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

The study of the mechanisms of action of the triptan group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine. In this context, two discoveries have been especially important: 1) these anti-migraine drugs are specifically recognized by three main types of serotonin receptors (5-HT1B, 5-HT1D, and 5-HT1F); and 2) these receptors are present in the meninges, where they are expressed by both smooth muscle cells and/or endothelial cells of the vascular wall and/or the perivascular trigeminal to be deleted axon terminals. These two findings have led to the most currently accepted physiopathogenic hypothesis, whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers, which would then trigger the release of vasoactive peptides (substance P, calcitonin gene-related peptide/CGRP) within the dura mater. Locally, i.e., in the dura mater in particular, these substances can provoke vasodilatation (CGRP) and plasmatic extravasation (substance P) with platelet lysis and mast cell degranulation, thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers, and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole. This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex, where it is integrated and expressed as migraine pain. The aim of this article was to report the main findings on endogenous substances (serotonin, peptides, nitric oxide [NO], etc.) which appear to play a key role in this physiopathogenic sequence.
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PMID:[Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine. Current hypotheses]. 1107 40

Calcitonin gene-related peptide has been shown to modulate inflammatory and immune responses in various systems. Recent studies in our laboratory and colleagues have shown that intracutaneously injected calcitonin gene-related peptide impairs the induction of contact hypersensitivity in mice, and participates in the pathogenesis of failed contact hypersensitivity induction after acute, low-dose ultraviolet B radiation. In this study we investigated the ability of calcitonin gene-related peptide to induce tolerance in normal and mast cell deficient mice and we examined the extent to which calcitonin gene-related peptide contributes to the tolerance induced by acute, low-dose ultraviolet B radiation. Calcitonin gene-related peptide was injected intradermally followed by application of 2,4-dinitro-1-fluorobenzene to the injected skin surface. Tolerance was assessed by re-exposing the mice 2 wk later to a second, sensitizing dose of 2, 4-dinitro-1-fluorobenzene on uninjected skin. We found that calcitonin gene-related peptide induced tolerance to 2, 4-dinitro-1-fluorobenzene in both normal and mast cell deficient mice. Calcitonin gene-related peptide-induced tolerance was blocked by intradermal injection of a calcitonin gene-related peptide antagonist [CGRP-(8-37)] that selectively blocks the calcitonin gene-related peptide receptor. Tolerance was also abolished by intraperitoneally injected anti-interleukin-10, but not anti-tumor necrosis factor alpha, antibodies. When 2,4-dinitro-1-fluorobenzene was painted on skin into which splenic dendritic cells pretreated with calcitonin gene-related peptide had been injected, tolerance was observed. Calcitonin gene-related peptide- treated dendritic cells mixed with anti-interleukin-10 antibody prior to intradermal injection failed to promote tolerance. Finally, injection of CGRP-(8-37) into skin that was subsequently exposed to acute, low-dose ultraviolet B radiation partially prevented tolerance induced by local application of 2,4-dinitro-1-fluorobenzene. These results indicate that calcitonin gene-related peptide has the capacity to promote cutaneous tolerance through an interleukin-10-dependent mechanism. This mechanism, which does not require the participation of mast cells, contributes to the tolerance promoted by acute, low-dose ultraviolet B radiation. Thus, calcitonin gene-related peptide from cutaneous nerve endings plays a key role in the local immune aberrations caused by ultraviolet B radiation.
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PMID:Hapten-specific tolerance promoted by calcitonin gene-related peptide. 1112 Nov 23

Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000
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PMID:Acute effects of substance P and calcitonin gene-related peptide in human skin--a microdialysis study. 1112 Nov 35

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

Protective vasodilation during acid back diffusion into the rat gastric mucosa depends on activation of sensory neurons and mast cell degranulation with histamine release. We hypothesized that these two mediator systems interact and that histamine partly exerts its effect via sensory nerves. Gastric blood flow (GBF) and luminal histamine were measured in chambered stomachs, and mast cell numbers were assessed by morphometry. Ablation of sensory neurons and depletion of mast cells were produced by pretreatment with capsaicin or dexamethasone, respectively. Mucosal exposure to 1.5 M NaCl and then to pH 1.0 saline in ablated and control rats caused increased luminal histamine and reduced numbers of mast cells. Enterochromaffin-like cell marker pancreastatin remained unchanged. Only control rats responded with an increase in GBF. Capsaicin stimulation (640 microM) of the undamaged mucosa induced identical increase in GBF and unchanged mast cell mass in normal and dexamethasone-treated rats. Increase in GBF after topical exposure to histamine (30 mM) in rats pretreated with capsaicin or a calcitonin gene-related peptide (CGRP)(1) antagonist human CGRP(8-37) or exposed to the calcium pore blocker ruthenium red was less than one-half of that in control rats. These data suggest that mast cell-derived histamine is involved in gastric vasodilatation during acid back diffusion partly via sensory neurons.
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PMID:Histamine is involved in gastric vasodilation during acid back diffusion via activation of sensory neurons. 1218 Nov 73

