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)

Mast cells have been implicated in a number of diseases involving chronic inflammation including asthma, rheumatoid arthritis, and inflammatory bowel diseases. They are a potent source of several cytokines, including IL-6 and TNF-alpha. Freshly isolated rat peritoneal mast cells will produce IL-6 in response to anti-IgE, LPS, PGE1, or PGE2; however, the mechanisms by which such cytokine production is regulated are poorly understood. IL-10 is recognized as an important immunoregulatory cytokine with effects on T cell development and the production of inflammatory cytokines. IL-10 has previously been described to enhance mast cell development in the context of IL-3 and IL-4. In the current study, we have examined the ability of IL-10 to modulate rat peritoneal mast cell IL-6 and TNF-alpha production in response to a variety of stimuli. We have observed that recombinant murine IL-10 can inhibit the production of both IL-6 and TNF-alpha by mast cells without altering the degree of histamine release in response to anti-IgE. Concentrations of IL-10 as low as 0.2 ng/ml were sufficient to inhibit IL-6 production by LPS- or anti-IgE-activated cells significantly. IL-10 also inhibited PGE1- and PGE2-induced IL-6 production. The relative potency of IL-10 as an inhibitor of mast cell IL-6 production was highly dependent upon the stimulus used, with a 10-fold difference in the IC50 for LPS- or anti-IgE-activated cells (0.21 ng/ml) and cells activated with a combination of LPS and PGE2 (2.29 ng/ml). This suggests that prostanoids may limit the ability of IL-10 to modulate mast cell IL-6 production in the context of inflammation. These data have important implications for the regulation of mast cell IL-6 in inflammatory diseases involving prostanoid production and the effects of treatment with cyclooxygenase inhibitors. Our results also demonstrate a dual role for IL-10 on mast cells as a growth factor and inhibitor of cytokine production.
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PMID:Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. 861 37

It is believed that aspirin (ASA) and other nonsteroidal antiinflammatory drugs elicit dysponea in ASA sensitive asthmatics by blocking the cyclooxygenase. It is unclear whether this bronchospasm is due to shunting of arachidonic acid into the lipooxygenase pathway or removal of cyclooxygenase product which prevent bronchospasm. Diminished tissue concentration of PGE may cause bronchoconstriction. PGE play also modulatory function to mast call decreasing the release of mediators of anaphylaxis. There are some evidences concerning the mast cell degranulation in postaspirin reaction in ASA sensitive asthmatics. The authors investigated the influence of synthetic analogue of PGE1--misoprostol (Cototec, Searle) on the postaspirin bronchoconstriction in seven ASA sensitive asthmatics aged 33-62. Aspirin threshold doses ranged from 10 to 150 mg. Postaspirin bronchoconstriction begun usually within 1-2 hrs after digestion of ASA and 200 micrograms were additionally given 2 h later. Seven days later misoprostol (400 micrograms) was administered together with previously determined dose of ASA. One the other day the bronchodilating effect of misoprostol alone was examined. In all but one patients we observed the protective influence of misoprostol on ASA induced bronchoconstriction. Max. fall in FEV1 in % after ASA in each of the patients was 40, 25, 24, 33, 47 and 54, and after ASA with misoprostol, respectively 10, 9, 4, (+8), 10, (+2) and 45. Misoprostol given together with ASA attenuated aspirin-induced bronchoconstriction reaching statistical significance at 3 and 3.5 h, and also diminished extrapulmonary symptoms. The authors discuss the possible mechanism of protective influence of misoprostol.
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PMID:[The influence of misoprostol on post-aspirin bronchoconstriction in patients with aspirin sensitive asthma]. 862 Jan 77

