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)

1. We have developed and characterized a model of immediate hypersensitivity/inflammation of the urinary bladder in vivo induced by local application of ovalbumin (OA) in OA- sensitive female rats. Two parameters of the inflammatory response were assessed following OA challenge: plasma protein extravasation (PPE) and changes in smooth muscle reactivity. The former was estimated by measurement of Evans blue extravasation at 0.5, 2, 4, 8 and 24 h time point following in vivo challenge. Changes in reactivity were determined by measurement of isotonic tension responses of urinary bladder strips following OA challenge in vitro. 2. Acute in vivo intravesical OA challenge (10 mg in 0.3 ml saline) in actively sensitized female Wistar rats caused a time-dependent PPE in the urinary bladder which was biphasic with peak responses at 2-4 and 24 h. 3. The PPE response to acute OA challenge, above base-line, at 2 h was abolished by systemic capsaicin pretreatment (50 mg kg(-1), s.c., 4 days before use) (P < 0.05) whilst the response at 24 h was unaffected. The 2 h time point was then used for further studies. 4. Degranulation of mast cells, achieved by pretreatment with compound 48/80 (5 mg kg(-1), s.c. for 3 consecutive days), completely abolished the PPE response to OA challenge at the 2 h time point. 5. The tachykinin NK1 receptor antagonist, SR 140333 (0.1 micromol kg(-1), i.v.), abolished the 2 h PPE response whilst the tachykinin NK2 receptor antagonist MEN 11420 (0.1 micromol kg(-1), i.v.) appeared to reduce the response by approximately 50% but this did not reach significance. The bradykinin B2 receptor antagonist, Hoe 140 (0.1 micromol kg(-1), i.v.), similarly to SR 140333, blocked the 2 h PPE response to OA, whereas the selective B1 receptor antagonist B 9858 (0.1 micromol kg(-1), i.v.) had no significant effect. Inhibition of cyclo-oxygenase (COX) achieved by pretreatment with the COX inhibitor dexketoprofen (5.3 micromol kg(-1), i.v.) also blocked the PPE response, whilst the leukotriene receptor antagonist ONO 1078 (1 micromol kg(-1), i.v.) significantly reduced PPE by about 80%. 6. In the rat isolated urinary bladder OA (1 mg ml(-1)) challenge produced a biphasic response with a rapidly achieved maximal contraction followed by a sustained contraction for approximately 25 min. In vitro capsaicin pretreatment (10 microM for 15 min) significantly attenuated the duration of the sustained contraction whilst having no effect on the maximum contractile response achieved. In vivo pretreatment of animals with compound 48/80 significantly attenuated (42%) the maximum contractile response. Combination of both treatments almost completely abolished the response. In vitro treatment with Hoe 140 (1 microM) had no significant effect on the response to OA and neither did ONO 1078 (1 microM). 7. These results show that both the early inflammatory response and alterations in smooth muscle reactivity to OA challenge in actively sensitized animals are dependent on mast cell degranulation and the activation of sensory C-fibres. Furthermore this model of allergic cystitis may be useful for investigating both the processes involved and potential novel therapies in the treatment of interstitial cystitis.
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PMID:Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats. 963 Mar 59

Our experiments were conducted to determine whether substance P (SP) would elicit an itch sensation mediated by mast cells in mice. An intradermal injection of SP (10-135 microgram site-1) into the rostral back of the ICR mouse dose-dependently produced scratching of the injected site. The SP- (135 microgram site-1 = 100 nmol site-1) induced scratching was inhibited by capsaicin (repeated administration) and naloxone; features being similar to itch in humans. SP elicited scratching in mast cell-deficient (WBB6F1 W/Wv) mice as well as control (+/+) mice. Pretreatment with compound 48/80 produced similar degrees of inhibition of SP-induced scratching in mast cell-deficient mice as well as control +/+ and ICR mice. Intradermal injections of the NK1 receptor agonist GR73632 produced dose-dependent scratching, while the NK2 agonist GR64349 and the NK3 agonist senktide were without effects. SP-induced scratching was inhibited by the NK1 receptor antagonists spantide and L-668,169, but not by the NK2 antagonist L-659,877. The results suggest that scratching of the mouse induced by an i.d. injection of SP is itch-associated response. The SP action may be mediated at least partly by cutaneous NK1 receptors, and mast cells may not be key factors in SP-induced itching.
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PMID:Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice. 973 70

