prostaglandin-d2 and Anaphylaxis

Human heart mast cells (HHMC), by elaborating vasoactive mediators, cytokines and chemokines, are the main primary effector cells of anaphylaxis. Mast cells have been identified perivascularly, close to myocytes and in the arterial intima in human heart tissue. Mast cells isolated from human heart tissue (HHMC) of patients undergoing cardiac transplantation express high-affinity receptors for IgE (FcepsilonRI) and C5a receptors. Activation of HHMC in vitro with anti-IgE or anti-FcepsilonRI induced the release of preformed mediators (histamine, tryptase, chymase, and renin) and the de novo synthesis of LTC(4) (approximately =18 ng/l0(6) cells) and PGD(2) (approximately =18 ng/l0(6) cells). Complement is activated and anaphylatoxin forms during anaphylaxis. C5a causes rapid release of histamine and tryptase from HHMC. These cells are activated in vitro by therapeutic (general anesthetics, protamine, etc.) and diagnostic agents (radiocontrast media, etc.) which can cause anaphylactoid reactions. Low concentrations of histamine and cysteinyl leukotrienes given to subjects undergoing diagnostic catheterization caused significant systemic and coronary hemodynamic effects. These results indicate that HHMC probably have a role in anaphylactic reactions.

Topics: Anaphylaxis; Animals; Complement Activation; Hemodynamics; Histamine Release; Humans; Intracellular Signaling Peptides and Proteins; Leukotriene C4; Mast Cells; Myocardium; Prostaglandin D2; Receptor, Anaphylatoxin C5a

A study was performed about the effects of increasing concentrations of muscle relaxants (suxamethonium, d-tubocurarine, vecuronium, and atracurium), hypnotics (propofol, ketamine, and thiopental), opioids (morphine, buprenorphine, and fentanyl), and benzodiazepines (diazepam, flunitrazepam, and midazolam) on the release of preformed (histamine and tryptase) and de novo synthesized (prostaglandin D2: PGD2 and peptide-leukotriene C4: LTC4) chemical mediators from human basophils and mast cells isolated from skin (HSMC), lung parenchyma (HLMC) and heart tissue (HHMC). None of the drugs tested induced the release of histamine or LTC4 from basophils of normal donors. Suxamethonium did not induce mediator release from any type of human mast cell tested. Only the highest concentration of d-tubocurarine used caused histamine release from HSMC and HLMC. Atracurium, more than vecuronium, induced concentration-dependent histamine release from HSMC and HLMC. Propofol induced a concentration-dependent histamine release from HLMC, but not from HHMC. Only the highest concentrations of ketamine and thiopental used caused a significant release of histamine from HLMC. The muscle relaxants and hypnotics examined did not induce any de novo synthesis of PGD2 or LTC4 in mast cells. Morphine only induced histamine and tryptase release from HSMC, but not the de novo synthesis of PGD2. In contrast, buprenorphine caused histamine and tryptase release from HLMC, and not from HSMC, whilst it also induced de novo synthesis of PGD2 and LTC4 in HLMC. Fentanyl did not give any histamine and tryptase release from mast cells. Diazepam and flunitrazepam only induced a small release of histamine from mast cells, whereas midazolam caused the release of histamine from HLMC. The biochemical pathways underlying the release of mediators from human mast cells induced by drugs used during general anaesthesia are different from those underlying the immune release of histamine. From the results obtained with the in vitro model described here, it is clear that new drugs promising for the anesthesiologic arena should be tested in vitro before their potential histamine-releasing activity is experienced in vivo.

Topics: Analgesics, Opioid; Anaphylaxis; Anesthetics; Anti-Anxiety Agents; Basophils; Benzodiazepines; Chymases; Histamine Release; Humans; Mast Cells; Neuromuscular Blocking Agents; Prostaglandin D2; Serine Endopeptidases; SRS-A; Tryptases

Topics: Anaphylaxis; Animals; Asthma; Bronchi; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Guinea Pigs; Humans; In Vitro Techniques; Lung; Lung Diseases; Models, Biological; Muscle, Smooth; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; SRS-A; Thromboxane A2

