Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term rat peritoneal mast cell (MC) cultures consisting of MC co-cultured with 3T3 fibroblasts (MC/3T3) were employed to study the effects of repeated and prolonged incubation with nedocromil sodium (10(-3) and 10(-5) M) on MC activation. When nedocromil sodium was added simultaneously with compound 48/80 to MC/3T3 on the first day of the experiment, it inhibited histamine release to the same extent as when added to the cultures a week later upon rechallenge. In other experiments activated MC/3T3 were incubated with nedocromil sodium for a week and on the last day of the experiment fresh nedocromil sodium was added simultaneously with compound 48/80. Under these conditions the drug was as potent in inhibiting histamine release from the activated MC as it was in cultures incubated for a week with medium alone. In addition, preincubation of naive MC with nedocromil sodium for two days inhibited histamine release from these cells when activated for the first time. Salbutamol (10(-3) and 10(-5) M) exhibited a similar inhibitory effect to nedocromil sodium upon simultaneous incubation with MC/3T3. However, prolonged incubation of salbutamol with MC/3T3 cultures resulted in tachyphylaxis. We conclude that nedocromil sodium is an effective MC stabilizing drug since it similarly inhibits histamine release from both primarily and secondarily challenged MC. Moreover this drug does not lose its efficacy upon prolonged incubation with MC.
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PMID:Nedocromil sodium modulates the function of long-term rat peritoneal mast cell cultures. 127 49

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Relationship between mediator release from human lung mast cells in vitro and in vivo. 240 26

Ten allergic subjects with exercise-induced bronchospasm were studied to determine whether albuterol could prevent sulfur dioxide (SO2)-induced bronchoconstriction. Albuterol or placebo (180 micrograms) were administered by metered-dose inhaler 20 minutes before a 10-minute exposure to SO2 or clean air during moderate exercise on a treadmill at an exercise level that by itself did not produce exercise-induced bronchospasm. Pulmonary functions (FEV1 and total respiratory resistance [RT]) were measured before the drug, after the drug, and after exposure to SO2 or clean air. Albuterol treatment produced significant bronchodilation and also prevented SO2-induced bronchoconstriction. Following SO2 inhalation after placebo, FEV1 decreased 15% (p less than 0.02) and RT increased 50% (p less than 0.03). Following SO2 inhalation after albuterol treatment, neither FEV1 or RT changed significantly. We conclude that albuterol, a beta 2-agonist, inhibits SO2-induced bronchoconstriction. This result suggests that the adrenergic nervous system or mast cell degranulation are involved in SO2-induced bronchoconstriction.
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PMID:The effects of albuterol on sulfur dioxide-induced bronchoconstriction in allergic adolescents. 380 47

A mist of distilled water obtained by means of powerful high density ultrasonic device has been used as nonspecific challenge test for assessing bronchial hyperreactivity in asthmatics. It looks an easier and/or more physiologic stimulation when compared with the nebulisation of other substances such as histamine, acetylcholine, methacholine, carbachol, citric acid, prostaglandins. Furthermore, this test shows good correspondence to the history of fog-induced asthma. In ten normal subjects the ultrasonic mist of H2O doesn't produce any functional change, while in thirteen asthmatic patients it results in a clear-cut bronchoconstriction, with a maximal evidence within 10 minutes and a subsequent decrease up to 30 minutes. Premedication with propranolol doesn't change the negativity of the test in normal subjects. Ultrasonic mist of saline doesn't determine any remarkable bronchoconstriction in asthmatics. In forty asthmatics a trial has been then carried out on prevention of water-induced bronchoconstriction by different pharmacologic means. Ipratropium fails to protect significantly the patients, while Disodium-cromoglycate, Salbutamol and prostaglandins E reduce significantly the entity of the so induced bronchospasm. These observations support the hypothesis of a mast cell mediated mechanism and disprove the vagal contribution to this type of bronchial challenge.
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PMID:Non-specific broncho-reactivity obtained with an ultrasonic aerosol of distilled water. 645 47

We examined the effects of a beta 2-agonist on dry air-induced injury in canine peripheral airways. Dry air-induced bronchoconstriction (AIB) was assessed by measuring peripheral airway resistance in anesthetized dogs. Salbutamol reduced AIB by approximately 75% compared with control values. Colloidal carbon was used to detect bronchovascular leakage in contralateral sublobar segments that were pretreated with saline or salbutamol. About 87% of the perimeter of bronchi was damaged after dry air challenge in saline-treated segments. Salbutamol reduced mucosal damage by approximately 30% (P < 0.05). The mucosa of bronchioles was not injured. The average goblet-to-ciliated cell ratio (which reflects mucosal perturbation) in bronchi decreased from 0.38 in control bronchi to 0.15 in challenged bronchi, and this effect was also evident in bronchioles. Salbutamol did not affect this decrement. Dry air challenge also caused degranulation of mast cells located below damaged mucosa, dilation of bronchial vessels, and leakage from capillaries and venules located below normal ciliated and damaged mucosa of bronchi. Thus, we conclude that salbutamol attenuates epithelial damage and AIB but fails to inhibit mast cell degranulation and vascular hyperpermeability.
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PMID:A beta 2-adrenergic agonist inhibits dry air-induced injury in canine peripheral airways. 766 14