Distension of the rat intestine causes a capsaicin-sensitive, pressure-dependent depressor response which is indicative of nociception. A hypersensitivity of jejunal distension which possibly involves tachykinin NK2 receptors and is restricted to areas with mast cell hyperplagia is observed in rats infected 30 days previously with Nippostrongylus brasiliensis. This study aimed to further investigate the role of mast cells, tachykinins and kinins in this intestinal hypersensitivity. The activity of a mast cell stabilizer (doxantrazole), kinin antagonists (des-Arg 10-[Leu9]-kallidin, B1, HOE 140, B2) and tachykinin antagonists (CP 99, 994, NK1, SR 142801, NK3) were tested against the distension-induced depressor responses in control and post-infected rats. The 30-day post-infection-induced hypersensitivity was significantly reduced by the mast cell stabilizer doxantrazole. The hypersensitivity had resolved in 90-day post-infected rats when mast cells levels had normalized. Des-Arg 10-[Leu9]-kallidin and HOE 140 did not inhibit the depressor responses in controls but produced a significant inhibition in 30-day post-infected rats. CP 99,994 inhibited the depressor responses in post-infected rats with an equal potency to that in control rats. SR 142801 was inactive in both groups. In conclusion, mast cells and kinin-mediated nociception appear to be involved in post-infection intestinal hypersensitivity whereas tachykinin NK1 and NK3 receptors do not.
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PMID:Role of kinin B1 and B2 receptors and mast cells in post intestinal infection-induced hypersensitivity to distension. 1005 Feb 55

Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.
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PMID:Neurogenic inflammation in the context of migraine. 1130 92

Dietary factors can modulate visceral sensitivity and are suggested to interact with neuroimmune pathways. To determine whether daily low-level exposure to a food contaminant (diquat) alters sensitivity to gastric distension (GD) and the role of mast cells and tachykinin receptors activation, two series of experiments were conducted in eight groups of eight male Wistar rats (200-250 g) receiving daily doses of either diquat (0.1 mg/kg per day orally) or water for 21 days. In the first series, rats were sacrificed at the end of treatments and the gastric mucosal mast cell (MMC) number was histologically quantified. In the second series, after 21 days of treatment the cardiovascular depressor (CVD) response and corresponding gastric volumes were recorded under GD (from 10 to 40 mmHg). Doxantrazole (5 mg/kg intraperitoneally (i.p.)), a mast cell stabilizer, and SR 140333 (1 mg/kg i.p.) and MEN 11420 (0.1 mg/kg intravenously), respectively NK1 and NK2 receptor antagonists, were administered before GD. Before and after GD, blood samples were taken to measure blood histamine and the gastric MMC number was determined after sacrifice. Diquat treatment increased the MMC number. In diquat-treated rats, GD increased the CVD response and blood histamine level and induced MMC degranulation. Doxantrazole did not modify the hypersensitivity to GD but prevented mast cell degranulation. Both NK1 and NK2 receptor antagonists blocked the enhanced CVD response induced by diquat and prevented mast cell degranulation. None of the drugs had any effect in control animals. Prolonged exposure to a food contaminant at doses possibly found in food increases gastric sensitivity to distension, activates tachykinin receptors and results in MMC degranulation after GD.
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PMID:Chronic low-level administration of diquat increases the nociceptive response to gastric distension in rats: role of mast cells and tachykinin receptor activation. 1132 43

