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)

The effects of ketotifen, a 'mast cell stabiliser,' on two models of experimental colitis were examined. The inflammatory response elicited by either trinitrobenzene sulphonic acid or acetic acid resulted in increased colonic synthesis of platelet activating factor, prostaglandin E2, thromboxane B2, leukotrienes B4 and C4, and myeloperoxidase activity. Intragastric administration of ketotifen 100 micrograms/100 grams twice daily significantly decreased mucosal damage when given prophylactically 48 hours before the induction of colitis and then throughout the experiment. This effect was consistent in both models and was accompanied by a significant reduction in mucosal generation of platelet activating factor, prostaglandin E2, thromboxane B2, and leukotrienes C4 and B4. Myeloperoxidase activity was reduced as well, reaching significance only in the acetic acid model. This study shows that both trinitrobenzene sulphonic acid and acetic acid colitis can be pharmacologically manipulated by ketotifen. The mechanism of action of ketotifen has not yet been determined. Ketotifen's potential in the treatment of active inflammatory bowel disease or in the prevention of exacertations, or both, remains to be elucidated.
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PMID:Ketotifen effectively prevents mucosal damage in experimental colitis. 145 75

The effect of immunosuppressive drugs, 4-aminosalicylic acid (4-ASA), acetyl 5-aminosalicylic acid (5-ASA), and ketotifen on human colonic eicosanoid accumulation was evaluated in view of enhanced accumulation in patients with active ulcerative colitis. Azathioprine (100 micrograms/ml), cyclosporin (100 micrograms/ml), and methotrexate (100 micrograms/ml) significantly inhibited, by 25-35%, prostaglandin E2 (PGE2) accumulation by organ-cultured colonic mucosa of ulcerative colitis patients. Methotrexate was the only immunosuppressive drug that inhibited leukotriene B4 (LTB4) accumulation (50%), whereas azathioprine inhibited the accumulation of leukotriene C4 (LTC4) (25%). 5-ASA and its metabolite, acetyl 5-ASA, inhibited by 20-70% PGE2, LTB4, and LTC4 accumulation in the culture, supporting the contention that acetyl 5-ASA is as active as 5-ASA in these respects. 4-ASA had no effect on any of the eicosanoids. Ketotifen, a mast cell stabilizer, significantly inhibited the accumulation of PGE2, LTB4, and LTC4 by 33-60%. These results suggest a potential, new, unrecognized mode by which the immunomodulators induce part of their therapeutic effects in inflammatory bowel disease and support the contention that acetyl 5-ASA is as active as 5-ASA. The results obtained also indicate that ketotifen, used effectively in the prevention of bronchial asthma, inhibits the accumulation of colonic eicosanoids and, thus, may be of value in the treatment of inflammatory bowel disease.
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PMID:Effect of drugs on colonic eicosanoid accumulation in active ulcerative colitis. 145 96

One hundred and seventeen coded intestinal biopsies were examined by electron microscopy and evaluated for morphological evidence of mast cell and basophil secretion in situ. Sixty percent of the biopsies had evidence of secretion. Mast cell secretion was evident in control biopsies, many of which were obtained from uninvolved tissues of patients with inflammatory bowel disease. Biopsies of inflamed continent pouches from ulcerative colitis (UC) patients showed more mast cell secretion than noninflamed UC pouch biopsies. This evidence of mast cell secretion supports recent work that documents high constitutive levels of histamine in jejunal fluids of Crohn's disease patients and suggests a proinflammatory role for mast cells in inflammation associated with pouchitis.
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PMID:Ultrastructural evidence for piecemeal and anaphylactic degranulation of human gut mucosal mast cells in vivo. 148 68

Mast cells are a significant component of the mucosa in the gastrointestinal tract. There is increasing evidence that these cells are involved in the pathophysiology of various intestinal disorders ranging from food allergy to inflammatory bowel disease. When activated, mast cells release a host of potent mediators and cytokines which are capable of inducing pathophysiology. The bulk of the evidence has come from hypersensitivity studies in experimental animals sensitized either by parasitic infection or by active immunization to an antigen using adjuvants which stimulate IgE production. Subsequent antigen challenge of the gut results in mast cell activation associated with alterations in intestinal functions including ion transport and epithelial permeability. Intestinal secretory transport responses are inhibited by antagonists of mast cell mediators and neurotoxins, implicating mast cell-nerve interactions with the epithelium. In genetically mast cell-deficient mice, antigen-induced secretion is reduced approximately 70% and this component is not affected by neural or mast cell inhibitors; adoptive transfer of bone marrow containing mast cell precursors derived from congenic normal mice restores the complete antigen response. These results provide more direct proof that mast cell activation causes abnormal gut function. Recently, we have begun studies which indicate that activation of mast cells induces ion secretion in surgically resected human intestine. Reduced secretory responses in specimens from patients with IBD suggest that mast cells may play a role in the pathophysiology of inflammatory bowel disease.
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PMID:Functional abnormalities in the intestine associated with mucosal mast cell activation. 150 88