Topics: Anaphylaxis; Arachidonic Acid; Arachidonic Acids; Asthma; Basophils; Blood Platelets; Bronchial Provocation Tests; Calmodulin; Cyclic AMP; Deuterium; Deuterium Oxide; Histamine Release; Humans; Lung Diseases; Mast Cells; Peptide Hydrolases; Phospholipids; Platelet Activating Factor; Platelet Factor 4; Prostaglandin D2; Prostaglandins D; Receptors, IgE; Receptors, Immunologic; Serotonin; Water

Topics: Adolescent; Anaphylaxis; Anti-Inflammatory Agents, Non-Steroidal; Dinoprost; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Prostaglandin D2; Salicylamides

Topics: Abdominal Pain; Adult; Anaphylaxis; Angioedema; Anti-Asthmatic Agents; Biomarkers; Cromolyn Sodium; Diarrhea; Dinoprost; Female; Histamine Antagonists; Humans; Leukotriene E4; Male; Mast Cells; Mastocytosis; Middle Aged; Omalizumab; Prostaglandin D2; Treatment Outcome; Tryptases; Urticaria

Topics: Anaphylaxis; Animals; Biomarkers; Blood Pressure; Capillary Permeability; Cell Degranulation; Disease Models, Animal; Inflammation Mediators; Mast Cells; Mice; Prostaglandin D2

IgE/Ag-stimulated mast cells release various pro-allergic inflammatory mediators, including histamine, eicosanoids, and pro-inflammatory cytokines. NecroX-5, a cell permeable necrosis inhibitor, showed cytoprotective effects in both in vitro and in vivo models. However, the anti-allergic effect of NecroX-5 has not yet been investigated. The aims of this study were to evaluate the anti-allergic activity of NecroX-5 in vivo and to investigate the underlying mechanism in vitro.. The anti-allergic activity of NecroX-5 was evaluated in vitro using bone marrow-derived mast cells (BMMCs) and IgE receptor-bearing RBL-2H3 or KU812 cells and in vivo using a mouse model of passive anaphylaxis. The levels of histamine, eicosanoids (PGD2 and LTC4 ), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured using enzyme immunoassay kits. The mechanism underlying the action of NecroX-5 was investigated using immunoblotting, immunoprecipitation, and gene knockdown techniques.. NecroX-5 markedly inhibited mast cell degranulation and the synthesis of eicosanoids, TNF-α, and IL-6 by suppressing the activation of Syk, LAT, phospholipase Cγ1, MAP kinases, the Akt/NF-κB pathway, and intracellular Ca(2+) mobilization via the activation of phosphatase SHP-1. Oral administration of NecroX-5 effectively suppressed mast cell-dependent passive cutaneous and systemic anaphylactic reactions in a dose-dependent manner.. NecroX-5 might be a potential candidate for the development of a novel anti-allergic agent that suppresses IgE-dependent mast cells signaling.

Topics: Anaphylaxis; Animals; Antigens; Arachidonate 5-Lipoxygenase; Calcium; Cell Degranulation; Cell Line; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Heterocyclic Compounds, 4 or More Rings; Immunoglobulin E; Intracellular Signaling Peptides and Proteins; Leukotriene C4; Male; Mast Cells; Mice; Prostaglandin D2; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein-Tyrosine Kinases; Signal Transduction; Sulfones; Syk Kinase

Anaphylactic shock sometimes accompanies pulmonary vaso- and broncho-constriction. We previously reported the hemodynamic features of mouse anaphylaxis (Life Sci. 2014; 116: 98-105). However, the effects of anaphylactic chemical mediators on the hemodynamics of in vivo mice are not well known. Furthermore, it is uncertain whether the mediators exert the same directional actions. Therefore, we determined their effects systematically on total peripheral resistance (TPR), pulmonary vascular resistance (PVR), or airway pressure (AWP) in anesthetized mice.. We measured directly pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, central venous pressure and aortic blood flow to determine PVR and TPR, as well as AWP, following injections of platelet-activating factor (PAF), histamine, serotonin, leukotriene (LT) C4, and prostaglandin (PG) D2 in anesthetized open-chest artificially ventilated BALB/c mice.. Consecutive administration of any agents increased PVR dose-dependently with the maximal responsiveness being PAF>LTC4>serotonin>>histamine=PGD2. Histamine caused a biphasic PVR response, an initial decrease, which was abolished by L-NAME, followed by an increase at high doses. PAF, serotonin, and histamine decreased TPR dose-dependently, while LTC4 or PGD2 yielded an increase or no change in TPR, respectively. Serotonin, but not the other agents, increased AWP.. Anaphylactic mediators exert non-uniform actions on the pulmonary and systemic circulation and airway in anesthetized BALB/c mice: PAF, LTC4 and serotonin cause substantial pulmonary vasoconstriction, while histamine biphasic responses of the initial nitric oxide dependent vasodilation followed by vasoconstriction; PAF, serotonin, and histamine, but not LTC4 or PGD2, evoke systemic vasodilatation; only serotonin induces airway constriction.