1. The contribution of sensory neurons and mast cells to the oedema evoked by adenosine A1 (N(6)-cyclopentyladenosine, CPA, 3 - 30 nmol site(-1)), A2 (5'N-ethylcarboxamidoadenosine, NECA, 1 - 10 nmol site(-1)) and A3 receptor agonists (N6-[3-iodobenzyl]-N-methyl-5'-carboxiamidoadenosine, IB-MECA, 0.01 - 3 nmol site(-1)) was investigated in the rat skin microvasculature, by the extravascular accumulation of intravenously-injected (i.v.) 125I-albumin. 2. Intradermal (i.d.) injection of adenosine and analogues induced increased microvascular permeability in a dose-dependent manner (IB-MECA > NECA > CPA > adenosine). The non-selective adenosine receptor antagonist theophylline (5 - 50 nmol site(-1)) markedly inhibited adenosine, CPA or NECA but not IB-MECA-induced plasma extravasation. The A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.3 - 3 micromol kg(-1), i.v.) significantly reduced CPA-induced plasma extravasation whereas responses to adenosine, NECA or IB-MECA were unchanged. The A2 receptor antagonist 3,7-dymethyl-1-proprargylxanthine (DMPX, 0.5 - 50 nmol site(-1)) significantly reduced NECA-induced plasma extravasation without affecting responses to adenosine, CPA and IB-MECA. 3. The tachykinin NK1 receptor antagonist (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333), but not the NK2 receptor antagonist (S)-N-methyl-N[4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]-benzamide (SR48968), significantly inhibited the plasma extravasation evoked by higher doses of adenosine (100 nmol site(-1)), CPA (100 nmol site(-1)), NECA (1 nmol site(-1)) and IB-MECA (0.1 - 1 nmol site(-1)). In rats treated with capsaicin to destroy sensory neurons, the response to higher doses of adenosine, CPA and NECA, but not IB-MECA, was significantly inhibited. 4. The effects of adenosine and analogues were largely inhibited by histamine and 5-hydroxytryptamine (5-HT) antagonists and by compound 48/80 pretreatment. 5. In conclusion, our results provide evidence that adenosine A1 and A2, but not A3, receptor agonists may function as cutaneous neurogenic pro-inflammatory mediators; acting via microvascular permeability-increasing mechanisms that can, depending on dose of agonist and purine receptor under study, involve the tachykinin NK1 receptor and mast cell amines.
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PMID:The plasma protein extravasation induced by adenosine and its analogues in the rat dorsal skin: evidence for the involvement of capsaicin sensitive primary afferent neurones and mast cells. 1152 2

To determine whether adenosine A3 receptor stimulation produces airway inflammation and, if so, what the mechanism of action is, we studied microvascular permeability in the rat trachea. After intravenous injection of Evans blue dye, adenosine and various adenosine analogues were given by inhalation, and the tracheal microvascular permeability was determined by a photometric measurement of extravasated dye. N6-2-(4-aminophenyl)-ethyladenosine (APNEA), an adenosine A3 receptor agonist, dose dependently increased plasma protein extravasation, whereas adenosine, the A1-receptor agonist N6-(R-phenylisopropyl)-adenosine, or the A2-receptor agonist 5'-N-ethyl-carboxamidoadenosine had no effect. The effect of APNEA was not altered by the adenosine A1/A2 receptor antagonist 8-(p-sulphophenyl)-theophylline, but was reduced by depletion of mast cell-derived mediators with compound 48/80 or pretreatment with the tachykinin NK1 receptor antagonist CP99,994. These results suggest that activation of A3 receptor specifically increase airway microvascular permeability probably via mast cell-derived mediators and tachykinins.
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PMID:Adenosine A3 receptor-mediated airway microvascular leakage: role of mast cells and tachykinins. 1175 79