Nerve growth factor (NGF) is known to produce hyperalgesia as well as to stimulate synthesis of neuropeptides in dorsal root ganglia (DRG). In the present study, we wanted to determine the effects of local NGF administration and assess to which extent mast cell-dependent factors are mediating NGF responses. Rats received 1 daily unilateral intraplantar injection for 3 days. Local edema (days 1-3), changes in thermal nociceptive threshold (days 1-4), and the content of calcitonin gene-related peptide (CGRP) and substance P (SP) in the sciatic nerve (day 4), were determined. NGF injection caused edema which was absent in rats pretreated with compound 48/80 as well as in rats treated neonatally with capsaicin ('capsaicin denervation'). NGF-induced edema was not reduced by the neurokinin-1 receptor antagonist SR140333, but attenuated by the CGRP receptor antagonist CGRP[8-37]. On each day, NGF injection caused a decrease in thermal nociceptive threshold which lasted for less than 3 h. Capsaicin denervation, but not treatment with indomethacin, abolished NGF-induced thermal hyperalgesia. Treatment with compound 48/80 attenuated hyperalgesia produced by the first, but not by subsequent, NGF injections. On day 4, 24 h after the last of 3 NGF injections, thermal nociceptive threshold was not different from control values, but at that time, CGRP and SP were elevated in the sciatic nerve. We suggest therefore that NGF-induced local edema was caused by mast cell-derived vasoactive compounds which act together with afferent neuron-derived CGRP to increase vascular permeability. NGF-induced thermal hyperalgesia most likely was caused by an increased sensitivity of peripheral endings of capsaicin sensitive afferents. This effect of NGF was not mediated by products of the cyclooxygenase pathway, and was also observed in mast cell-depleted rats.
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PMID:Intraplantar injection of nerve growth factor into the rat hind paw: local edema and effects on thermal nociceptive threshold. 874 Jun 10

In order to determine the mast cell requirements in murine delayed-type hypersensitivity (DTH), the effects of the antihistamine chlorpheniramine, the inhibitor of mast cell degranulation repirinast (CAS 73080-51-0, MY-5116), the lipoxygenase and cyclooxygenase inhibitor BW-755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline), and the cyclooxygenase inhibitors ibuprofen, diclofenac and phenylbutazone on murine DTH reactions were examined. When chlorpheniramine (50 mg/kg) was administered orally immediately after, 5 h, or 9 h after antigen challenge, it did not show any effect on sheep red blood cells (SRBC)-induced delayed footpad reaction (FPR) in mice. On the other hand, when chlorpheniramine was administered orally 16 h after antigen challenge, it significantly inhibited SRBC-induced delayed FPR (p < 0.01). When repirinast (30, 100 mg/ kg) was administered orally 16 h after antigen challenge, it significantly inhibited delayed FPR in a dose-dependent manner. BW-755C (50 mg/kg) showed no significant effect on delayed FPR when it was administered 1 h, 7 h, or 13 h after challenge. However, it significantly inhibited delayed FPR when it was administered 16 h after antigen challenge (p < 0.01). Ibuprofen, diclofenac, or phenylbutazone showed no significant effect on delayed FPR even if it was administered 16 h after antigen challenge. These results demonstrate that mast cells could be involved in DTH reactions and that histamine and leukotrienes may play an important role in DTH reactions in mice.
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PMID:Pharmacologic modulation of delayed-type hypersensitivity in mice. 887 37

Olopatadine (AL-4943A; KW-4679) [(z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2 acetic acid hydrochloride] is an anti-allergic agent which inhibits mast cell mediator release and possesses histamine H1 receptor antagonist activity. Studies were conducted to characterize the in vitro and in vivo pharmacological profile of this drug relevant to its topical ocular use. AL-4943A inhibits histamine release in a concentration-dependent fashion (IC50 = 559 microM) from human conjunctival mast cell preparations in vitro. Histamine release was not stimulated by AL-4943A at concentrations as high as 10 mM. In contrast, ketotifen stimulated histamine release at concentrations slightly higher than effective inhibitory concentrations. AL-4943A did not display any in vitro cyclooxygenase or 5-lipoxygenase inhibition. Topical ocular application of AL-4943A effectively inhibits antigen- and histamine-stimulated conjunctivitis in guinea pigs. Passive anaphylaxis in guinea pig conjunctiva was attenuated by AL-4943A applied 30 min prior to intravenous or topical ocular antigen challenge (ED50 values 0.0067% and 0.0170%, w/v, respectively). Antihistaminic activity in vivo was demonstrated using a model of histamine-induced vascular permeability in guinea pig conjunctiva. AL-4943A applied topically from 5 min to 24 hrs prior to histamine challenge effectively and concentration-dependently inhibited the vascular permeability response, indicating the compound has an acceptable onset and a long duration of action. Drug concentrations 5-fold greater than those effective against histamine-stimulated conjunctival responses failed to inhibit vascular permeability responses induced with either serotonin or Platelet-Activating-Factor. These data indicate that the anti-histaminic effect observed with AL-4943A is specific. These anti-allergic/antihistaminic activities of AL-4943A observed in preclinical model systems have been confirmed in clinical trials in allergic patients.
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PMID:The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. 895 75