The therapeutic potential of salbutamol, a beta2-adrenergic agonist, was explored in collagen-induced arthritis. This study was based on a report that salbutamol, by elevating intracellular cAMP, inhibits IL-12 production by macrophages and dendritic cells, thus preventing Th1 development. Ten-week-old male DBA/1 mice were immunized by intradermal injection of type II collagen in CFA. Arthritis developed 15-30 days later and the mice were treated after onset of disease with salbutamol, 200 microgram i.p. After 10 days, the mice were sacrificed, and the hind paws were evaluated histologically. Salbutamol, 200 microgram daily or every other day, had a profound therapeutic effect on the clinical progression of arthritis, as assessed by clinical score and paw thickness. The therapeutic effect was dose dependent. Daily administration of 200 microgram of salbutamol offered the best protection against joint damage, as assessed by histology. In vitro, salbutamol reduced IL-12 and TNF-alpha release by peritoneal macrophages in a dose-dependent manner, as well as TNF release by synovial cells from arthritic mice. Ex vivo, draining lymph node cells of the salbutamol-treated arthritic mice showed a diminished CII-specific IFN-gamma production and proliferation. In vivo, salbutamol specifically blocked mast cell degranulation in joint tissues. In conclusion, salbutamol has important effects on the immunoinflammatory response and a significant therapeutic action in collagen-induced arthritis.
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PMID:The beta2-adrenergic agonist salbutamol is a potent suppressor of established collagen-induced arthritis: mechanisms of action. 1022 75

Short-acting beta2-agonists provide greater protection against bronchoconstriction induced by adenosine 5'-monophosphate (AMP) than by direct-acting bronchoconstrictors such as histamine and methacholine. AMP is thought to cause bronchoconstriction via release of mediators from mast cells, which suggests that these drugs stabilize mast cells in vivo. This in vivo property has not yet been demonstrated for long-acting beta2-agonists. We undertook a double-blind, randomized, placebo-controlled, cross-over study to investigate the effects of a single dose of formoterol inhaled via Turbuhaler (12 micrograms) and of albuterol inhaled via Turbuhaler (200 micrograms) on airway responsiveness to AMP and histamine in 16 subjects with mild atopic asthma. Albuterol reduced airway responsiveness to AMP and histamine by 4.1 +/- 0.5 and 3.5 +/- 0.4 doubling doses, respectively. In contrast, formoterol caused a greater protective effect against AMP than against histamine challenge, decreasing airway responsiveness by 6.0 +/- 0.8 and 4.2 +/- 0.4 doubling doses, respectively (p < 0.05). Thus, the long-acting beta2-agonist formoterol appears to have a mast cell-stabilizing effect in vivo in mild asthma.
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PMID:Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma. 1035 19

Beta(2 ) agonists were designed to emulate the bronchodilation and mast cell suppression effects of human adrenaline, an endogenous neuromediator. Endogenous adrenaline is produced exclusively as the single enantiomer or isomer, (R)-adrenaline, although all selective beta(2 ) agonists are marketed as racemic drugs, composed of a precise 50:50 mixture of R and S isomers. Isomers are compounds that are nonsuperimposable mirror images. The R isomers of beta agonists, essentially all congeners of (R)-adrenaline, exhibit the observed bronchodilation and clinical benefit of the racemate. The S isomers of the racemic beta agonists are devoid of clinical benefit, are assumed to be benign, and have not been studied until recently. In contradistinction to their assumed benign status, extensive studies with (S)-albuterol have shown that it opposes the bronchodilation effects of (R)-albuterol (levalbuterol), may be proinflammatory, and exhibits the potential to exacerbate airway reactivity to a variety of spasmogens by enhancing contractile responses. Clinically, (S)-albuterol can increase airway reactivity and, because of its slow metabolism, exists in higher and prolonged plasma concentrations than levalbuterol. The sustained presence of (S)-albuterol may help to explain why racemic beta agonists have not demonstrated a significant clinical anti-inflammatory potential. Furthermore, the adverse effects (S)-albuterol may contribute to paradoxic bronchospasm and the occurrence of severe reagenic-like reactions seen with racemic albuterol. These adverse effects of (S)-albuterol are completely avoided with single isomer version of (R)-albuterol (levalbuterol). The removal of (S)-albuterol increased the clinical potency of levalbuterol, such that bronchodilator efficacy is achieved at one-fourth the dose of racemic albuterol, but with marked reduction in side effects. Levalbuterol, a third generation beta agonist, retains the clinical benefit of racemic albuterol without the proinflammatory and potentially detrimental effects of (S)-albuterol.
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PMID:The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists. 1045 91

1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.
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PMID:Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells. 1256 76

Human mast cells express the intermediate conductance Ca2+-activated K+ channel iKCa1, which opens following IgE-dependent activation. This results in cell membrane hyperpolarization and potentiation of both Ca2+ influx and degranulation. Mast cell activation is attenuated following exposure to beta2-adrenoceptor agonists such as salbutamol, an effect postulated to operate via intracellular cyclic AMP. In this study, we show that salbutamol closes iKCa1 in mast cells derived from human lung and peripheral blood. Salbutamol (1-10 microM) inhibited iKCa1 currents following activation with both anti-IgE and the iKCa1 opener 1-EBIO, and was reversed by removing salbutamol or by the addition of the selective beta2-adrenoceptor antagonist and inverse agonist ICI 118551. Interestingly, ICI 118551 consistently opened iKCa1 in quiescent cells, suggesting that constitutive beta2-receptor signaling suppresses channel activity. Manipulation of intracellular cAMP, Galphai, and Galphas demonstrates that the beta2-adrenergic effects are consistent with a membrane-delimited mechanism involving Galphas. This is the first demonstration that gating of the iKCa1 channel is regulated by a G protein-coupled receptor and provides a clearly defined mechanism for the mast cell "stabilizing" effect of beta2-agonists. Furthermore, the degree of constitutive beta2-receptor "tone" may control the threshold for human mast cell activation through the regulation of iKCa1.
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PMID:Beta2-adrenoceptor regulation of the K+ channel iKCa1 in human mast cells. 1581 38


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