The mast cell serine protease tryptase has been implicated as a critical mediator of airway hyperresponsiveness in vitro and in vivo. We have previously demonstrated that tryptase promotes hyperresponsiveness in isolated guinea pig bronchi. In this study, we have investigated the potential role of tryptase-mediated activation of proteinase-activated receptor-2 (PAR-2) in promoting airway hyperresponsiveness. Ex vivo exposure of guinea pig bronchi to the PAR-2 agonists H(2)N-Ser-Leu-Ile-Gly-Arg-Leu-CONH(2) (SLIGRL) and t-cinnamoyl-H(2)N-Leu-Ile-Gly-Arg-Leu-O-CONH(2) (t-c-LIGRLO) (0.1-10 microM) induced a concentration-dependent increase of contractile response to histamine. Treatment with 10 microM SLIGRL or t-c LIGRLO for 45 min increased subsequent responsiveness to histamine (0.3mM) by 54+/-3% and 69+/-5%, respectively (P<0.05 vs. control). In contrast, the PAR-1 agonist peptide H(2)N-Ser-Phe-Leu-Leu-Arg-Asn-CONH(2) (SFLLRN) did not promote significant changes in the airway. Effects of the peptides were observed following at least a 30-min preincubation with the tissue. Coincubation with indomethacin or removal of epithelial cells is required for PAR-2-mediated hyperreactivity. The inactive analogue H(2)N-Leu-Ser-Ile-Gly-Arg-Leu-CONH(2) (LISGRL; 10 microM) failed to promote hyperresponsiveness. Neuropeptide antagonists blocked the effect of the PAR-2 agonists. Selective antagonists of NK1 (L-703,606), NK2 (L-659,877), and CGRP (alphaCGRP 8-37) provided additive inhibition of PAR-2-mediated hyperreactivity. Pretreatment of bronchi with capsaicin (0.8 microM) also prevented the effects of SLIGRL. These results demonstrate the potential involvement of tryptase-mediated activation of PAR-2 in promoting airway hyperresponsiveness. These results further demonstrate that the PAR-2-mediated response involves a neurogenic mechanism involving neuropeptide release.
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PMID:Proteinase-activated receptor-2 mediates hyperresponsiveness in isolated guinea pig bronchi. 1290 52

Mast cell activation, bronchoconstriction, inflammation and airway hyperreactivity are prominent features of non-atopic hypersensitivity reactions in mouse airways. We studied the role of tachykinin receptors in mice that were skin-sensitized with dinitrofluorobenzene (or vehicle) and challenged intranasally with dinitrobenzene sulfonic acid. Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge. In contrast, treatment with the tachykinin NK2 receptor antagonist SR48968 did not affect the dinitrofluorobenzene-induced hypersensitivity reaction. We have previously shown that mast cells play a crucial role in the development of non-atopic asthma. However, we did not observe an inhibitory effect of the tachykinin receptor antagonists or the genetic absence of tachykinin NK1 receptors on mast cell protease release. In conclusion, distal from mast cell activation, the tachykinin NK1 receptor is crucial for the infiltration of pulmonary neutrophils and the development of tracheal hyperreactivity in non-atopic asthma.
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PMID:The tachykinin NK1 receptor is crucial for the development of non-atopic airway inflammation and hyperresponsiveness. 1296 72

Paclitaxel is one of the most extensively used anticancer agents, however, its use is often limited by severe hypersensitivity reactions, including respiratory distress, bronchospasm, and hypotension, which can occur despite premedication with dexamethasone and histamine H1 and H2 antagonists. The present study was designed to determine the mechanisms of paclitaxel hypersensitivity. In rats, paclitaxel (15 mg/kg, intravenously) caused a marked increase in pulmonary vascular permeability and edema. PaO2 decreased, whereas PaCO2 increased, transiently after paclitaxel injection. The paclitaxel-induced pulmonary vascular hyperpermeability was blocked by dexamethasone but not by histamine H1 or H2 antagonists. Paclitaxel increased the vascular permeability in lungs of mast cell-deficient rats Ws/Ws(-/-) to almost the similar extent as that elicited in wild-type rats. On the other hand, the paclitaxel-induced pulmonary vascular hyperpermeability was reversed by sensory denervation with capsaicin or pretreatment with LY303870 and SR48968, NK1 and NK2 antagonists, respectively. Consistent with these findings, a marked elevation of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide was observed in rat bronchoalveolar lavage fluid after paclitaxel injection. These findings suggest that sensory nerves rather than mast cells are implicated in the etiology of paclitaxel hypersensitivity.
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PMID:Role of sensory nerve peptides rather than mast cell histamine in paclitaxel hypersensitivity. 1456 55


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