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 protective action of zinc compounds in Crohn's disease-like inflammatory bowel disease in animals has been shown. A similar action of zinc sulfate on ulcerative colitis has not been defined. The present study aimed to delineate the protective action of zinc sulfate and the pathogenic mechanisms of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced ulcerative colitis in rats. Zinc sulfate at different concentrations was given either orally (p.o.) or rectally (p.r.) to rats at 42, 48, 66 and 72 h following the induction of colonic inflammation by DNBS. Rats were killed 96 h after instillation of DNBS rectally to assess the severity of colonic damage, myeloperoxidase and xanthine oxidase activities. The involvement of mast cell degranulation and histamine release in the pathogenesis of DNBS-induced colitis was determined by using a mast cell stabilizer (ketotifen) and histamine receptor blockers (terfenadine and ranitidine). DNBS given rectally produced inflammation and ulceration in rats with a pathology resembling ulcerative colitis. Myeloperoxidase activity but not xanthine oxidase activity was sharply increased by this agent. Intrarectal administration of zinc solution and parenteral injection of histamine blockers significantly reduced tissue damage and myeloperoxidase but not xanthine oxidase activity. Ketotifen, a mast cell stabilizer, also significantly decreased mucosal injury and myeloperoxidase activity in the colon. In conclusion, mast cell degranulation followed by histamine release plays an important role in the pathogenesis of DNBS-induced ulcerative colitis. Zinc given rectally has a therapeutic effect against this colitis model, perhaps through the reduction of inflammation and inhibition of the above pathogenic mechanisms.
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PMID:Delineation of the protective action of zinc sulfate on ulcerative colitis in rats. 1204 10

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

Recent advances in our understanding of allergic and autoimmune disorders have begun to translate into novel, effective and safe medicines for these common maladies. Examples include an anti-IgE monoclonal antibody recently approved for severe asthmatics and the TNF-alpha antagonists that have demonstrated their ability to suppress rheumatoid arthritis, Crohn's disease and other chronic inflammatory processes. However, protein therapies are difficult and expensive to develop, manufacture and administer. Clearly, there is also a need for small-molecule inhibitors of novel targets that have safe and effective characteristics. Syk is an intracellular protein tyrosine kinase that was discovered 15 years ago as a key mediator of immunoreceptor signalling in a host of inflammatory cells including B cells, mast cells, macrophages and neutrophils. These immunoreceptors, including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders. In addition, as Syk is positioned upstream in the cell signalling pathway, therapies targeting Syk may be more advantageous relative to drugs that inhibit a single downstream event. Syk inhibition during an allergic or asthmatic response will block three mast cell functions: the release of preformed mediators such as histamine, the production of lipid mediators such as leukotrienes and prostaglandins and the secretion of cytokines. In contrast, commonly used antihistamines or leukotriene receptor antagonists target only a single mediator of this complex cascade. Despite its expression in platelets and other non-haematopoietic cells, the role of Syk in regulating vascular homeostasis and other housekeeping functions is minimal or masked by redundant Syk-independent pathways. This suggests that targeting Syk would be an optimal approach to effectively treat a multitude of chronic inflammatory diseases without undue toxicity.
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PMID:Targeting Syk as a treatment for allergic and autoimmune disorders. 1521 16

Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that shares similarities with Crohn's disease and psoriasis. IC, often regarded as a neurogenic cystitis, is associated with urothelial lesions that likely compromise the bladder permeability barrier and thereby contribute to patient morbidity. Here, we use a murine model of neurogenic cystitis to investigate the mechanism of urothelial lesion formation and find that urothelial apoptosis induces formation of lesions. Lesions formed in wild-type mice but not in mice deficient in TNF, TNF receptors, or mast cells. In urothelial cultures, only siRNAs targeting TNFR1, but not TNFR2, blocked TNF-induced apoptosis, indicating a primary role for TNFR1. Trans-epithelial resistance, a measure of bladder barrier function, decreased during neurogenic cystitis in wild-type and TNFR2(-/-) mice but was stabilized in TNF(-/-) mice. Anti-TNF antibodies both altered bladder mast cell localization and stabilized barrier function. Based on these findings, we conclude that mast cell activation and release of TNF drive urothelial apoptosis and lesion formation in a murine neurogenic cystitis model, and we hypothesize that anti-TNF therapy may stabilize bladder barrier function in IC patients.
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PMID:Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis. 1662 79