The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.
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PMID:Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. 1270 13

The immunohistochemical identification of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P, alpha-melanocyte stimulating hormone and gamma-melanocyte stimulating hormone) quantification of mast cells and their subsets (tryptase/chymase-immunoreactive mast cells = TCMC and tryptase-immunoreactive mast cells = TMC) were determined in biopsies of six patients with leprosy reactions (three patients with type I reaction and three with type II). Biopsies were compared with those taken from the same body site in the remission stage of the same patient. We found a relative increase of TMC in the inflammatory infiltrate of the reactional biopsies compared to the post-reactional biopsy. Also, the total number of mast cells and the TMC/TCMC ratio in the inflammatory infiltrate was significantly higher than in the intervening dermis of the biopsies of both periods. No significant difference was found regarding neuroptide expression in the reactional and post-reactional biopsies. The relative increase of TMC in the reactional infiltrates could implicate this mast cell subset in the reported increase of the immune response in leprosy reactions.
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PMID:Mast cell subsets and neuropeptides in leprosy reactions. 1280 99

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

Mast cell activation, or neurogenic inflammation, is known to induce lowering of interstitial fluid pressure (P(if)) and plasma protein extravasation (PPE) in several tissues from both rats and mice. To examine a possible role of connective tissue mast cells (CTMCs) in these inflammatory responses, we used mice with dysfunctional CTMCs due to lack of the N-deacetylase/N-sulfotransferase-2 enzyme (NDST-2(-/-)). P(if) and PPE were measured after challenge with compound 48/80 (C48/80), and P(if) alone was measured after treatment either with capsaicin, substance P (SP), or calcitonin gene-related peptide (CGRP). Measurements of P(if) in anesthetized (fentanyl/fluanison and midazolam, 1:1) mice were performed in paw skin with glass capillaries connected to a servo-controlled counterpressure system. PPE was measured with microdialysis by using hollow plasmapheresis fibers (cutoff at 3,000 kDa) placed subcutaneously on the back. Intravenous administration of C48/80 lowered P(if) significantly (P < 0.05) in NDST-2(-/-) mice (-1.67 +/- 0.42 mmHg) compared with vehicle (-0.57 +/- 0.17 mmHg) but the lowering was significantly (P < 0.05) less compared with that of the NDST-2(+/+) mice (-2.31 +/- 0.47 mmHg). PPE was increased 300% after treatment with C48/80 in NDST-2(+/+) mice, whereas there was no increase in PPE in NDST-2(-/-) mice. Capsaicin, SP, and CGRP lowered P(if) significantly (P < 0.05) compared with vehicle and to the same extent in both NDST-2(+/+) and NDST-2(-/-) mice. We can conclude that although NDST-2(-/-) mice demonstrate an altered response in P(if) after mast cell activation, there was no similar alteration after neurogenic inflammation. Therefore, we suggest that neurogenic inflammation in mouse skin is not exclusively dependent on intact CTMCs.
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PMID:Neurogenic inflammation in mice deficient in heparin-synthesizing enzyme. 1460 57

Neuropeptides such as substance P (SP) and related peptides are supposed to act as mast cell agonists, and thus as mediators of neuroimmune interactions. The data supporting this hypothesis were obtained mostly from rodent experiments. Here, we studied for the first time the effect of SP and other peptides on mediator release in human intestinal mast cells, either unpurified or enriched to 85-99% purity. We found that SP at 0.1-100 micromol L(-1), or other peptides including neurokinin A and B, calcitonin gene-related peptide, vasoactive intestinal peptide and serotonin at 1 micromol L(-1) do not induce release of mediators such as histamine, sulphidoleukotrienes, and tumour necrosis factor alpha. The peptides also failed to cause mediator release in mast cells isolated from inflamed tissue derived from Crohn's disease. Using reverse transcriptase-polymerase chain reaction, flow cytometry and immunohistochemistry, we could show that human intestinal mast cells do not express the tachykinin receptors NK-1, NK-2, or NK-3 under basal conditions. However, upon stimulation by immunoglobulin E (IgE) receptor-crosslinking, which induces an extensive mediator release reaction, a subpopulation of mast cells clearly expressed NK-1, the SP receptor. In conclusion, our data show that SP and other neuropeptides do not act as secretagogues in human intestinal mast cells that have not been pre-activated by IgE receptor-crosslinking.
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PMID:Substance P and other neuropeptides do not induce mediator release in isolated human intestinal mast cells. 1508 72


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