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)

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

Sudden reperfusion of the gut following prolonged ischemia can itself have more deleterious consequences than the ischemia alone. Studies of vasodilator factors influencing the increased flow on reperfusion are therefore of importance. In the present study, a possible role of histamine in the postischemic flow response was examined after a period of total segmental ischemia. The artery supplying the terminal ileum was occluded in anesthetized dogs. Ischemia of 30 min duration was followed by a 30 min reperfusion period (control postischemic flow response), and the arterial blood flow to the segment was measured. After the control postischemic flow response, one of the following drugs was administered intravenously: histamine H1-or H2-blockers (tripelennamine, .5 mg/kg, cimetidine, 10 mg/kg, ranitidine, 2 mg/kg), cromolyn (a mast cell stabilizer, 25 mg/kg), and aminoguanidine (a diamine oxidase blocker, 50 mg/kg). The 30 min ischemia-30 min reperfusion cycle was then repeated (test postischemic flow response). A 30 min mesenteric ischemia-reperfusion period is reproducible once without a significant change in its hemodynamic parameters. The duration and volume of the postischemic flow response were significantly decreased by cimetidine, ranitidine, or cromolyn, and were increased by aminoguanidine. Tripelennamine did not affect the postischemic vasodilator response. At the onset of reperfusion, a release of endogenous histamine occurs from the gut, originating mainly from mast cells. It is proposed that histamine participates in the postischemic flow response through the H2-receptors.
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PMID:Role of histamine in the intestinal flow response following mesenteric ischemia. 774 71

The goals of this study were to investigate the in vivo effects of intestinal ischemia-reperfusion on mucosal mast cells, and to evaluate the morphological changes induced by standardized arterial occlusion in anesthetized rats. Complete segmental ileal ischemia was maintained for 15, 30, or 60 min, and was followed by a 30 min reperfusion period. Intestinal biopsies taken at the end of ischemia and in the 30th min of reperfusion were evaluated by image analysis, and the rate of release of type II rat mast cell protease, a marker of mast cell exocytosis, was determined from the venous effluent of the segment. Electron microscopy revealed cytoplasmic vacuolization of the mast cells of the villi after the 15 min ischemia. Ischemia induced a continuous diminution of the mucosal thickness and a significant fall in the number of mast cells in the villi; with immunoperoxidase staining with a monoclonal antibody that recognizes the AD1 mast cell surface antigen, the decrease was 57, 49, and 66% in the 15, 30, and 60 min ischemia groups, respectively. In these groups, the mucosal type II mast cell protease concentration increased to 2.4-, 2.5-, and 3.6-fold, respectively, and a significant increase in plasma protease levels was observed on reperfusion. These results lead us to conclude that mucosal mast cells are very sensitive to intestinal ischemia, with the majority of mast cells in the ileal villi already involved in the response to ischemia after a short period of arterial occlusion.
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PMID:Response of mucosal mast cells to intestinal ischemia-reperfusion injury in the rat. 774 39

The objective of this study was to determine whether ischemia-reperfusion (I/R) of the small bowel activated mast cells and, if so, to determine whether this event contributed to granulocyte infiltration and mucosal barrier dysfunction. Autoperfused segments of the jejunum were exposed to 30 min of ischemia followed by 60 min of reperfusion. Epithelial permeability was assessed by the clearance of 51Cr-labeled EDTA from plasma to lumen. Plasma rat mast cell protease II (RMCP II) was measured and used as an index of mucosal mast cell degranulation, whereas myeloperoxidase (MPO) activity was used as an index of granulocyte infiltration. I/R caused a significant increase in plasma RMCP II levels, MPO activity, and epithelial permeability. The mucosal mast cell stabilizer doxantrazole prevented the I/R-induced increase in all three parameters. The connective tissue mast cell stabilizer ketotifen had no effect. To determine whether oxidants were involved in mast cell degranulation, some animals were pretreated with superoxide dismutase and catalase. This regimen completely abolished the I/R-induced rise in plasma RMCP II levels and attenuated mucosal MPO activity and epithelial permeability. Selective inhibitors of two mast cell-derived mediators, platelet-activating factor and histamine, did not attenuate the rise in epithelial permeability. These data suggest that oxidant-induced mucosal mast cell degranulation is a key event in the granulocyte infiltration and tissue dysfunction associated with reperfusion of the ischemic intestine.
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PMID:Mast cells contribute to ischemia-reperfusion-induced granulocyte infiltration and intestinal dysfunction. 807 30