Mast cells were described by Erhlich at the end of XIX-th century. Their role was deeply investigated in asthma and allergy. The massive degranulation of mast cells in allergy can lead to anaphylactic shock. Recently, mast cells have been recognized again as a very interesting topic for investigation, due to their possible role in chronic inflammation. Moreover, through adenosine receptors, mast cells can be activated or inactivated. That is why these cells are regarded as a potential target of new drugs. It has been reported, that mast cells generate intracellular reactive oxygen species (ROS) in response to stimulation with divergent physiologically relevant stimulants. The intensification of ROS production may be measured by the level of carbonyl groups, as a marker of protein peroxidation. However, the role of mast cells in other than asthma diseases with chronic inflammation needs further investigation. It was found out that the information about mast cell distribution in colonic mucosa may serve as help in differentiation between inflammatory bowel disease and collagenous colitis. Moreover, its accumulation in focal active gastritis was confirmed in patients with Crohn's disease. An important role in regulation of inflammatory process seems to be reserved for adenosine receptors present on mastocytes. The activation of mast cells through the adenosine receptor is connected with 11-8 release, which stimulate the migration of leukocytes and oxidation reactions. The detection of mast cells in tissues should not be limited only to the simple histologic examination. It should be completed by the detection of products of degranulation, e.g. tryptase. This is the way to find out their actual function and state of activation.
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PMID:[Mast cells, their adenosine receptors and reactive oxygen species in chronic inflammatory pathologies of childhood]. 1720 8

Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in bone marrow and other organs. Gastrointestinal (GI) symptoms are common in both SM and cutaneous mastocytosis [urticaria pigmentosa (UP)], and are usually caused by the release of histamine and other inflammatory mediators. Occasionally, neoplastic mast cells may also directly infiltrate the GI tract. Previous studies have suggested that enumeration of the mast cells in GI biopsies may help establish the diagnosis of SM. However, mast cells have been reported to be increased in various inflammatory diseases, and mast cell density has not been systematically evaluated in other GI disorders. Recently, expression of CD25 by mast cells in bone marrow has been shown to be specific for SM. The purpose of this study was (1) to quantitate and compare mast cells in mucosal biopsies from patients with SM involving the GI tract, UP with GI symptoms, and a control group of diverse inflammatory disorders, and (2) to determine whether immunostaining for CD25 can be used to distinguish neoplastic from reactive mast cells in GI biopsies. Seventeen GI biopsies from 6 patients with SM; 17 GI biopsies from 5 patients with UP; and 157 control cases including 10 each normal stomach, duodenum, terminal ileum, and colon, Helicobacter pylori gastritis, bile reflux gastropathy, peptic duodenitis, celiac disease, Crohn disease, ulcerative colitis, lymphocytic colitis, and collagenous colitis, 20 biopsies from 16 patients with irritable bowel syndrome, 8 biopsies from 5 patients with parasitic infections, and 9 biopsies from 7 patients with eosinophilic gastroenteritis were immunostained for mast cell tryptase, c-kit (CD117), and CD25. Mucosal mast cells were quantitated, and the presence or absence of CD25 expression on mast cells was determined. In SM patients, mast cells in the small intestine and colon numbered >100/high-power field (HPF) in nearly all cases (mean 196/HPF; range 74 to 339). This was significantly higher than in GI biopsies from UP patients (mean 17/HPF; range 8 to 32, P<0.0001) and all inflammatory diseases (P<0.01). Mast cell density in other disorders ranged from a mean of 12/HPF in H. pylori gastritis to 47/HPF in parasitic infections. Interestingly, all SM biopsies (and none of the other cases) contained aggregates or confluent sheets of mast cells. In addition, mast cells in all SM cases were positive for CD25, whereas GI mucosal mast cells in UP and all other control cases were negative. In conclusion, quantitation of mast cells can be helpful to diagnose SM in GI mucosal biopsies, although mast cells are also markedly increased in parasitic infections. Aggregates or sheets of mast cells are only seen in SM. Immunoreactivity for CD25 in GI mucosal mast cells is specific for SM and can be used to confirm the diagnosis.
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PMID:Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. 1805 23

The pathomechanism of inflammatory bowel disease (IBD), i.e. Crohn's disease and ulcerative colitis, is not well understood. There is growing evidence that mast cells take part in the course of these diseases. It is well known that mast cells are numerous in the gastrointestinal tract. What is more, the number of mast cells increases in intestinal tissues in IBD. Mast cells release several mediators, cytokines, and chemokines that can influence the inflammatory process in the gastrointestinal tract in various ways. One mediator that plays a very important role in the development of IBD is tumor necrosis factor (TNF). Other mast cell-derived cytokines and chemokines also seem to be involved in the development of intestinal inflammation. Moreover, some unique mast cell mediators, such as histamine, tryptase, and chymase, play crucial roles in the course of IBD. Finally, there is some data showing that mast cell-derived metalloproteinases (especially MMP-9), leukotrienes (LTs), platelet activating factor (PAF), and heparin take part in inflammation during IBD. It seems that current data about the role of mast cell-derived mediators and cytokines in IBD should be taken into consideration when new approaches to treating these diseases are being introduced.
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PMID:[The role of mast cells in the development of inflammatory bowel diseases]. 1903 90

