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)

Metabolism of arachidonic acid was studied in the unique human mast cell line HMC-1. By HPLC and/or gas chromatography mass spectrometry (GC-MS), 19 oxygenated metabolites were identified, including monohydroxy acids, leukotrienes, prostaglandins, and thromboxane. Intact cells incubated with the calcium ionophore A23187 and arachidonic acid expressed 5-lipoxygenase activity and produced 5-hydroxyeicosatetraenoic acid (5-HETE) as the major metabolite (745 pmol/10(7) cells) followed by leukotriene (LT) C4 (245 pmol/10(7) cells) and 11-trans-LTC4 (74 pmol/10(7) cells). Low but clearly detectable levels of LTB4 were also observed. The total amounts of 5-LO products were comparable to those obtained with RBL-1 cells and corresponded to approx. 30% of the levels obtained with isolated human polymorphonuclear leukocytes. Time-course experiments revealed that HMC-1 cells contained the enzyme activities required to metabolize LTC4 into LTD4 and further into LTE4. The profile of prostanoids included, prostaglandin (PG) E2, PGF2 alpha, and PGD2, whereas 6-keto-PGF1 alpha, reflecting prostacyclin formation, could not be detected. Furthermore, we were able to unambiguously establish that HMC-1 cells could produce substantial amounts of thromboxane (TX) A2, measured as TXB2 (0.1-2.2 nmol/10(7) cells). Generation of TXA2 in such quantities, exceeding those of LTC4, suggests that mast cells may be an important source of thromboxane and points to a possible role for these cells in hemostasis and thrombosis. After approx. 10 passages in culture, 5-lipoxygenase activity in HMC-1 cells drastically declined concomitantly with changes in growth behavior and cell morphology. Analysis by Northern and Western blots revealed that loss of 5-lipoxygenase activity correlated well with a reduced 5-lipoxygenase gene expression at both a transcriptional and translational level. This loss of enzyme activity and gene expression may be related to a genetic abnormality propagated in HMC-1 cells, i.e., a 10;16 translocation, which thus involves the chromosome containing the 5-lipoxygenase gene.
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PMID:Arachidonic acid metabolism in the human mast cell line HMC-1: 5-lipoxygenase gene expression and biosynthesis of thromboxane. 759 81

Beta-adrenoceptor agonists have several pharmacological actions in the lung which affect airway function. They have a direct relaxant effect on human bronchial smooth muscle and several additional properties, including attenuation of mast cell mediater release, reduction in airway microvascular leakage, and inhibition of cholinergic neurotransmission within the airway, in vitro. However, direct evidence in vivo for any anti-inflammatory effects of beta-adrenocepter agonists is limited. We reported that beta-agonists (procaterol, salmeterol) inhibited significantly I. A. R. and L. A. R. Salmeterol also reduced urinary secretion of LTE4. It is suggested that beta-agonists have some of anti-allergic effects in the clinical pharmacological study. From recent clinical studies, it is recommended on demand use more than regular use of inhaled beta-agonists.
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PMID:[Anti-allergic effects of beta-adrenoceptor agonists in the clinical pharmacological studies]. 895 Sep 56

Antibodies against integrins have been shown to inhibit allergic airway responses. The purpose of this study was to test the hypothesis that the beta1 integrin, very late antigen-4 (VLA-4), is involved in mast cell activation triggered by allergen exposure in sensitized animals. To do this we studied Brown Norway rats that were sensitized to ovalbumin (OA; 1 mg subcutaneously) using Bordetella pertussis as an adjuvant. Two weeks later rats were challenged with OA, pulmonary resistance (RL) was determined, and the concentrations of histamine and tryptase in bronchoalveolar lavage fluid and N-acetyl-leukotriene (LT)E4 in bile were measured. Pretreatment with a monoclonal antibody against VLA-4 (TA-2) attenuated the early response after OA challenge (342.9 +/- 24.4% baseline RL versus 153.3 +/- 19.4%; p < 0.01). There were significantly lower concentrations of histamine (67.11 +/- 11.90 microgram/ml versus 26.69 +/- 1.84; p < 0.01) and tryptase (0.143 +/- 0. 035 microgram/ml versus 0.053 +/- 0.022 microgram/ml; p < 0.01) in TA-2-treated animals. The increases in the concentrations of biliary N-acetyl-LTE4 after OA challenge were also significantly lower in TA-2-treated animals. These data suggest that a selective anti-VLA-4 monoclonal antibody prevents early responses through inhibition of mast cell activation.
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PMID:Involvement of alpha-4 integrins in allergic airway responses and mast cell degranulation in vivo. 976 71

