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)

Cromolyn is a prototype of a new series of drugs, the pharmacologic activities of which may offer an entirely new approach in the treatment of asthma. Whereas bronchodilator drugs and steroids act primarily at tissue sites to counteract the effects of various toxic mediators released from tissue mast cells, cromolyn prevents the release of such mediators from mast cell membranes. The advent of cromolyn sodium therapy has been recognized as a significant advance by the pharmaceutical industry, which is rapidly developing a series of cromolyn-like drugs with similar properties. Many of these compounds are active orally, and some preliminary investigations suggest that they also could be clinically effective. Cromolyn has therapeutic value in immunologic and nonimmunologically induced bronchospasm, being particularly suited for conditions amenable to long-term prophylactic therapy. The risk-to-benefit ratio of cromolyn sodium therapy is excellent. Cromolyn sodium is an important adjunct in the treatment of asthma. By topical administration the drug has been effective in seasonal and perennial rhinoconjunctivitis and in selected cases of gastrointestinal allergy to foods.
 ...
PMID:Therapy with cromolyn sodium. 9 84

Cromolyn pretreatment frequently reduces antigen inhalation-induced bronchospasm possibly by inhibiting mast cell degranulation and mediator release. However, the local effects of cromolyn on type I hypersensitivity skin reactions are not well understood. We studied the effect of local cromolyn on antigen-induced skin reaction, histamine release, cellular inflammatory response, and ultramicroscopic changes of mast cells in 10 ragweed-sensitized subjects. Results showed that cromolyn 2% (nonirritant dose) does not modulate ragweed-induced skin whealing response, histamine release, and ultramicroscopic changes of mast cells. Thus, unlike the situation in the tracheobronchial tree, allergic skin reactions and associated events are not inhibited by local cromolyn application.
 ...
PMID:Cromolyn does not modulate human allergic skin reactions in vivo. 618 53

Morphine and muscle relaxants are classical mast cell activators and cromolyn is a mast cell inhibitor. However, the mechanisms underlying the effects of these drugs are obscure. We asked the question whether morphine and muscle relaxants may activate heterotrimeric guanine nucleotide-binding proteins (G-proteins), and whether cromolyn may prevent this activation. Morphine activated Gi-proteins in HL-60 membranes and purified transducin (TD) at concentrations above 1 mM, but the effects on morphine did not reach saturation up to 10 mM. d-Tubocurarine activated Gi-proteins and TD in a saturable manner, with EC50 values of 0.3 mM and 4.2 mM, respectively. Gallamine and succinylcholine were less effective activators of TD than d-tubocurarine, Morphine and d-tubocurarine were about similarly effective activators of Gi-proteins, whereas d-tubocurarine was a more effective activator of TD than morphine. Cromolyn at 10 microM and 100 microM had little effect on TD activity but reduced the stimulatory effect of morphine by 50% and 80%, respectively. Our data suggest the following: (1) Receptor-independent G-protein activation by morphine and muscle relaxants presumably accounts for their mast cell-activating properties. (2) Cromolyn may act by preventing G-protein activation. (3) The variability in responsiveness of mast cells towards morphine and muscle relaxants could be due to differential expression of G-proteins with different sensitivity to activation by these drugs.
 ...
PMID:Morphine and muscle relaxants are receptor-independent G-protein activators and cromolyn is an inhibitor of stimulated G-protein activity. 908 43

The objective of this study was to investigate the significance of mast cell-induced reactions in the mucosal functional and morphological alterations induced by 30 min segmental ischemia and 120 min reperfusion in anesthetized dogs. The rates of changes in permeability of the mucosa to sodium fluorescein (NaFL) in the plasma-to-lumen and lumen-to-plasma directions were studied, the local hemodynamics, intramucosal pH (pHi) alterations, mast cell number and degranulation, and degree of tissue injury were determined. The effects of pretreatments with cromolyn (a peritoneal-type mast cell stabilizer), quercetin (a mucosal-type mast cell stabilizer), and dexamethasone (an aspecific membrane stabilizer and mast cell depleter) were evaluated. We found that ischemia-reperfusion induced significant tissue injury, elevated the segmental vascular resistance, and decreased pHi. The plasma-to-lumen clearance of NaFL increased significantly during ischemia and reperfusion. Cromolyn and quercetin pretreatments significantly inhibited the permeability changes, but did not influence the pHi and morphological alterations induced by ischemia-reperfusion. Dexamethasone pretreatment did not influence the number of mast cells, but the degree of mast cell degranulation and fluorescein leakage decreased. We conclude that intestinal mast cells and mast cell-induced reactions contribute to the mucosal permeability alterations during reperfusion, but play only a minor role in ischemia-reperfusion-induced structural injury.
 ...
PMID:The role of mast cells in mucosal permeability changes during ischemia-reperfusion injury of the small intestine. 932 30

