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 physiology 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. 758 76

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

There is growing evidence that endogenous nitric oxide (NO) regulates mucosal barrier integrity under physiological conditions and counters the increase in mucosal permeability associated with acute pathophysiological states. The potential mechanisms of action for the protective effects of NO are discussed. These include maintenance of blood flow, inhibition of platelet and leukocyte adhesion and/or aggregation within the vasculature, modulation of mast cell reactivity, and scavenging of reactive oxygen metabolites such as superoxide. On the basis of the data presented, we conclude that both constitutive nitric oxide synthase (cNOS)-derived endogenous NO and exogenous NO (from NO donors) appear to reduce the sequelae of acute inflammation. The second section of this review summarizes the data germane to prolonged (chronic) inflammatory conditions associated with the overproduction of NO from the inducible form of NOS (iNOS). Some emphasis is placed on the role of NO in sepsis and inflammatory bowel disease (IBD), and data to suggest that NO, or more specifically a NO-derived mediator, is involved in these disorders are summarized. These studies are compared with recent publications suggesting that inhibition of NO synthesis with nonspecific inhibitors of NOS or selective iNOS inhibitors may not protect in models of sepsis or IBD. Overall, the review highlights the potential importance of the type of NOS enzyme involved in the particular inflammatory process being studied.
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PMID:A critical role for nitric oxide in intestinal barrier function and dysfunction. 877 63

The expression of a primary initiator of tumor angiogenic responses, vascular endothelial growth factor (VEGF), may be induced by nitric oxide (NO) in carcinoma cells. However, the net impact of NO on carcinogenesis remains unclear, because manipulation of NO levels has been shown to either stimulate or inhibit tumor growth. We have investigated the relationship between inducible NO synthase (NOS II), VEGF expression, and growth of B16-F1 melanoma over 14 days in wild-type (NOS II+/+) mice and in those in which the gene for NOS II has been deleted (NOS II-/-). B16-F1 tumor growth was measured as wet weight of the excised tissue. Tumor NOS II and VEGF localization were evaluated by immunohistochemistry, and VEGF mRNA levels were measured by Northern blot analysis. In NOS II+/+ mice inoculated with B16-F1 melanoma cells, macroscopic tumors were always observed at 14 days; however, 22% of NOS II-/- mice had no detectable tumor mass. Immunoreactive NOS II was detected in tumor cells of tumors grown in NOS II+/+ but not in NOS II-/- mice. Although immunoreactive VEGF was detected in the granules of tumor-associated mast cells from both NOS II+/+ and NOS II-/- mice, VEGF mRNA expression in tumors from NOS II-/- was half that in NOS II+/+ mice. Neither NOS II inhibition, exogenous NO, nor peroxynitrite influenced DNA synthesis in culture B16-F1 melanoma cells. The NO donor did not alter either VEGF mRNA levels or degranulation in cultures of the mast cell line RBL-2H3, but peroxynitrite increased both VEGF mRNA expression and degranulation. We conclude that host expression of NOS II contributes to induction of NOS II in the tumor and to melanoma growth in vivo, possibly by regulating the amount and availability of VEGF.
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PMID:Nitric oxide synthase II gene disruption: implications for tumor growth and vascular endothelial growth factor production. 1130 6

We examined the presence of estrogen receptors (ER) in vascular mast cells and a possible genomic effect of estrogens on the expression of mast cell (MC) mediators such as chymase, TNF alpha, NOS and IL-10, which are known to affect the course of atherosclerosis. Immunocytochemical detection of mast cell tryptase and the co-localization of ERs in MCs from abdominal aortic vessels from 10 fertile woman, 10 postmenopausal women and 15 men was performed. The genomic expression of IL-10, TNF alpha, and NOS was analyzed by RT-PCR and chymase activity by spectrophotometry after 24 h incubation with 17-beta estradiol (0.2-0.5 ng/mL) in rat purified peritoneal MCs. A similar number of MCs were found in both intima and adventitia layers from men, and fertile and postmenopausal women, while ERs were detected only in the arterial walls from fertile women. The mRNA expressions of IL-10 and TNF alpha, as well as chymase activity, were not affected. A moderate increment of NO and both NOS, and a reduction in TNF alpha cytotoxicity was observed after incubating peritoneal MCs with 17-beta estradiol at a concentration of 0.5 ng/mL. Taken together, these results indicate that vascular MCs express ERs. The data demonstrate that estrogens can directly modify vascular MC activity. This is a novel mechanism of synergistic cooperation for the protective role of estrogens in the genesis of atherosclerosis.
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PMID:Estrogen receptors in mast cells from arterial walls. 1205 78

Nitric oxide (NO) plays diverse roles in physiological and pathological processes. During immune and inflammatory responses, for example in asthma, NO is generated at relatively high and sustained levels by the inducible form of nitric oxide synthase (NOS-2). NOS-2 derived NO regulates the function, growth, death and survival of many immune and inflammatory cell types. In the case of mast cells, NO suppresses antigen-induced degranulation, mediator release, and cytokine expression. The action of NO on mast cells is time dependent, requiring several hours, and noncGMP mediated, most probably involving chemical modification of proteins. NO inhibits a number of mast cell-dependent inflammatory processes in vivo, including histamine mediated vasodilatation, vasopermeation and leucocyte-endothelial cell attachment. In human asthma and animal models of lung inflammation the role of NO is harder to define. However, although there are conflicting data, the balance of evidence favours a predominantly protective role for NO. Mimicking or targeting NO dependent pathways may prove to be a valuable therapeutic approach to mast cell mediated diseases.
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PMID:Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation. 1210 16