Prostaglandin D2 (PGD2) is the major cyclooxygenase metabolite of arachidonic acid released after stimulation of mast cells. Quantification of metabolites of PGD2 can be used as an objective indices of PGD2 production and hence mast cell activation in vivo. The aim of this thesis was to investigate the feasibility of measuring the primary urinary metabolite of PGD2, 9 alpha,11 beta-PGF2 with enzyme immunoassay (EIA). Measurements of 9 alpha,11 beta-PGF2 in urine made by EIA were compared with values obtained by negative ion chemical ionisation gas chromatography-mass spectrometry (NCI GC-MS), the gold standard method. Levels of 9 alpha,11 beta-PGF2, in urine samples measured by NCI GC-MS were consistently lower than those obtained by EIA. NCI GC-MS analysis revealed the presence of two additional dinor compounds, shorter metabolites of 9 alpha,11 beta-PGF2 in the urine. One of the compounds was identical to 9 alpha,11 beta-2,3-dinor-PGF2 which was generated by beta-oxidation of 9 alpha,11 beta-PGF2 and identified by electron impact (EI GC-MS). Thus, urinary 9 alpha,11 beta-PGF2 concentrations measured by EIA represent the sum of three PGD2 metabolites. For convenience sake, the metabolites are collectively referred to as 9 alpha,11 beta-PGF2 in the subsequent studies. A 3-fold increase in the urinary excretion of 9 alpha,11 beta-PGF2 was documented after allergen-induced bronchoconstriction in nine atopic asthmatics. This challenge was considered a positive control since it is unambiguous that mast cell activation occurs during the early phase of allergen-induced airway obstruction. Histamine-induced bronchoconstriction did not result in an increase in the levels of 9 alpha,11 beta-PGF2 demonstrating that PGD2 was not formed as a consequence of the bronchoconstriction per se. Moreover, bronchial challenge with lysine-aspirin in eight aspirin-intolerant asthmatics elicited bronchoconstriction and was accompanied by a significant increase in the urinary excretion of 9 alpha,11 beta-PGF2. Challenge with a higher dose of aspirin produced an even greater increase in 9 alpha,11 beta-PGF2 levels, indicating a dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. The pattern of mediator release during the early (EAR) and late asthmatic response (LAR) to allergen was investigated by subjecting twelve mild atopic asthmatics to allergen challenge. Within one hour of the maximal bronchoconstrictor response, there was a significant increase in the urinary concentrations of the mast cell markers, 9 alpha,11 beta-PGF2 and N tau-methylhistamine, urinary metabolite of histamine, and the end product of the cysteinyl-leukotrienes, leukotriene (LT)E4. Levels of all three mediators were also significantly elevated above baseline during the LAR. Urinary levels of eosinophil protein X (EPX), a marker of eosinophil activation, remained unaltered during both the EAR and LAR. Preliminary evidence suggests a diurnal variation in the urinary excretion of EPX. Increased airway fluid osmolarity in the lower airways as a result of exercise, has been suggested to trigger mast cell activation and subsequent bronchoconstriction in a subset of asthmatics. Twelve subjects with a history of exercise-induced bronchoconstriction (EIB), exercised on a stationary bicycle ergometer for 5 minutes. Seven of the subjects (responders) experienced bronchoconstriction, whereas, the pulmonary function of the remaining five subjects (non-responders) remained stable. The urinary excretion of 9 alpha,11 beta-PGF2 in the responder group increased significantly compared to the non-responders at 30 and 90 minutes after exercise. The urinary excretion of LTE4 and N tau-methylhistamine was not significantly different between the two groups at either time point after exercise, although there was a tendency for elevated levels of N tau-methylhistamine in the responder group. (ABSTRACT TRUNCATED)
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PMID:On the role of PGD2 metabolites as markers of mast cell activation in asthma. 1035 58

