UNIPROT:P15088 - FACTA Search

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Query: UNIPROT:P15088 (mast cell)
14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell. There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H1 receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD. To date, four subtypes (A1, A2A, A2B, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD. This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.
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PMID:Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease. 1472 64

The mechanism(s) of bradykinin-induced bronchoconstriction was investigated in the Brown Norway (BN) rat model of allergic asthma. Bronchoconstrictor responses to i.v. bradykinin in BN rats were maximally augmented 24 h following challenge with allergen and declined at later time points. Histological evaluation of the inflammatory status of the lungs after ovalbumin (OA) challenge showed a marked inflammatory response, which was maximal at 24 h and declined thereafter. However, pretreatment with budesonide did not inhibit the augmented bronchoconstrictor response to bradykinin 24 h after allergen challenge. The selective B1 receptor agonist, Lys-[desArg9]-BK had no bronchoconstrictor effects, whereas the selective B2 receptor antagonist, HOE 140, abolished the response to bradykinin in OA-challenged animals. The augmented response to bradykinin was not affected by methysergide, indomethacin, disodium cromoglycate, iralukast, the 5-lipoxygenase inhibitor, CGS8515, or the NK2 receptor antagonist, SR48968. It was, however, partially inhibited by atropine both in saline- and OA-challenged animals. Pretreatment with captopril and thiorphan markedly potentiated responses to bradykinin both in saline- and OA-challenged animals. Thus, augmentation of the bronchoconstrictor response to bradykinin occurs in actively sensitised BN rats 24 h after challenge with OA and is associated with marked pulmonary inflammation. The response is entirely B2 receptor mediated and approximately 50% of the response is cholinergic. However, mast cell activation, the products of the cyclooxygenase or 5-lipoxygenase pathways and tachykinins are not involved. Peptidase inhibition mimics the effect of allergen challenge on the bronchoconstrictor response to bradykinin and it remains possible that the mechanism of the augmented response to bradykinin following allergen challenge involves downregulation of peptidase activity as a consequence of the inflammatory response.
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PMID:Airway hyperresponsiveness to bradykinin induced by allergen challenge in actively sensitised Brown Norway rats. 1472 5

5-Lipoxygenase is the key enzyme in the biosynthesis of leukotrienes, powerful lipid mediators involved in inflammation, cell-cell communication, and other important physiological and pathological conditions. Particularly, cysteinyl-leukotrienes have been recognized as playing a significant role in the pathophysiology of asthma and potent and effective Cys-LT1 receptor antagonists have been developed for the treatment of this illness. Here we report that montelukast, a structural Cys-LT1 receptor antagonist, also exerts a substantial and apparently direct inhibitory effect on 5-lipoxygenase activity in vitro, at concentrations in the lower micromolar range, which are of potential therapeutic relevance. Thus, when human mast cells HMC-1 were stimulated with the Ca ionophore A23187 in the presence of montelukast (up to 100 microM) a substantial decline in 5-lipoxygenase biosynthesis was observed. Similar results were obtained in the rat mast cell-like RBL-1 cell model (IC50 congruent with 2.5 microM) and in human polymorphonuclear leukocytes. Moreover, montelukast directly inhibited human recombinant 5-lipoxygenase. Kinetic experiments revealed that the inhibition was of the non-competitive type, suggesting that montelukast binds a yet undefined allosteric site on 5-lipoxygenase. 5-Lipoxygenase inhibition by montelukast appears to be highly selective since the drug had no effects on other enzymes of the leukotriene cascade, viz. LTC4 synthase and LTA hydrolase.
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PMID:Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast. 1547

The PMN-dependent plasma extravasation is a major mechanism of permeability enhancement in acute inflammation. To reveal the pathophysiological significance of the PMN-dependent plasma extravasation, we prepared a systemic leukocytotic guinea pig model by a daily injection of recombinant human (rh)G-CSF. The extent of the PMN-dependent plasma extravasation, regarded as the late-phase permeability induced by an intradermal injection of zymosan-activated guinea pig plasma (ZAP) or of rhC5a, clearly correlated to the circulating PMN number. The augmentation of local response following the systemic response seemed to be the characteristic feature of the PMN-dependent plasma extravasation. We then revealed the molecular mechanism of the PMN-dependent plasma extravasation. Neither the antihistaminic agent diphenhydramine, nor the bradykinin B2 receptor antagonist, HOE140, affected the ZAP-induced, late-phase extravasation. In contrast to this, pretreatment with an antagonist of cysteinyl leukotriene (cys-LT) 1 receptor, pranlukast, significantly reduced the late-phase extravasation. Similarly, it was reduced by pretreatment with a 5-lipoxygenase inhibitor, MK-886, indicating the participation of cys-LTs in the PMN-dependent plasma extravasation. Histologically, pretreatment with pranlukast or MK-886 did not affect the ZAP-induced PMN infiltration. Consistently, a combined treatment with pranlukast and diphenhydramine completely suppressed the early-phase extravasation. As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells.
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PMID:Roles of leukocytosis and cysteinyl leukotriene in polymorphonuclear leukocyte-dependent plasma extravasation. 1694 Mar 29

