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)

Eosinophilic colitis is a rare entity of unknown etiology characterized by diarrhea, abdominal pain, and gastrointestinal bleeding. Diagnosis includes histopathological infiltration of more than 20 eosinophils in colon. It is frequently associated with milk hypersensitivity and, less usual, with other foods and increased IgE. Histopthological appearance of eosinophil mediators has been observed in the gut. It is sometimes related to the degree of infiltration of eosinophils in the gut as well as to the disease severity. There is not an established treatment for this entity, although systemic steroids have been used with certain efficacy. However, there is a recurrence of the symptoms when the therapy stops, besides the well known side effects of the long-term use of steroids. Cromolyn inhibits mast cell degranulation and prevents liberation of mediators. It is successful in certain cases, specially the severe ones. However, it is not available for its use in our country. Ketotifen, as last resource in our patients with bad response to habitual treatment and restriction diet, was used. Although its use is controversial, we consider that stabilizing mast cell membrane with subsequent inhibition of degranulation and recruitment of eosinophils to sites of inflammation, would also restrain histamine liberation and blockage of H1 receptors, which would diminish local damage induced by eosinophils. Nonetheless ketotifen mechanism of action is unknown, our patients improved after treatment with this drug.
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PMID:[Eosinophilic colitis. A report of two cases with non conventional treatment]. 1579 16

RX 77368 (RX) increases gastric mucosal blood flow by a vagal cholinergic mechanism. The relative roles of mucosal and connective tissue mast cells (MMC and CTMC) were investigated in RX-injected rats. Blood flow and mast cell degranulation were measured after intracisternal RX. RX significantly increased gastric mucosal blood flow, and sequentially degranulated CTMC and MMC. Ketotifen or doxantrazole inhibited the hyperemic response. Ondansetron, RS-039604-90, or famotidine, but not ketanserin or pyrilamine, reduced hyperemia. Mast cells mediate RX-induced gastric hyperemia via 5-HT3, 5-HT4, and H2 receptors; initial increase depends upon CTMC whereas MMC contributes to the later response.
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PMID:Role of gastric mast cells in the regulation of central TRH analog-induced hyperemia in rats. 1611 96

Ketotifen is a mast cell stabilizer and useful in younger children with allergic diseases such as asthma and allergic rhinitis. Macrophage-derived chemokine (MDC) is a T-helper cell type 2 (Th2)-related chemokine involved in recruitment of Th2 cells toward allergen-challenged inflammation. However, the Th1-related chemokines, interferon-inducible protein 10 (IP-10)/CXCL10, and the monokine induced by interferon-gamma (MIG)/CXCL9 are also important in allergen-induced asthma in animal models. We investigated the effects of ketotifen on the expression of Th1- and Th2-related chemokines of human monocytes in vitro and ex vivo. Ketotifen (5-50 microM) significantly down-regulated lipopolysaccharide (LPS)-induced MDC, MIG and IP-10 (p < 0.05, each comparison) in THP-1 cells and human primary monocytes in a dose-dependent manner. SB203580 [p38-mitogen-activated protein kinase (MAPK) inhibitor] suppressed LPS-induced MDC and IP-10 expression, and PD98059 (ERK-MAPK inhibitor) could only suppress LPS-induced IP-10, but not MDC expression. LPS-induced pp38 and p-ERK expression of THP-1 monocytic cells was suppressed by ketotifen. These data demonstrate that ketotifen is effective in down-regulating LPS-induced MDC, MIG and IP-10, which play important roles in the pathogenesis of airway inflammation. The suppressive effect on MDC and IP-10 may, at least in part, involve the down-regulation of LPS-induced p38 and ERK-MAPK expression.
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PMID:Suppressive effects of ketotifen on Th1- and Th2-related chemokines of monocytes. 1761 6