Since asthma has been recognized as a chronic inflammatory airway disease, inflammatory markers are useful tools to show the degree of allergic airway inflammation. Asthmatic airway is characterized with infiltration of activated Th2 lymphocyte, eosinophils and mast cells/basophils. Eosinophil derived proteins such as ECP, MBP and EDN are important markers indicating eosinophilic inflammation. Histamine and tryptase are the products of mast cell/basophil activation. These markers are detected in sputum, BALF, serum and urine, and increased in asthmatics. In addition to these markers, NO concentration in exhaled air, cytokines such as IL-4, IL-5, chemokines such as RANTES, eotaxin, LTE4, MMP are inflammatory markers to indicate the quality and quantity of asthmatic airway inflammation. Assessment of these markers, therefore, contributes to better control of asthmatic symptoms with appropriate therapy.
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PMID:[Airway inflammatory marker]. 1167 35

The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction. Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before and for 90 min after challenge. The urinary concentrations of leukotriene (LT)E4, the prostaglandin (PG)D2 metabolite and the mast cell marker 9alpha,11beta-PGF2 were measured by enzyme immunoassay. N(tau)-methylhistamine was measured by radioimmunoassay. In asthmatic subjects, inhalation of a mean+/-SEM dose of 272+/-56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5+/-2.1%. This was associated with increases in urinary 9alpha,11beta-PGF2 (91.9+/-8.2 versus 66.9+/-6.6 ng x mmol creatinine(-1), peak versus baseline) and LTE4 (51.3+/-7.5 versus 32.9+/-4.7). In nonasthmatic subjects, the reduction in FEV1 was 1.0+/-0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9alpha,11beta-PGF2 (68.4+/-6.9 versus 56.0+/-5.8 ng x mmol creatinine(-1)) and LTE4 (58.5+/-5.3 versus 43.0+/-3.3 ng x mmol creatinine(-1)) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of N(tau)-methylhistamine in the nonasthmatics, but not in the asthmatics. The increased urinary levels of 9alpha,11beta-prostaglandin F2 support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects.
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PMID:Evidence of mast cell activation and leukotriene release after mannitol inhalation. 1451 40

The persistence of wheezing after early wheezing episodes in infancy may be related to the virus involved and to the type of inflammation during the initial wheezing. The role of mast cell activation and leukotriene secretion in wheezing, and the relation to outcome, is not known. Our objective was to study markers of mast cell activation and leukotriene secretion from wheezing infants, and the relation to respiratory syncytial virus (RSV) infection and persistent wheezing. Urinary 9alpha,11beta-PGF(2), a marker of mast cell activation, and urinary leukotriene E4 were measured in 106 infants hospitalized for wheezing during their first year of life. Results were related to the presence of RSV infection and the persistence of wheezing at follow-up 20 months later. Levels of 9alpha,11beta-PGF(2) were higher in infants positive for RSV than in those with RSV negative wheezing, but both groups had higher levels than controls. Leukotriene E4 levels were higher in wheezing infants than in controls. Urinary 9alpha,11beta-PGF(2) levels were higher in infants with transient compared with persistent wheezing. We found a positive correlation between 9alpha,11beta-PGF(2) and leukotriene E4, strongest in infants with RSV negative disease and in infants with persistent wheezing. The results suggest that mast cells play an important role in infant wheezing, and may be a major source of leukotriene secretion in these infants. Mast cell activation and leukotriene secretion were not associated with persistent wheezing.
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PMID:Mast cell activation and leukotriene secretion in wheezing infants. Relation to respiratory syncytial virus and outcome. 1642 53