Leukocyte-endothelial cell adhesion and an altered metabolism of endothelial cell-derived nitric oxide (NO) have been implicated in the microvascular dysfunction associated with ischemia/reperfusion (I/R). The objective of this study was to determine whether NO donors can attenuate the reperfusion-induced increase in venular albumin leakage via an effect on leukocyte-endothelial cell adhesion. Leukocyte adherence and emigration as well as albumin extravasation were monitored in single postcapillary venules in rat mesentery subjected to 20 minutes of ischemia followed by 30 minutes of reperfusion. This I/R protocol elicits significant leukocyte adherence and emigration as well as a profound albumin leakage response. Superfusion of the mesenteric microcirculation with the NO donors sodium nitroprusside, spermine-NO, and SIN1 significantly reduced the I/R-induced leukocyte adherence/emigration and albumin leakage in postcapillary venules, whereas neither spermine nor the NO synthase inhibitor NG-nitro-L-arginine methyl ester affected the I/R-induced responses. Platelet-leukocyte aggregation and mast cell degranulation were also observed in the postischemic mesentery, and the responses were also attenuated by the NO donors. Plasma nitrate/nitrite levels in the superior mesenteric vein were significantly reduced by I/R. The results of this study indicate that I/R-induced microvascular dysfunction (albumin leakage) is attenuated by NO and that the protective effect of NO donors may be related to their ability to reduce leukocyte-endothelial cell and leukocyte-platelet interactions and/or mast cell degranulation.
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PMID:Modulation of ischemia/reperfusion-induced microvascular dysfunction by nitric oxide. 811 46

The role of mast cells in pulmonary artery occlusion/reperfusion injury was examined. Lung tissue was obtained from dogs after left pulmonary artery occlusion for 48 h (n = 5) or after similar occlusion followed by 4 h of reperfusion (n = 11). By light microscopy and morphometry, the percentage of mast cells increased 2.4-fold (p < 0.05) in nonoccluded right lungs and 2.9-fold (p < 0.05) in occluded left lungs without reperfusion compared with that in control lungs. After reperfusion, the occluded left lung contained 1.8-fold (p < 0.05) as many mast cells as the nonoccluded right lung and 4.2-fold (p < 0.05) more than that in control lungs. Hydroxyurea did not significantly affect the number of mast cells observed in the right and left lungs after ischemia/reperfusion; 39.8% and 54.4% of the mast cells were degranulated in nonoccluded right lung and occluded left lung preparations, respectively, after left pulmonary artery ischemia/reperfusion (each, p < 0.05 compared with control lungs). The release of eicosanoids into the airways during ischemia/reperfusion injury was also examined. Thromboxane B2 and leukotriene B4 were markedly increased (each, p < 0.05 compared with that in control lungs) in bronchial lavage fluids from both nonoccluded and occluded lungs compared with sham-occluded lungs. Thus, mast cell recruitment and degranulation may play a role in lung ischemia/reperfusion injury.
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PMID:Lung mast cells increase in number and degranulate during pulmonary artery occlusion/reperfusion injury in dogs. 838 32

The amino acid L-glutamate is a neurotransmitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.
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PMID:The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. 863 2