Because degranulation of brain mast cells activates adrenocortical secretion (41, 42), we examined whether activation of such cells increases renin and vasopressin (antidiuretic hormone: ADH) secretion. For this, we administered compound 48/80 (C48/80), which liberates histamine from mast cells, to pentobarbital-anesthetized dogs. An infusion of 37.5 microg/kg C48/80 into the cerebral third ventricle evoked increases in plasma renin activity (PRA), and in plasma epinephrine (Epi) and ADH concentrations. Ketotifen (mast cell-stabilizing drug; given orally for 1 wk before the experiment) significantly reduced the C48/80-induced increases in PRA, Epi, and ADH. Resection of the bilateral splanchnic nerves (SPX) below the diaphragm completely prevented the C48/80-induced increases in PRA and Epi, but potentiated the C48/80-induced increase in ADH and elevated the plasma Epi level before and after C48/80 challenge. No significant changes in mean arterial blood pressure, heart rate, concentrations of plasma electrolytes (Na+, K+, and Cl-), or plasma osmolality were observed after C48/80 challenge in dogs with or without SPX. Pyrilamine maleate (H1 histaminergic-receptor antagonist) significantly reduced the C48/80-induced increase in PRA when given intracerebroventricularly, but not when given intravenously. In contrast, metiamide (H2 histaminergic-receptor antagonist) given intracerebroventricularly significantly potentiated the C48/80-induced PRA increase. A small dose of histamine (5 microg/kg) administered intracerebroventricularly increased PRA twofold and ADH fourfold (vs. their basal level). These results suggest that in dogs, endogenous histamine liberated from brain mast cells may increase renin and Epi secretion (via the sympathetic outflow) and ADH secretion (via the central nervous system).
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PMID:Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs. 1818 67

This study was designed to investigate the cardioprotective effects of pharmacological interventions, modulating resident cardiac mast cells, on ischemia-reperfusion-induced injury. Isolated rat hearts were mounted on Langendorff apparatus and subjected to 30-min global ischemia followed by 120-min reperfusion. The extent of mast cell degranulation was assessed by release of mast cell peroxidase (MPO). The release of lactate dehydrogenase (LDH) and creatine kinase (CK) and estimation of infarct size were used to assess the extent of myocardial injury. Left ventricle developed pressure (LVDP) and its derivatives, that is, dp/dt(max) and dp/dt(min), were recorded to evaluate the postischemic recovery of the contractility of heart. Ketotifen (0.1 microM) and low-dose carvedilol (0.1 microM), without beta-blockade activity, attenuated ischemia-reperfusion-induced mast cell degranulation along with the reduction in myocardial injury, suggesting the protective effects of mast cell stabilization during ischemia and reperfusion. Administration of compound 48/80 (1 microg/ml), a specific mast cell degranulating agent, completely degranulated cardiac mast cells before global ischemia. Moreover, it also resulted in the attenuation of ischemia-reperfusion-induced myocardial injury. Decreased release of cytotoxic mediators from already degranulated (empty) mast cells during sustained global ischemia may be responsible for the cardioprotective effects of compound 48/80. Administration of carvedilol or ketotifen after compound 48/80 perfusion did not further enhance the cardioprotective effects, suggesting that the cardiac mast cells may be the common target site for ketotifen, compound 48/80 and low-dose carvedilol.
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PMID:Cardioprotective effects of mast cell modulators in ischemia-reperfusion-induced injury in rats. 1819 10

Skin wound healing in Yorkshire pigs closely approximates human wound healing. Conversely, red Duroc pigs form fibroproliferative, hypercontractile scars. As mast cells have been implicated in several fibrotic conditions, the present study used these models to evaluate the potential role of mast cells in wound contraction and fibrosis. Immediately following the creation of full-thickness excisional wounds, the mast cell stabilizer ketotifen was used to treat both Yorkshire and red Durocs. Control red Durocs showed significantly more wound contraction than Yorkshires, both before and after reepithelialization. Ketotifen treatment significantly reduced the first phase of contraction in red Duroc wounds to a level equivalent to Yorkshire wounds, but had no detectable effect on the postepithelialization phase of contraction. Cessation of drug treatment after 10 weeks did not lead to resumption of excessive contraction in red Durocs, indicating that ketotifen blocked rather than delayed such contraction during a critical phase of healing. Ketotifen treatment also reduced the deposition of collagen within the red Duroc wounds, but did not affect Yorkshire wound contraction or collagen deposition. These results suggest that ketotifen may be an effective treatment for the reduction of excessive wound contraction and fibrosis in human cutaneous injuries, without affecting the normal healing process.
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PMID:The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs. 1831 8

Eosinophils play a major role in the development and severity of asthma. Robust and rapid preclinical animal models are desirable to profile novel therapeutics inhibiting the influx of eosinophils into the airways. To develop a rapid, airway eosinophil recruitment model in the rat, Brown-Norway (BN) rats were immunised with ovalbumin (OVA)/alum on day 0, 1 and 2 and challenged with OVA aerosol on day 5 and 6. On day 7 bronchoalveolar lavage fluid (BALF) was analysed for eosinophil numbers, eosinophil peroxidase (EPO) activity and cytokines. Lung sections were also examined. The immunised animals showed a strong selective influx of eosinophils into the airways correlating with enhanced EPO activity, Interleukin (IL-4), IL-5 and monocytes chemo attractant protein levels in the BALF in comparison to sham-sensitised rats. In addition the immunised rats developed goblet cell metaplasia in the lung and showed OVA specific IgG1 and IgE levels in the serum but no airway hyperreactivity after metacholine challenge. Airway inflammation was suppressed by applying the steroids Budesonide (intra tracheally) and Prednisolone (per orally), Roflumilast a phosphodiesterase-4 inhibitor, and the H1 receptor antagonists Epinastine and Ketotifen. Montelukast, a Leukotriene receptor antagonist and Chromoglycate, a mast cell stabiliser, had no effect in this model. In summary, in this novel preclinical rat model therapeutics expected to inhibit the development of airway eosinophilia can rapidly be tested.
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PMID:Development and characterisation of a novel and rapid lung eosinophil influx model in the rat. 1849 Jan 84