The mast cell has been a fundamental focus for nearly half a century in the effort to understand the biology of the cysteinyl leukotrienes (cysLTs). My initial interest in the cysLTs, once termed the slow reacting substance of anaphylaxis (SRS-A), was based on the findings of others that this activity was elaborated by lung tissue and constricted bronchial smooth muscle in the presence of an antihistamine. We now know that leukotriene C4 (LTC4) is formed when arachidonic acid is cleaved from membrane phospholipids, and metabolized to an epoxide intermediate, LTA4 that in turn is conjugated to reduced glutathione by an integral membrane protein, LTC4 synthase. The LTC4 is exported in an energy-dependent step and subjected to extracellular cleavage of the glutamic acid and then the glycine to provide LTD4 and LTE4, respectively. Mice with targeted disruption of the LTC4S gene are partially protected against plasma leakage elicited in the ear by adaptive immune mast cell activation or in the peritoneal cavity by microbial carbohydrate stimulation of the macrophages. Such mice are also partially protected against pulmonary fibrosis after intratracheal administration of bleomycin. A strain with targeted disruption of the CysLT1 receptor gene is protected against the pathobiological insults that augment microvascular permeability, whereas a strain with targeted disruption of the CysLT2 receptor gene is protected against pulmonary fibrosis. Thus, the expression of these receptors on endothelium, smooth muscle and cells of the haematopoietic lineage such as mast cells, macrophages, and granulocytes extends the possible role of this lipid mediator pathway to both acute and chronic inflammation.
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PMID:The mast cell and the cysteinyl leukotrienes. 1660 34

The cysteinyl leukotrienes (LTs), LTC(4), LTD(4), and LTE(4), are potent inflammatory mediators and are involved in allergic reactions, such as bronchoconstriction, eosinophilic inflammation, and allergic cell proliferation. The present study aimed to elucidate the role of constitutively produced cysteinyl LTs in mast cell activation. We used a newly developed quantification method based on mass spectrometry to detect cysteinyl LTs in the cultured medium of mouse bone marrow-derived mast cells (BMMCs), which were obtained by interleukin (IL)-3-conditioned culture of mouse bone marrow. BMMCs were stimulated with immunoglobulin (Ig) E and antigen (IgE/Ag) or lipopolysaccharide for 1 or 24 h. This new quantification method revealed that unstimulated BMMCs produced and secreted LTB4 and LTE4 after 24 h of incubation. The treatment of unstimulated BMMCs for 2 h with montelukast, an antagonist of a cysteinyl LT receptor, CysLT1, resulted in the suppression of a downstream signaling event of this receptor, i.e., the decrease in phosphorylation of extracellular responsive kinases. Thus, cysteinyl LTs constitutively simulate BMMCs through the CysLT1 receptor in an autocrine manner. Treatment of BMMCs for 3 weeks with montelukast, which caused long-term inhibition of the autocrine cyteinyl LT-derived signal, significantly attenuated the IgE/Ag-dependent degranulation, as judged by the decrease in the release of beta-hexosaminidase, an enzyme contained in the granules, whereas the production of cytokines, such as IL-6 and tumor necrosis factor-alpha, were largely unaffected. In conclusion, an autocrine signal derived from constitutively produced cysteinyl LTs predisposes mast cells to the degranulation upon allergic stimulation.
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PMID:Cysteinyl leukotrienes enhance the degranulation of bone marrow-derived mast cells through the autocrine mechanism. 1928 53

Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)-reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4-induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE4 but not for direct binding of LTE4, suggesting that P2Y12 complexes with another receptor to recognize LTE4. Administration of LTE4 to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses persist in mice lacking both CysLT1R and CysLT2R but not in mice lacking P2Y12 receptors. The effects of LTE4 on P2Y12 in the airway were abrogated by platelet depletion. Thus, the P2Y12 receptor is required for proinflammatory actions of the stable abundant mediator LTE4 and is a novel potential therapeutic target for asthma.
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PMID:Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. 1982 47


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