The objective of this study was to investigate the role of intestinal mast cells in mucosal functional and morphological alterations induced by 30 min segmental ischemia and 120 min reperfusion in anesthetized dogs. The time course of permeability changes of the mucosa to sodium fluorescein (NaFl) in blood-lumen and lumen-blood directions was studied in two separate series of experiments. Local hemodynamics, intramucosal pH (pHi) alterations, mast cell number and degranulation and the degree of tissue injury were determined. The effects of cromolyn (peritoneal-type mast cell stabilizer), quercetin (mucosal-type mast cell stabilizer), and dexamethasone (aspecific membrane stabilizer and mast cell depleter) pretreatments were evaluated. Ischemia-reperfusion induced significant tissue injury, elevated segmental vascular resistance, and decreased pHi. The blood to lumen clearance of NaFl increased significantly during ischemia and reperfusion. Cromolyn and quercetin pretreatment significantly inhibited permeability changes, but did not influence pHi and morphological alterations induced by ischemia-reperfusion. Dexamethasone pretreatment did not influence the number of mast cells, however, the degree of mast cell degranulation and the degree of mucosal damage decreased. These results demonstrate that mast cells or mast cell-induced reactions contribute to the mucosal permeability alterations and barrier lesions during reperfusion, but play a minor role in reperfusion-induced structural injury.
 ...
PMID:Mucosal permeability changes during intestinal reperfusion injury. The role of mast cells. 940 93

The objective of this study was to characterize the role of mast cells in the development of vasculitis and joint swelling in adjuvant-immunized rats. Leukocyte trafficking within mesenteric venules (rolling and adhesion) and mast cell activation (ruthenium red uptake) were examined in vivo. Elevated leukocyte trafficking was observed by 4 days after immunization, whereas joint swelling developed between days 10 and 12. Perivascular mast cells took up ruthenium red and appeared activated by electron microscopy at 4 but not 12 days after immunization. Treatment with the mast cell stabilizer cromolyn on days 1 to 4 after immunization blocked ruthenium red uptake at day 4 and reduced leukocyte rolling and adhesion by approximately 50%. This treatment also reduced rolling, adhesion, and joint swelling at day 12 by approximately 50%. Cromolyn treatment over days 9 to 12 reduced joint swelling but increased leukocyte emigration into the mesentery. Peritoneal mast cells isolated 4 days after immunization elicited significant neutrophil chemotaxis in vitro, whereas day 12 mast cells did not. Mast cell activation and vasculitis were absent in adjuvant-resistant Fisher/344 rats. These data suggest that mast cells play an early role in the initiation of vasculitis and may function by day 12 to limit infiltration of leukocytes from the vasculature. In the joint, however, mast cells appear to contribute to inflammation at early as well as later time points.
 ...
PMID:A role for mast cells in the development of adjuvant-induced vasculitis and arthritis. 946 82