We have previously reported that there is an altered response to mast cell-mediated inflammation in copper-deficient rats. In the current study we determined the microvascular reactivity to inflammatory stimuli with lipopolysacccharide (LPS) during dietary copper restriction. Male Sprague-Dawley rats were fed purified diets which were either copper-adequate (CuA, 6 micrograms Cu/g) or copper-deficient (CuD, 0.4 micrograms Cu/g) for 4 weeks. Rats were anesthetized and the cremaster muscle was prepared for in vivo television microscopy. Arteriolar diameters were measured and then 2.5 mg/kg LPS was injected i.p. In separate groups, animals were pretreated with the NO-synthase inhibitor L-NAME (2 x 10(-4) M), the cyclooxygenase inhibitor ibuprofen (9.6 x 10(-5) M) or the histamine receptor antagonist diphenhydramine (DPH, 10(-6) M). LPS caused arteriolar dilation in both dietary groups with the response being significantly greater in the CuD group. Ibuprofen and DPH but not L-NAME, each significantly reduced but did not block the dilation in the CuD group. Ibuprofen and DPH together blocked the dilation. These results suggest that dietary copper deficiency increases arteriolar dilation to LPS. The mechanism appears to involve a greater response to arachidonic acid metabolites and histamine but not NO.
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PMID:Arteriolar dilation to endotoxin is increased in copper-deficient rats. 917 21

The effect of epithelial cells on mast cell responses was investigated by examination of degranulation of the rat mast cell line RBL-2H3 after overnight culture in media conditioned by the BEAS-2B human bronchial epithelial cell line [epithelial cell-conditioned media (ECM)]. These studies indicate that BEAS-2B cells secrete an inhibitor(s) of immunoglobulin E and A-23187-mediated degranulation of the RBL-2H3 cell line. The inhibitory activities of ECM are recovered after filtration through a 3-kDa cutoff filter. Pharmacological inhibition of cyclooxygenase in the BEAS-2B cells before preparation of ECM has no effect on subsequent inhibition of mast cell degranulation by ECM. However, cycloheximide treatment of the BEAS-2B cells before the conditioning process does preclude development of mast cell inhibitor activity in ECM, suggesting that this activity depends on protein synthesis. The effects of ECM on mast cell function are reversible, demonstrating that these effects do not result from overt cytotoxicity. Finally, media conditioned by primary cultures of human respiratory epithelial cells, but not fibroblasts, influence RBL-2H3 degranulation in a manner similar to ECM, suggesting that secretion of mast cell inhibitors may be somewhat unique to epithelial cells.
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PMID:Epithelial cell-conditioned media inhibits degranulation of the RBL-2H3 rat mast cell line. 922 21

New sources of human and mouse mast cells, which were isolated from individual organs (i.e., lung, colon, synovium, skin, uterus, heart), developed from progenitors in vitro in the presence of stem cell factor and/or interleukin (IL)-3, or enriched from fetal or adult blood, spleen or bone marrow by cell sorting, have made possible new studies of the cell biology of mast cells. Advances resulting from these new mast cell sources as well as from new methods for labeling specific products in subcellular sites and structures in resting and functional mast cells are the subject of this review. Specific advances discussed are as follows: identification of an Fc epsilonRI+ c-kit- mouse basophil population from bone marrow and spleen that is associated with IL-4 production and an Fc epsilonRI- c-kit- granulated mouse mast cell progenitor in fetal blood; identification of hyperplasia and functional activation of human skin mast cells in vivo when exposed to recombinant stem cell factor and spontaneous degranulation in X-linked immunodeficient mouse mast cells; use of an enzyme-affinity-gold method to detect histamine in mature and immature human mast cell granules, in secretion and recovery of histamine during anaphylactic degranulation of human lung mast cells ex vivo, and in secretion of histamine in vivo by piecemeal degranulation of IL-4 transgenic mouse mast cells in inflammatory eye disease and of human gut mast cells in inflammatory bowel disease; use of immunogold methods to localize cyclooxygenase and tumor necrosis factor-alpha to subcellular structures in human and rat mast cells and to localize the Charcot-Leyden crystal protein in human basophils to aid in the identification of mast cells arising in mixed cellular populations; use of a low-density lipoprotein (LDL)-gold affinity method to demonstrate a rat mast cell granule-mediated uptake of LDL by macrophages in peritoneal fluid.
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PMID:New aspects of mast cell biology. 930 24