NO is generated by NOS activity and known to act as a negative regulator of mast cell activation. We reported previously that Ag (I) directly evokes mast cell degranulation and LTC(4) release via Ca(2+) influx through thiol-sensitive, store-independent channels. Here, we report that NO generated independently of NOS activity mediates the store-independent Ca(2+) influx. Exposure of mast cells to Ag (I) resulted in increased intracellular NO levels and NO(2)(-)/NO(3)(-) contents in the extracellular fluid. The NO increase was blocked by NO scavenger Hb and DTT but not by NOS inhibitors such as amino-BH(4) and L-NAME. This NO production occurred independently of the Src family kinase and PI3K activities, both of which were necessary for antigen-induced, NOS-dependent NO production. Hb and DTT reduced Ag (I)-induced beta-hexosaminidase release and LTC(4) release, whereas the NO scavengers and NOS inhibitors augmented antigen-induced mediator release. Moreover, Hb and DTT, but not the NOS inhibitors, abolished the Ag (I)-induced Ca(2+) influx, and none of the drugs blocked CRAC channel activity. Finally, Ag (I)-induced Ca(2+) influx was distinct from LTCC activity in terms of its sensitivities to wortmannin and LTCC antagonists and the effects of Ca(v)1.2 LTCC gene silencing. These data show that NOS-independent NO regulates mast cell activation positively via a unique store-independent Ca(2+) influx pathway. The present findings suggest multiple sources and functions of NO in mast cell biology.
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PMID:Nitric Oxide positively regulates Ag (I)-induced Ca(2+) influx and mast cell activation: role of a Nitric Oxide Synthase-independent pathway. 1970 39

Autism Spectrum Disorders (ASD) are diagnosed in early childhood and include Autism, Asperger's disorder and Pervasive neurodevelopmental disorder--not otherwise specified (PDD-NOS, or atypical autism). ASD are associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors, as well as attention and learning disabilities. Most ASD patients also have food intolerance and other allergic symptomatology indicative of mast cell activation. The number of ASD cases have increased over the last decade to 1/100, but there is no definite pathogenesis or curative therapy. We report that the apparent prevalence of ASD in patients with mastocytosis, a rare disease occurring in 1/4,000 children and characterized by an increased number of hypersensitive mast cells in many organs, is about 1/10 or 10 times higher than the general population. A child with skin mastocytosis (urticaria pigmentosa), and regressive autism is presented to illustrate the point. Allergic, infectious, neuroimmune and environmental triggers may activate mast cells to release vasoactive, inflammatory and neurotoxic molecules. These could disrupt the gut-blood-brain-barriers, and/or activate susceptibility genes, thus contributing to brain inflammation and ASD.
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PMID:Autism spectrum disorders and mastocytosis. 2007 49

In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K(+) was observed in mesenteric arteries of wild-type and COX-2(-/-) mice but it was significantly diminished in preparations from endothelial NOS (eNOS)(-/-) mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2(-/-) mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS(-/-) mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10(-6) mol/l) or the TP-receptor antagonist S18886 (10(-7) mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS(-/-) mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine.
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PMID:Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse. 2339 53

Chronic NG-nitro-l-arginine methyl ester (L-NAME) administration induces cardiac hypertrophy in rodent models. Our aims is to determine the role of c-kit expression in L-NAME induced cardiac hypertrophy. 12-20 week old C57BL/6J mice (5 per group) were administered L-NAME (0.325mg/ml) in the drinking water. Hearts were excised at 1-day, 2-days, 5-days, 2-weeks or 6-weeks; or controls which received no L-NAME. Ventricular cross-sectional wall thickness and individual cardiac myocytes cross-sectional area and cardiomyocyte/nuclear ratio to determine cardiac hypertrophy. Immuno-histochemical staining for c-kit, sca-1 and BCRP undertaken. Six weeks L-NAME administration induced significant cardiac hypertrophy compared to control hearts, evidenced by an increase in the thickness of the cross-sectional free ventricular wall (p<0.05) and an increase in mean individual cross-sectional area of cardiac myocytes in the LV wall (p<0.007). We observed c-kit(+) cells (predominately non-mast cell sub-types) in both healthy mice and in the L-NAME treated mice. C-kit staining in the left ventricular cross sections following L-NAME remained stable at 1 and 2 days compared to controls (p=NS). After 5 days of L-NAME we observed c-kit expression to decrease below control levels (p<0.05) and these lower levels were sustained at 2 and 6 weeks. C-kit expression does not decrease during two days of L-NAME administration, suggesting, firstly, that the later decrease in c-kit is not due to NOS inhibition directly and, secondly, there is the possibility for c-kit(+) cell differentiation into other cell types, possibly inducing myocardial cellular hyperplasia, without significant replacement of the original pool of c-kit(+) cells.
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PMID:Chronic NG-nitro-l-arginine methyl ester (L-NAME) administration in C57BL/6J mice induces a sustained decrease in c-kit positive cells during development of cardiac hypertrophy. 2438 87


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