Disodium cromoglycate (cromolyn) is a well documented inhibitor of immunologically-induced histamine release from rat peritoneal mast cells and has been shown to stimulate the phosphorylation of a mast cell protein of apparent molecular mass 78,000 Da (78 kDa), an event which may be involved in terminating secretion. Here we aimed to determine the role of the ubiquitous enzyme, protein kinase C, in the phosphorylating activity of cromolyn by examining the effects of phorbol esters (activators of protein kinase C) on protein phosphorylation in [32P]orthophosphate loaded rat peritoneal mast cells. Protein kinase C-activating phorbol esters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA) and 4beta-phorbol 12,13-dibutyrate (PdBu) were found to potently inhibit cromolyn-induced phosphorylation when added to mast cells simultaneously with cromolyn (IC50 22 and 79 nM respectively). 4Alpha-phorbol 12,13-didecanoate (PdD), a phorbol ester which does not activate protein kinase C, had no effect on cromolyn-induced phosphorylation. Addition of TPA to mast cells previously exposed to cromolyn for 60 sec (i.e. when 78-kDa protein phosphorylation is maximal) also caused a very rapid dephosphorylation of the 78-kDa protein. Phosphorylation of the 78-kDa protein can also be induced by dibutyryl cyclic GMP and this action was similarly inhibited by TPA and PdBu. Cromolyn inhibited secretion induced by anti-IgE, but not by TPA, and thus inhibition of secretion by cromolyn is further correlated to its phosphorylation of the 78-kDa protein. The data suggest that the inhibitory action of cromolyn on mast cell secretion and phosphorylation of the 78-kDa protein are not mediated through a phorbol ester-sensitive protein kinase C, but more likely that such an enzyme could be involved in regulating dephosphorylation of the 78-kDa protein. Further explanations for this novel dephosphorylating activity of phorbol esters are discussed.
 ...
PMID:Inhibition of cromolyn-induced phosphorylation of a 78-kDa protein by phorbol esters in rat peritoneal mast cells. 951 69

Disodium cromoglycate (cromolyn) inhibits mast cell secretion, but its mechanism has not been elucidated. One possibility is the phosphorylation of a 78-kDa mast cell protein, two fragments of which are homologous to moesin, a member of the ezrin, radixin, moesin family. These proteins appear to be involved in signal transduction by regulating functional associations between the cell surface and the cytoskeleton. Moesin cDNA was cloned from rat basophil leukemia cells, which are similar to mucosal mast cells, and polyclonal antiserum was prepared against recombinant moesin expressed in Escherichia coli. Moesin phosphorylated in mast cells treated with cromolyn shifted from the soluble to the precipitable fraction and associated with Sepharose-linked beta-actin. Recombinant moesin also associated with Sepharose-linked beta-actin, and so did purified RBL moesin, but only if the latter was first denatured. Moesin thus appears to have actin binding sites that are not exposed under normal conditions but may become available by in vivo phosphorylation or by denaturation. Immunocytochemistry using confocal microscopy showed moesin to be primarily localized on the inner aspect of the plasma membrane and around secretory granules. Double immunocytochemistry for moesin and actin colocalized them in most areas. Ultracryoimmunoelectron microscopy to preserve the antigenicity of moesin identified the protein close to the plasma and secretory granule membranes. Cromolyn appeared to induce clustering of moesin around secretory granules. It is hypothesized that conformational changes of moesin, regulated by phosphorylation/dephosphorylation, may lead to positional rearrangements with respect to the membrane/cytoskeleton that could possibly regulate mast cell secretion.
 ...
PMID:Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell "stabilizer" cromolyn. 1094 28

Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1beta. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course.
 ...
PMID:Role of mast cells in zymosan-induced peritoneal inflammation in Balb/c and mast cell-deficient WBB6F1 mice. 1120 65

The objectives of this study were to investigate the temporal response of left ventricular (LV) matrix metalloproteinase (MMP) activity and collagen volume fraction (CVF) induced by an aortocaval fistula and the role of cardiac mast cells in regulating MMP activity. LV tissue was analyzed for MMP activity, CVF, and mast cell number in rats euthanized at 0.5, 1, 2, 3, 5, 14, 21, 35, and 56 days. Additional rats treated with the mast cell membrane-stabilizing drug cromolyn sodium were euthanized 1, 2, and 3 days postfistula. Marked increases in MMP activity occurred rapidly and remained significantly elevated for 5 days before returning toward normal. A significant decrease in CVF occurred by day 5, but thereafter CVF rebounded to normal or above normal values. The number of myocardial mast cells also significantly increased postfistula, and there was a close association between mast cell density and MMP activity. Cromolyn treatment prevented the increase in mast cell number and MMP activity. Thus it is concluded that cardiac mast cells play a major role in the regulation of MMP activity.
 ...
PMID:Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity. 1212 96


1 2 3 Next >>