The effects of peroxisome proliferators, the ligands of a nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha, on cysteinyl leukotriene production were investigated in rodent mast cells. Peroxisome proliferators Wy-14,643 (30 microM) and fenofibrate (100 microM) significantly inhibited the cysteinyl leukotriene production that was induced by antigen (Ag) treatment after overnight sensitization to Ag specific immunoglobulin E (IgE) in a rat basophilic leukemia (RBL)-2H3 mast cell line. Similar inhibition by these drugs was observed in IgE and Ag-treated mouse bone marrow-derived mast cells, A23187-treated RBL-2H3 and A23187-treated mouse peritoneal macrophages. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not affect the release of radioactivity from RBL-2H3 pre-incubated with [(3)H]-arachidonic acid, which is considered an index of phospholipase A(2) activity. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not directly inhibit 5-lipoxygenase activity. Troglitazone was found to directly inhibit the activity of 5-lipoxygenase. The PPARalpha mRNA level was at less than the limit of detection for the realtime polymerase chain reaction both in RBL-2H3 and bone marrow-derived mast cells. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not induce acyl-CoA oxidase mRNA in RBL-2H3, which was reported to be induced by peroxisome proliferators via PPARalpha in hepatocytes. Wy-14,643 (30 microM) and fenofibrate (100 microM) inhibited the cysteinyl leukotriene production in bone marrow-derived mast cells from PPARalpha-null mice. It was concluded that the inhibitory effects of these peroxisome proliferators on cysteinyl leukotriene production are independent of PPARalpha in mast cells.
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PMID:Peroxisome proliferator-activated receptor alpha-independent effects of peroxisome proliferators on cysteinyl leukotriene production in mast cells. 1711 79

In nonexcitable cells, receptor stimulation evokes Ca(2+) release from the endoplasmic reticulum stores followed by Ca(2+) influx through store-operated Ca(2+) channels in the plasma membrane. In mast cells, store-operated entry is mediated via Ca(2+) release-activated Ca(2+) (CRAC) channels. In this study, we find that stimulation of muscarinic receptors in cultured mast cells results in Ca(2+)-dependent activation of protein kinase Calpha and the mitogen activated protein kinases ERK1/2 and this is required for the subsequent stimulation of the enzymes Ca(2+)-dependent phospholipase A(2) and 5-lipoxygenase, generating the intracellular messenger arachidonic acid and the proinflammatory intercellular messenger leukotriene C(4). In cell population studies, ERK activation, arachidonic acid release, and leukotriene C(4) secretion were all graded with stimulus intensity. However, at a single cell level, Ca(2+) influx was related to agonist concentration in an essentially all-or-none manner. This paradox of all-or-none CRAC channel activation in single cells with graded responses in cell populations was resolved by the finding that increasing agonist concentration recruited more mast cells but each cell responded by generating all-or-none Ca(2+) influx. These findings were extended to acutely isolated rat peritoneal mast cells where muscarinic or P2Y receptor stimulation evoked all-or-none activation of Ca(2+)entry but graded responses in cell populations. Our results identify a novel way for grading responses to agonists in immune cells and highlight the importance of CRAC channels as a key pharmacological target to control mast cell activation.
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PMID:All-or-none activation of CRAC channels by agonist elicits graded responses in populations of mast cells. 1791 11

The 5-lipoxygenase (5-LOX) pathway has been associated with a variety of inflammatory diseases including asthma, atherosclerosis, rheumatoid arthritis, pain, cancer and liver fibrosis. Several classes of 5-LOX inhibitors have been identified, but only one drug, zileuton, a redox inhibitor of 5-LOX, has been approved for clinical use. To better evaluate the efficacy of 5-LOX inhibitors for pharmacological intervention, a rat model was modified to test the in vivo efficacy of 5-LOX inhibitors. Inflammation was produced by adding carrageenan into a newly formed air pouch and prostaglandins produced. While macrophages and neutrophils are present in the inflamed pouch, little 5-LOX products are formed. Cellular 5-LOX activation was obtained by adding calcium ionophore (A23187) into the pouch thus providing a novel model to evaluate the efficacy and selectivity of 5-LOX inhibitors. Also, we described modifications to the in vitro 5-LOX enzyme and cell assays. These assays included a newly developed fluorescence-based enzyme assay, a 5-LOX redox assay, an ex vivo human whole blood assay and an IgE-stimulated rat mast cell assay, all designed for maximal production of leukotrienes. Zileuton and CJ-13,610, a competitive, non-redox inhibitor of 5-LOX, were evaluated for their pharmacological properties using these assays. Although both compounds achieved dose-dependent inhibition of 5-LOX enzyme activity, CJ-13,610 was 3-4 fold more potent than zileuton in all-assays. Evaluation of 5-LOX metabolites-by LC/MS/MS and ELISA confirmed that both compounds selectively inhibited all products downstream of 5-hydroperoxy eicosatetraenoic acid (5-HPETE), including 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxoETE), without inhibition of 12-lipoxygenase (12-LOX), 15-lipoxygenase (15-LOX), or cyclooxygenase (COX) products. In the rat air pouch model, oral dosing of CJ-13,610 and zileuton resulted in selective inhibition 5-LOX activity from pouch exudate and ex vivo rat whole blood with similar potency to in vitro assay. These data show that the rat air pouch model is a reliable and useful tool for evaluating in vivo efficacy of 5-LOX inhibitors and may aid in the development of the next generation of 5-LOX inhibitors, such as the non-redox inhibitors similar to CJ-13,610.
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PMID:A rat air pouch model for evaluating the efficacy and selectivity of 5-lipoxygenase inhibitors. 1829 98