We previously demonstrated that oral chronic exposure to ovalbumin (OVA) causes intestinal hypermotility in Sprague-Dawley rats. In this study, the objective was to determine the mechanism of action of OVA and the role of mucosal mast cells in the regulation of motor activity in this model. Rats were orally exposed to OVA during 6 weeks. Intestinal mucosal mast cells (IMMCs) were counted and rat mast cell protease II (RMCPII) measured in duodenum, jejunum, ileum and colon. Anti-OVA IgE, IgG, and IL-4 were measured in serum. Eosinophils and IgE(+) cells were counted in jejunum. In an additional study rats were treated with the mast cell stabilizer ketotifen and mast cell number, RMCPII concentration and motor activity in vitro were evaluated. OVA exposed rats showed an increase in mucosal mast cell number and in RMCPII content in small intestine and colon. However, variables of a Th(2) type response were not affected by exposure to OVA: (i) neither OVA specific IgE nor IgG were found; (ii) IL-4 did not increase and, (iii) the number of eosinophils and IgE(+) cells was identical in the exposed and unexposed groups. These results brought us to hypothesize a possible non-Ig-mediated action of OVA on mast cells. Ketotifen significantly diminished the response to OVA: Ketotifen reduced the number of mast cells and the RMCPII content and blocked increased intestinal contractility. In addition ketotifen modified motor response in both OVA exposed and unexposed animals giving evidence of the importance of mast cells in intestine motor activity driving.
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PMID:Mucosal mast cells mediate motor response induced by chronic oral exposure to ovalbumin in the rat gastrointestinal tract. 1968 67

Rats were intraperitoneally treated once with compound 48/80 (C48/80), a mast cell degranulator, (0.75 mg/kg). Serum serotonin, histamine and corticosterone levels increased 0.5 h after C48/80 treatment, but their increases were reduced thereafter. Adrenal total ascorbic acid (ascorbic acid plus dehydroascorbic acid), ascorbic acid and dehydroascorbic acid levels decreased 0.5, 3 or 6 h after C48/80 treatment, adrenal lipid peroxide level increased at 3 and 6 h, adrenal non-protein-SH level decreased at 3 and 6 h and adrenal beta-tocopherol level decreased at 3 h. Ketotifen, a mast cell stabilizer (1 mg/kg) administered intraperitoneally at 0.5 h before C48/80 treatment, attenuated all these changes found in the serum and adrenal at 3 h after treatment, while beta-tocopherol (250 mg/kg), administered orally at 0.5 h after C48/80 treatment, attenuated all these changes in the adrenal tissue. These results indicate that C48/80 causes oxidative stress in rat adrenal gland through mast cell degranulation.
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PMID:Compound 48/80 causes oxidative stress in the adrenal gland of rats through mast cell degranulation. 1988 53

Mast cells are essential in allergic responses and beyond. White adipose tissue from obese humans contains large numbers of mast cells. Serum mast cell tryptase levels are also significantly higher in obese subjects than in lean subjects, suggesting a role of these inflammatory cells in obesity and diabetes. Two types of mast cell-deficient mice, along with corresponding wild-type control mice, were fed a Western diet to induce obesity and diabetes. We also used two anti-allergy drugs, cromolyn and ketotifen (Zaditor), to treat wild-type mice during intake of a Western diet or after the onset of obesity and diabetes, to examine the possible prevention or reversal of these conditions. Mast cell deficiency or pharmacological stabilization reduced body weight gain and improved glucose and insulin sensitivities. These common, side effect-free drugs also reduced pre-established obesity and diabetes without noticeable toxicity. Mechanistic studies suggest that mast cells participate in these metabolic disorders by affecting energy expenditure, protease expression, angiogenesis, apoptosis, and preadipocyte differentiation. These observations open a new era of basic research regarding mast cells, and offer hope to patients suffering from these metabolic disorders.
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PMID:Mast cell stabilization: novel medication for obesity and diabetes. 2206 85


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