchial responsiveness. PAF attracts eosinophils into tissues and potently activates these cells, which may lead to epithelial damage, a key feature of asthmatic airways. PAF is also a potent inducer of microvascular leakage in airways, which may result in submucosal edema and plasma exudation into the airway lumen in the future. PAF antagonists will reveal whether PAF plays an important role in the eosinophilic inflammation of asthma. Neural mechanisms may also make an important contribution. Inflammatory mediators may influence neurotransmitter release from airway nerves, and neurotransmitters may be proinflammatory. Neural control is complex and cholinergic, adrenergic, and NANC mechanisms may contribute to bronchial hyperresponsiveness. Many neuropeptides, which may be the transmitters of NANC nerves, have been identified in airways. Neuropeptides in airway sensory nerves, such as substance P, have potent proinflammatory effects and, if these are released by an axon reflex, may amplify the inflammatory response in asthma. Since asthma may be chronic eosinophilic bronchitis, it is logical that the primary treatment should involve drugs that suppress this inflammatory response. At present, corticosteroids appear to be the most effective therapy; they have potent effects against eosinophils and macrophages (but not on mast cells) and reduce bronchial hyperresponsiveness and symptoms. By contrast, bronchodilators, such as beta-agonists, although they reduce symptoms, do not reduce the chronic inflammatory response or bronchial hyperresponsiveness and may mask the underlying inflammation. New therapies should be directed toward controlling eosinophil infiltration and activation in airways.
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PMID:New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. 265 43

Mediators acting on different cells in the lung may produce features of asthma such as bronchoconstriction, plasma leakage from the tracheobronchial microcirculation and mucus secretion. The clinical effectiveness of anticholinergic agents has stimulated the search for mediators other than acetyolcholine and the hope that specific antagonists would improve asthma therapy. The purine, nucleoside adenosine, produces certain asthma-like signs such as bronchoconstriction in asthmatics. Studies with theophylline and nonadenosine-blocking bronchodilator xanthines have, however, demonstrated that adenosine is unlikely to be an asthma mediator, although it may still possess significant extrapulmonary actions. Sensory nerves within the lung show immunoreactivity to a wide variety of peptides, including substance P and other tachykinins. Tachykinins produce bronchoconstriction and plasma extravasation in guinea-pig and rat lungs. In asthmatic subjects, nebulized neurokinin A reduces specific airways conductance. Inhalation of capsaicin, which presumably acts through stimulation of chemosensitive afferent C-fibres, produces cough and a transient upper airway constriction. Elucidation of a role in asthma must await the development of a clinically useful tachykinin antagonist. Accumulating data seems to indicate that asthma pathology is caused by released substances acting in conjunction on target cells in the lung. Functional antagonism, rather than inhibition of a single mediator, thus appears to be essential for clinically effective antiasthma drugs.
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PMID:Purines and sensory neuropeptides in human asthma. 282 85


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