We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca(2+)) entry. However, whereas IgE+Ag more potently stimulates Ca(2+) entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca(2+) entry than IgE+Ag initially, they all trigger a more prolonged Ca(2+) influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and Ca(2+) influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H(2)O(2) to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.
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PMID:IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species. 1876 39

Mast cells are key components of the immune system, where they help orchestrate the inflammatory response. Aberrant mast cell activation is linked to a variety of allergic diseases, including asthma, eczema, rhinitis, and nasal polyposis, which in combination affect up to 20% of the population in industrialized countries. On activation, mast cells release a variety of signals that target the bronchi and vasculature and recruit other immune cells to the inflammatory site. Prominent among such signals are the cysteinyl leukotrienes, a family of potent proinflammatory lipid mediators comprising leukotriene C(4) (LTC(4)), LTD(4), and LTE(4). LTC(4), the parent compound, is secreted from mast cells following Ca(2+) influx through store-operated calcium release-activated calcium (CRAC) channels. Here, we show that activated mast cells release a paracrine signal that evokes Ca(2+) signals in spatially separate resting mast cells. The paracrine signal was identified as a cysteinyl leukotriene because 1) RNAi knockdown or pharmacological block of the 5-lipoxygenase enzyme prevented activated mast cells from stimulating resting cells. 2) Block of cysteinyl leukotriene type I receptors on resting mast cells with the clinically prescribed receptor antagonist montelukast prevented their activation by active mast cells. 3) RNAi knockdown of cysteinyl leukotriene type I receptors on resting cells prevented them from responding to the paracrine signal derived from activated mast cells. 4) Purified LTC(4) evoked Ca(2+) signals in mast cells that were identical to those triggered by the paracrine signal. Low levels of stimulus intensity released sufficient levels of leukotriene to activate resting cells. Leukotriene secretion still occurred tens of minutes after stimulation, suggesting a role as a long-lasting trigger in mast cell activation. Stimulation of the cysteinyl leukotriene receptor activated CRAC channels and evoked prominent store-operated Ca(2+) entry. This resulted in further cysteinyl leukotriene production, triggering a positive feedback cascade. Acutely isolated mast cells from patients with allergic rhinitis exhibited store-operated Ca(2+) influx through CRAC channels and responded to cysteinyl leukotrienes. Histological analysis of samples taken from patients revealed clustering of mast cells, often located within 20 microm of each other, a distance sufficient for paracrine signaling by leukotrienes to operate effectively. We conclude that a positive-feedback cascade involving CRAC channels and cysteinyl leukotrienes constitute a novel mechanism for sustaining mast cell activation.
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PMID:Intercellular Ca2+ wave propagation involving positive feedback between CRAC channels and cysteinyl leukotrienes. 1897 54

Activated mast cells are a major source of the eicosanoids PGD(2) and leukotriene C(4) (LTC(4)), which contribute to allergic responses. These eicosanoids are produced following the ERK1/2-dependent activation of cytosolic phospholipase A(2), thus liberating arachidonic acid, which is subsequently metabolized by the actions of 5-lipoxygenase and cyclooxygenase to form LTC(4) and PGD(2), respectively. These pathways also generate reactive oxygen species (ROS), which have been proposed to contribute to FcepsilonRI-mediated signaling in mast cells. In this study, we demonstrate that, in addition to ERK1/2-dependent pathways, ERK1/2-independent pathways also regulate FcepsilonRI-mediated eicosanoid and ROS production in mast cells. A role for the Tec kinase Btk in the ERK1/2-independent regulatory pathway was revealed by the significantly attenuated FcepsilonRI-dependent PGD(2), LTC(4), and ROS production in bone marrow-derived mast cells of Btk(-/-) mice. The FcepsilonRI-dependent activation of Btk and eicosanoid and ROS generation in bone marrow-derived mast cells and human mast cells were similarly blocked by the PI3K inhibitors, Wortmannin and LY294002, indicating that Btk-regulated eicosanoid and ROS production occurs downstream of PI3K. In contrast to ERK1/2, the PI3K/Btk pathway does not regulate cytosolic phospholipase A(2) phosphorylation but rather appears to regulate the generation of ROS, LTC(4), and PGD(2) by contributing to the necessary Ca(2+) signal for the production of these molecules. These data demonstrate that strategies to decrease mast cell production of ROS and eicosanoids would have to target both ERK1/2- and PI3K/Btk-dependent pathways.
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PMID:The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells. 1901 59

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