Traditionally, mast cells were regarded as key cells orchestrating type I hypersensitivity responses. However, it is now recognized that mast cells are widely involved in nonallergic (non-IgE) chronic diseases. Also, in inflammatory bowel disease (IBD), a disease not associated with increased IgE concentrations, clear signs of activation of mast cells have been found. In this study, we investigated if Ig-free L chain-induced hypersensitivity-like responses through activation of mast cells could contribute to the pathophysiology of IBD. As a mast cell-dependent model for IBD, mice were skin-sensitized with dinitrofluorobenzene followed by intrarectal application of the hapten. In this murine IBD model, F991 prevented mast cell activation and also abrogated the development of diarrhea, cellular infiltration, and colonic lymphoid follicle hyperplasia. Furthermore, passive immunization with Ag-specific Ig-free L chains (IgLCs) and subsequent rectal hapten challenge elicited local mast cell activation and increased vascular permeability in the colon of mice. Clinical support is provided by the observation that serum concentrations of IgLCs of patients suffering from Crohn's disease are greatly increased. Moreover, increased presence of IgLCs was evident in tissue specimens from colon and ileum tissue of patients with IBD. Our data suggest that IgLCs may play a role in the pathogenesis of IBD, which provides novel therapeutic means to prevent or ameliorate the adverse gastrointestinal manifestations of IBD.
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PMID:Ig-free light chains play a crucial role in murine mast cell-dependent colitis and are associated with human inflammatory bowel diseases. 2050 43

Extracts from the gum resin of Boswellia serrata and some of is constituents including boswellic acids affect the immune system in different ways. Among the various boswellic acids 11-keto-beta-boswellic acid (KBA) and acetyl-11-keto-beta-boswellic acid have been observed to be active. However, also other boswellic acids may exhibit actions in the immune system. In the humoral defence system a mixture of boswellic acis at higher doses reduced primary antibody titres; on the other hand lower doses enhanced secondary antibody titres following treatment with sheep erythrocytes. In the cellular defence boswellic acides appear to increase lymphocyte proliferation whereas higher concentrations are even inhibitory. Moreover, BAs increase phagocytosis of macrophages. BAs affect the cellular defence system by interaction with production/release of cytokines. Thus, BAs inhibit activation of NFkappaB which is a product of neutrophile granulocytes. Consequently a down regulation of TNF-alpha and decrease of IL-1, IL-2, IL-4, IL-6 and IFN-gamma, which are proinflammatory cytokines by BEs and BAs has been reported. Suppressions of the classic way of the complement system was found to be due to inhibition of the conversion of C3 into C3a and C3b. However, which of these pharmacological actions contribute to the therapeutic effects and which is finally the best dosage of a standardized extract needs further examination. And it is also a question whether or not a single BA will have the same therapeutic effect as a standardized extract. Among the mediators of inflammatory reaction, mast cell stabilisation has been described by a BE. Inhibition of prostaglandin synthesis appears to play only a minor role as far as the anti-inflammatory effect is concerned. On the other hand the inhibitory action of BAs on 5-LO leading to a decreased production of leukotrienes has received high attention by the scientific community since a variety of chronic inflammatory diseases is associatied with increased leukotriene activity. At the end of the cascade of events in the cellular immune system as far as it directs to various tissues of the body - i.e. autoimmune diseases - formation of oxygen radicals and proteases (for example elastase) play an important destructive role. Here, BEs as well as BAs have been found to be inhibitory. From the pharmacological properties of BEs and BAs it is not surprising that positive effects of BEs in some chronic inflammatory diseases including rheumatoid arthritis, bronchial asthma, osteoarthritis, ulcerative colitis and Crohn's disease have been reported.
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PMID:Modulation of the immune system by Boswellia serrata extracts and boswellic acids. 2069 59

Mast cells are known effector cells in allergic and inflammatory diseases, but their precise roles in intestinal inflammation remain unknown. Here we show that activation of mast cells in intestinal inflammation is mediated by ATP-reactive P2X7 purinoceptors. We find an increase in the numbers of mast cells expressing P2X7 purinoceptors in the colons of mice with colitis and of patients with Crohn's disease. Treatment of mice with a P2X7 purinoceptor-specific antibody inhibits mast cell activation and subsequent intestinal inflammation. Similarly, intestinal inflammation is ameliorated in mast cell-deficient Kit(W-sh/W-sh) mice, and reconstitution with wild-type, but not P2x7(-/-) mast cells results in susceptibility to inflammation. ATP-P2X7 purinoceptor-mediated activation of mast cells not only induces inflammatory cytokines, but also chemokines and leukotrienes, to recruit neutrophils and subsequently exacerbate intestinal inflammation. These findings reveal the role of P2X7 purinoceptor-mediated mast cell activation in both the initiation and exacerbation of intestinal inflammation.
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PMID:Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. 2294 16


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