Topics: Anaphylaxis; Animals; Arterial Pressure; Dose-Response Relationship, Drug; Histamine; Leukotriene C4; Male; Mice; Mice, Inbred BALB C; NG-Nitroarginine Methyl Ester; Nitric Oxide; Platelet Activating Factor; Prostaglandin D2; Serotonin; Vascular Resistance; Vasoconstriction; Vasodilation

Red kidney bean (Phaseolus vulgaris L.), a protein rich legume, is consumed globally due to its delicacy. This study was aimed to purify, characterize and assess allergenicity of one of its clinically relevant allergens, later identified as phaseolin. This study was carried out using clinical, in vivo and ex vivo approaches. Phaseolin, an abundant protein of red kidney bean, was purified by column chromatography and reverse-phase-HPLC techniques and characterized by peptide mass fingerprinting. The IgE immunoblotting using red kidney bean allergic patients sera showed phaseolin as a major IgE binding protein of red kidney bean. Phaseolin treated mice demonstrated enhanced levels of specific IgE and IgG1, mouse mast cell protease-1, mRNA expressions of IL-4, IL-5, IL-13 and GATA-3 in the lungs, spleen and intestine along with anaphylactic symptoms indicative of allergic responses. Further, flow cytometry analysis and immunohistochemical studies indicated increased levels of IL-4, IL-5, IL-13 and GATA-3, respectively as compared to controls. The level of Foxp3 was found suppressed in the intestine of phaseolin treated mice when compared to the control. Further, phaseolin treated mice showed positive results in type 1 skin test. Bone marrow derived mast cells (BMMCs) and rat basophilic leukemia (RBL-2H3) cells showed enhanced release of allergic mediators like β-hexosaminidase, histamine, cysteinyl leukotrienes and prostaglandin D2. Taken together, phaseolin was found to possess characteristics of a potential allergen that may lead to hypersensitivity responses in the susceptible individuals and this may be one of the major proteins responsible for allergenicity of red kidney bean.

Topics: Adult; Aged; Allergens; Anaphylaxis; Animals; beta-N-Acetylhexosaminidases; Cell Line, Tumor; Cells, Cultured; Cytokines; Female; Food Hypersensitivity; Histamine; Humans; Immunoglobulin E; Immunoglobulin G; Male; Mast Cells; Mice; Mice, Inbred BALB C; Phaseolus; Plant Proteins; Prostaglandin D2; Rats; Skin Tests; Spleen

The purpose of this study is to investigate the effects of n-hexane extracts from bones and internal organs of Japanese eel, Anguilla japonica (HEE), on cyclooxygenase-2 (COX-2)-dependent prostaglandin D₂(PGD₂) generation in stem cell factor (SCF), IL-10, plus LPS-induced mouse bone marrow-derived mast cells (BMMCs) and on passive cutaneous anaphylaxis (PCA) in mice. HEE suppressed SCF/IL-10/LPS-induced PGD₂ generation, and concomitantly reduced COX-2 protein expression dose-dependently. To understand the mechanistic basis for the inhibition of PGD₂ generation by HEE, we examined the effects of HEE on upstream signaling pathways essential for COX-2 induction. HEE was found to inhibit the translocation of nuclear factor-κB (NF-κB) p65 subunit to the nucleus and its DNA-binding ability through the inhibition of TAK1, IKK and IκB phosphorylation. Furthermore, HEE also attenuated mitogen-activated protein kinase (MAPK)-mediated regulation of DNA binding of activator protein-1 (AP-1). Moreover, oral administration of HEE inhibited anti-dinitrophenyl (DNP) IgE-induced PCA in a dose dependent manner. Taken together, the present study provides new insights into the anti-inflammatory activity of HEE, which could be a promising candidate to be used for an inflammatory therapy.