To understand better the pathophysiology of random skin flaps, randomized skin flaps of human (3 cases) and guinea pig (53 cases) were investigated. Proximal (normal), proximomedial (viable), mediodistal (between viable and necrotic parts), and distal (necrosis) locations of the skin flaps were biopsied. Lipid peroxidase, hydrolytic enzymes of cytosol (Ca(2+)-dependent cysteine protease: calpain), and lysosome (acid phosphatase) of skin were used as markers. Measurements were taken of the flap blood flow; the numbers of capillaries, postcapillary venules, pericapillary arterioles, leukocytes, and mast cells per unit square of dermis. Apoptotic cells were identified by specific staining. Flaps were sampled at postoperative weeks 1 and 3 (human) and hours 1 and 6, and days 1 to 7 (guinea pig). The values for normal skin were regarded as the control. Obstruction (by leukocytes) of venous microvessels, rather than arterial microvessels, was the major cause of temporary hypoxia in the proximomedial location, constant hypoxia (venous stasis) in the mediodistal location, and ischemia in the distal location. Increases in the number of mast cells (mastocytosis) and microvessels (angiogenesis) were significant only in the viable parts of the flaps. This phenomenon and the rate of blood flow increased with time in viable locations (guinea pig). Epidermal necrosis, dermal fibrosis, and apoptosis were evident mostly in the mediodistal location. Elevated levels of leukocytes, lipid peroxidase, acid phosphatase, and calpain, combined with necrotic changes, were seen mostly in the distal skin location. There is a strong possibility that the following factors are involved: lipid piroxidation and hydrolysis in necrosis of the distal flap location after ischemia; constant hypoxia in fibrosis and apoptosis in the mediodistal location; and initial or temporary hypoxia in mastocytosis-induced angiogenesis in the viable location. The results presented here indicate that guidelines for further investigations include combined suppression of leukotaxis, lipid peroxidase, and hydrolysis, or the application of mast cell growth factors in an effort to salvage the flap maximally.
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PMID:Possible contributions of mastocytosis, apoptosis, and hydrolysis in pathophysiology of randomized skin flaps in humans and guinea pigs. 870 Sep 87

In this review we have summarized some of the evidence to support the view that mast cells play a critical role in leukocyte recruitment to sites of inflammation. Initially, data using a pharmacological tool, compound 48/80, which directly activates mast cells, is reviewed, demonstrating that this reagent can induce the multi-step recruitment of leukocytes (rolling, adhesion and emigration) to sites of inflammation. The adhesive mechanisms and pro-inflammatory mediators implicated in mast cell-induced leukocyte recruitment are discussed. Additionally, data are presented to implicate mast cells in delayed-type hypersensitivity reactions as they pertain to leukocyte recruitment. There is a growing body of evidence to suggest that mast cells also recruit leukocytes in IgE-independent leukocyte recruitment. Ischemia/reperfusion- and bacterial toxin- (Helicobacter pylori and Clostridium difficile) induced leukocyte recruitment is at least in part mast cell dependent. Future directions including preliminary work highlighting the role of nitric oxide as a modulator of mast cell function and subsequent leukocyte recruitment is also discussed.
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PMID:Leukocyte-endothelial cell interactions evoked by mast cells. 891 88

Preconditioning the heart with a short period of ischemia makes it resistant to infarction from a subsequent ischemic insult. We have proposed that preconditioning is triggered by the release of endogenous substances including adenosine which activate protein kinase C through receptormediated cell signaling pathways. However, it has also been proposed that the initial brief ischemia may result in mast cell degranulation without significant myocardial damage, making it less likely that the toxic granule contents could be released to irreversibly damage vulnerable myocardial cells during the subsequent prolonged ischemia. To study the role of mast cells in ischemic preconditioning (PC) isolated rabbit hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 31.9 +/- 2.6% of the risk zone. Preconditioning with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 5.6 +/- 6.1% (p < 0.01). When disodium cromoglycate (DSCG)(10 microM), a mast cell stabilizer, was infused shortly before the long ischemia it did protect the heart (12.8 +/- 2.9% infarction, p < 0.01 vs control) which supports the mast cell theory. However, a mast cell degranulating agent, compound 48/80 (24 mg/L), added to the perfusate prior to the 30 min ischemic period could not mimic PC (39.7 +/- 5.6% infarction). Mast cell granules are rich in histamine, and the latter was assayed in myocardium by immunoassay as a marker of intact granules. In homogenized left ventricle from normal rabbit hearts and those following a standard PC protocol of 5-min global ischemia/10-min reperfusion, histamine contents were 9.3 +/- 1.4 and 8.9 +/- 1.4 ng/g wet tissue, respectively. Compound 48/80 reduced histamine levels to 2.9 +/- 0.6 ng/g (p < 0.05 vs control). Although baseline histamine contents were 10-fold higher in rats, PC also had no effect, but compound 48/80 reduced content by 91%. Therefore, histamine tissue content and presumably mast cell granules were unaffected by a PC protocol which successfully protected ischemic myocardium, while pharmacological myocardial histamine depletion was not associated with protection. Hence, mast cells do not appear to be important in ischemic preconditioning. Although a mast cell stabilizer such as DSCG can protect ischemic myocardium, it may do so by one of its other properties, e.g., membrane stabilization.
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PMID:Mast cell degranulation does not contribute to ischemic preconditioning in isolated rabbit hearts. 899 31


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