Rats were sensitized against egg albumin and the response of the longitudinal muscle from the proximal small intestine to the antigen was tested. Egg albumin (1-100 micrograms/ml) concentration-dependently induced a contraction of the longitudinal muscle in tissues from sensitized animals but not from nonsensitized animals. The response to the antigen was resistant to neuronal blockers like tetrodotoxin, atropine and hexamethonium. Inhibitors of thromboxane synthesis such as the cyclooxygenase inhibitor, indomethacin, the thromboxane synthase blocker, 1-benzylimidazole, or the combined cyclooxygenase/lipoxygenase/thromboxane synthase inhibitor, sulfasalazine, inhibited the contraction evoked by egg albumin. A similar concentration-dependent inhibition of the antigen response was observed with two thromboxane A2 receptor blockers, SK&F 88046 and KW-3635. None of these blockers affected the response to the muscarinic agonist, carbachol, excluding unspecific effects of the drugs on smooth muscle contractility. The effect of antigen was reduced by the mast cell stabilizing agent, quercetin, and by the histamine H1 receptor blocker, mepyramin. These drugs, however, also inhibited the response to carbachol. When contractions were stimulated directly by the stable thromboxane derivative, carbocyclic thromboxane A2, the smooth muscle proved to be more than three orders of magnitude more sensitive to this agonist of the thromboxane pathway compared to histamine. Consequently, thromboxane A2 seems to be one of the main mediators of anaphylactically induced longitudinal muscle contractions in the rat small intestine.
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PMID:Inhibition of antigen-induced muscle contractions by inhibitors of thromboxane pathway in rat small intestine. 934 27

Prostanoid generation may proceed via both isoforms of cyclooxygenase, Cox-1 and Cox-2. Cox-1 is thought to be ubiquitously expressed, whereas Cox-2 is mostly assumed to be dynamically regulated, responding to inflammatory stimuli. The cellular localization of Cox-1 and Cox-2 in the lung, an organ with high cyclooxygenase activity, is not known. In normal rat lungs the expression and localization of Cox-1 and Cox-2 were examined with immunogold-silver staining and the RT-PCR technique. Quantitative image analysis of the staining intensity was performed by measuring mean gray values of digitized epipolarization images. Expression of both Cox-1 and Cox-2 was readily detectable in rat lungs. Cox-1 immunoreactivity localized predominantly to bronchial epithelial cells, smooth muscle cells of large hilum veins, and (with lower expression) to alveolar macrophages and pulmonary artery endothelial cells. The most intense Cox-2 staining was noted in macrophage- and mast cell-like cells, detected in close vicinity to the bronchial epithelium and in the connective tissue surrounding the vessels. In addition, strong Cox-2 expression was found in smooth muscle cells of partially muscular vessels and large veins of the hilum. Bronchial epithelial cells displayed Cox-2 immunoreactivity with limited intensity. Alveolar macrophages and alveolar septal cells were only occasionally stained with anti-Cox-2 antibodies. Both Cox-1 and Cox-2 are constitutively expressed in several cell types of normal rat lung, but display clearly different patterns of cellular localization. Cox-2 may not be related only to lung inflammation, but is suggested to be implicated in regulatory processes under physiological conditions as well.
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PMID:Cyclooxygenase isoenzyme localization and mRNA expression in rat lungs. 953 35


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