Topics: Anaphylaxis; Anguilla; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone and Bones; Complex Mixtures; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Hexanes; Interleukin-10; Lipopolysaccharides; Male; MAP Kinase Kinase Kinases; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; NF-kappa B; Prostaglandin D2; Transcription Factor AP-1

Mast cells play a critical role in the pathogenesis of allergic diseases; however, how mast cell function is regulated is still not well understood. Both phosphatidic acid (PA) and diacylglycerol (DAG) are important secondary messengers involved in mast cell activ-ation. Lipin1 is a phosphatidate phosphatase that hydrolyzes PA to produce DAG, but the role of lipin1 in mast cell function has been thus far unknown. Here we show that lipin1 is an important and selective inhibitor of mast cell degranulation. Lipin1 deficiency enhanced FcεRI-mediated β-hexosaminidase and prostaglandin D2 release from mast cells in vitro and exacerbated the passive systemic anaphylaxis reaction in vivo. Lipin1 deficiency, however, did not exert obvious effects on IL-6 or TNF-α production following FcεRI engagement. FcεRI-induced PKC and SNAP-23 phosphorylation were augmented in the lipin1-deficient mast cells. Moreover, inhibition of PKC activity reduced SNAP-23 phosphorylation and mast cell degranulation in lipin1-deficient mast cells. Together, our findings suggest that lipin1 may negatively control mast cell degranulation and the anaphylactic response through inhibiting the PKC-SNAP-23 pathway.

Topics: Anaphylaxis; Animals; beta-N-Acetylhexosaminidases; Cell Degranulation; Cells, Cultured; Immunosuppression Therapy; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Nuclear Proteins; Phosphatidate Phosphatase; Phosphorylation; Prostaglandin D2; Protein Kinase C; Qb-SNARE Proteins; Qc-SNARE Proteins; Receptors, IgE; Signal Transduction

The high-affinity receptor for immunoglobulin E (IgE) (FcεRI)-mediated activation of mast cells plays an important role in various allergic diseases. To assess the anti-allergic activity of natural vanadium-containing Jeju groundwater (JW), an in vivo passive cutaneous anaphylaxis (PCA) animal model and in vitro mouse bone marrow-derived mast cells (BMMCs) was used. JW inhibited cyclooxygenase-2 (COX-2)-dependent prostaglandin D(2) (PGD(2)) generation in a dose-dependent manner, with a concomitant reduction of COX-2 protein expression in IgE-induced BMMCs. In addition, JW inhibited 5-lipoxygenase (5-LOX)-dependent generation of leukotriene C(4) (LTC(4)) as well as degranulation in a dose-dependent manner. These results demonstrate that JW has dual COX-2/5-LOX inhibitory activity. In addition, vanadium pentoxide (V(2)O(5)), which is the major vanadium component of JW, also inhibited PGD(2) and LTC(4) generation as well as degranulation in IgE-induced BMMCs. Furthermore, oral administration of JW dose-dependently inhibited mast cell-dependent passive anaphylactic reaction in IgE-sensitized mice. Taken together, these results suggest that JW may be useful in regulating mast cell-mediated allergic response through the suppression of eicosanoid generation and degranulation in mast cells.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Bone Marrow Cells; Calcium; Cell Degranulation; Groundwater; Immunoglobulin E; Leukotriene C4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Prostaglandin D2; Vanadium; Water Pollutants, Chemical

To detect the changes of leukotriene E4(LTE4), prostaglandin D2(PGD2), carboxypeptidase A3(CPA3) and platelet activating factor (PAF) in guinea pigs died from anaphylactic shock.. Guinea pigs were used for establishing anaphylactic shock models. The levels of LTE4, PGD2 and CPA3, and PAF were detected in urine, plasma, and brain tissues with ELISA kit, respectively. The significant biomarkers were selected comparing with control group. The changes of PGD2, CPA3 and PAF in the guinea pigs at time zero, 12 and 24 hours after death were observed and compared respectively. The effect of platelet activating factor acetylhydrolase (PAF-AH) to PAF in guinea pig brain was examined and compared.. There were no statistically differences of LTE4 levels in urine observed between experimental group and control group. The levels of CPA3, PGD2 and PAF in the experimental group were significantly higher than that in the control group at 0 h. The levels of PAF at 12 and 24 hours after anaphylactic shock were significantly higher than that in the control group. The levels of PAF decreased significantly after pretreatment with PAF-AH.. LTE4 in urine cannot be selected as a biomarker to determine the anaphylactic shock. PGD2 and CPA3 in plasma, and PAF in brain tissue may be used as biomarkers to determine the anaphylactic shock. PAF-AH may be potentially useful for clinical treatment of anaphylactic shock.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Anaphylaxis; Animals; Brain; Carboxypeptidases; Case-Control Studies; Disease Models, Animal; Egg Proteins; Enzyme-Linked Immunosorbent Assay; Female; Guinea Pigs; Leukotriene E4; Male; Mice; Platelet Activating Factor; Prostaglandin D2; Time Factors