Inflammatory mediators from intestinal mast cells may serve as initiators of acute and delayed inflammation. Mast cell histamine release was measured in 19 patients with inflammatory bowel diseases using gut mast cells from enzymatically dispersed endoscopic forceps biopsy specimens of macroscopically inflamed and normal tissue. Mast cells and corresponding basophils were challenged with anti-IgE, anti-IgG, subclass anti-IgG4, and formyl-methionyl-leucyl-phenylalanine (FMLP) and results were compared with those from nine patient control subjects. The mast cell count in patients with ulcerative colitis was increased compared with that in control subjects and patients with Crohn's disease, and the mast cell count obtained from inflamed tissue was greater than that of normal tissue. The study also shows the heterogeneity of the responsiveness of the histamine releasing cells to various secretagogues. Thus, mast cells released 0.4 (0.0-2.0) (median (range)) ng histamine per sample at anti-IgE challenge, and basophils were also anti-IgE responsive. In contrast, mast cells did not respond to FMLP but the corresponding basophils did. Gut mast cells released 0.3 (0.0-1.0) (median (range)) ng histamine per sample at anti-IgG4 challenge; however, the corresponding basophils did not respond to anti-IgG4. In addition, the anti-IgG4 mediated histamine release was primarily confined to patients with inflammatory bowel disease. This study substantiates previous histopathological findings that mast cells may play a functional role in the inflammatory process of inflammatory bowel diseases and provides evidence for a possible role of subclass IgG4 as a reaginic antibody.
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PMID:Histamine release from gut mast cells from patients with inflammatory bowel diseases. 169 60

Intestinal mast cells are thought to contribute to the mucosal inflammation in ulcerative colitis and Crohn's disease through release of inflammatory mediators. Since sulfasalazine and its metabolite 5-aminosalicylic acid are effective therapeutic agents in inflammatory bowel disease and have been shown to inhibit generation of inflammatory products in other cells, we examined the effect of these agents in vitro on human intestinal mast cell mediator release. Sulfasalazine (5 x 10(-4)-10(-3) M) was found to significantly enhance goat anti-human IgE-induced histamine release from intestinal mast cells, which is the same response as seen in human blood basophils, whereas its metabolite 5-aminosalicylic acid was an effective inhibitor of stimulated histamine release in both mast cells and basophils. 5-Aminosalicylic acid also inhibited production of prostaglandin D2 by the stimulated intestinal mast cells. Sulfasalazine alone, without immunologic stimulation, did not induce histamine release from mast cells or basophils, but the enhancement of ongoing mast cell activation by sulfasalazine may explain some cases of adverse reactions to the drug. The inhibition of mast cell histamine release and prostaglandin generation by 5-aminosalicylic acid demonstrates a potential therapeutic modality of this agent.
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PMID:Modulation of mediator release from human intestinal mast cells by sulfasalazine and 5-aminosalicylic acid. 170 70

Mast cell degranulation in the gut causes mucus secretion, mucosal edema, and increased gut permeability and may be responsible for some of the symptoms and signs of inflammatory bowel disease. We have used a novel monoclonal antibody (AAI) against tryptase expressed exclusively in the granules of mast cells to enumerate mast cells in rectal biopsies in order to study the effect of inflammatory bowel disease and drug treatment upon rectal mast cell numbers. Rectal mast cell numbers are significantly reduced in inflammatory bowel disease patients taking corticosteroids (mean 4.95 cells/mm2) when compared with control patients (10.1, P less than 0.001) and inflammatory bowel disease patients not taking corticosteroids (9.7, P less than 0.001 Wilcoxon rank sum test). The reduction in mast cell counts was independent of the degree of inflammation or architectural distortion. There was a negative correlation between the dose of corticosteroids and mast cell count (r = 0.53, P less than 0.05 Spearman rank correlation), and the mast cell count was reduced within a few days of treatment and remained low throughout steroid therapy. Mucosal mast cell depletion may be an important mechanism of action of corticosteroids in inflammatory bowel disease.
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PMID:Corticosteroid treatment reduces mast cell numbers in inflammatory bowel disease. 197 67

The gastrointestinal tract is a rich source of mast cells with an enormous surface area that permits a high degree of interaction between the mast cell and intestinal luminal contents. The active metabolic products of the mast cell influence gastrointestinal secretion, absorption, and motility through paracrine effects of local mast cell degranulation and also cause systemic effects through the release of cellular products into the blood stream. Systemic mastocytosis influences physiologic function through the systemic effects of mast cell products released from focal (e.g., bone marrow) or wide spread increases in mast cell number. Local gastrointestinal proliferation of mast cells in response to recognized (e.g., gluten in celiac sprue) or obscure stimuli can alter gastrointestinal function and induce systemic symptoms. Celiac sprue, inflammatory bowel disease, and non-ulcer dyspepsia are three examples of gastrointestinal diseases in which mast cells can be implicated in the pathophysiology of the symptoms.
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PMID:The role of the mast cell in clinical gastrointestinal disease with special reference to systemic mastocytosis. 200 61

The effect of sulphasalazine on two mast cell populations and human peripheral leukocytes is reported. Sulphasalazine inhibited histamine release from mouse and rat mast cells, but it caused a potentiation of secretion in human peripheral leukocytes. The drug alone did not induce histamine release when administered without an anaphylactic stimulus. The results are discussed in terms of a possible mode of action of sulphasalazine in the treatment of inflammatory bowel disease.
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PMID:Inhibition of IgE-mediated mast cell degranulation by sulphasalazine. 257 29

IgE production by peripheral blood lymphocytes (PBL) and rectal mucosal biopsies in vitro has been examined in patients with ulcerative colitis (UC) and Crohn's disease (CD). The degranulation of peripheral blood basophils to food antigens has also been investigated in these patients. Mitogen-induced IgE production was reduced in patients with UC, but enhanced in PBL cultures from patients with CD. Increased numbers of basophils degranulated in the presence of cows' milk in UC patients, but normal responses occurred in patients with CD. This evidence supports the suggested role of IgE-mediated mechanisms involving mast cell/basophil interactions in the pathogenesis of inflammatory bowel disease.
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PMID:In vitro IgE production by peripheral blood lymphocytes and rectal mucosal biopsies and antigen-induced basophil degranulation in patients with inflammatory bowel disease. 376 55


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