The high-affinity receptor for IgE (FcɛRI)-mediated activation of mast cells plays an important role in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Emodin, a naturally occurring anthraquinone derivative in oriental herbal medicines, has several beneficial pharmacologic effects, such as anti-cancer and anti-diabetic activities. However, the anti-allergic effect of emodin has not yet been investigated. To assess the anti-allergic activity of emodin, in vivo passive anaphylaxis animal model and in vitro mouse bone marrow-derived mast cells were used to investigate the mechanism of its action on mast cells. Our results showed that emodin inhibited degranulation, generation of eicosanoids (prostaglandin D(2) and leukotriene C(4)), and secretion of cytokines (TNF-α and IL-6) in a dose-dependent manner in IgE/Ag-stimulated mast cells. Biochemical analysis of the FcɛRI-mediated signaling pathways demonstrated that emodin inhibited the phosphorylation of Syk and multiple downstream signaling processes including mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and NF-κB pathways. When administered orally, emodin attenuated the mast cell-dependent passive anaphylactic reaction in IgE-sensitized mice. Thus, emodin inhibits mast cell activation and thereby the anaphylactic reaction through suppression of the receptor-proximal Syk-dependent signaling pathways. Therefore, emodin might provide a basis for development of a novel anti-allergic drug.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Calcium; Cell Degranulation; Cells, Cultured; Emodin; Enzyme Activation; Immunoglobulin E; Interleukin-6; Intracellular Signaling Peptides and Proteins; Leukotriene C4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Prostaglandin D2; Protein-Tyrosine Kinases; Syk Kinase; Tumor Necrosis Factor-alpha

Topics: Adult; Anaphylaxis; Biomarkers; Child; Cysteine; Humans; Inflammation Mediators; Leukotriene E4; Leukotrienes; Mast Cells; Prostaglandin D2

Anaphylaxis is a life-threatening syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. However, pathological evidence of the association between inflammatory mediators and human anaphylaxis is insufficient.. The aim of this study was to better understand the relationship between in vivo production of inflammatory mediators and the pathogenesis of anaphylaxis. We also sought to evaluate mast cell activation in anaphylaxis.. We measured the concentrations of various inflammatory mediators in urine samples, which were collected from 32 anaphylactic patients during the onset of anaphylaxis and during clinical remission, 21 patients with asthma on acute exacerbation and 15 healthy control subjects. Blood and urine specimens were collected from the patients after provocation test. Urinary leukotriene E4 (LTE4), 9alpha, 11beta-prostaglandin F2 (9alpha, 11beta-PGF2), eosinophil-derived neurotoxin (EDN) and leukotriene B4 glucuronide (LTBG) concentrations were determined by enzyme immunoassay, and the activity of plasma platelet-activating factor acetylhydrolase and serum tryptase concentration were measured using commercially available kits.. Significantly higher concentrations of urinary LTE4 and 9alpha, 11beta-PGF2, which immediately decreased during clinical remission, were observed in the anaphylactic patients than in asthmatic patients on acute exacerbation and healthy control subjects. Concentrations of EDN and LTBG were not significantly different among the anaphylactic patients, asthmatic patients on acute exacerbation and healthy subjects. There was a significant correlation between urinary LTE4 and 9alpha, 11beta-PGF2 concentrations in the anaphylactic patients (r=0.672, P=0.005, n=32). In addition, LTE4 concentration in patients with anaphylactic shock is significantly elevated compared with that in patients without anaphylactic shock.. This is a report on the significant increase in urinary LTE4 and 9alpha, 11beta-PGF2 concentrations during anaphylaxis. Urinary LTE4 and 9alpha, 11beta-PGF2 concentrations may be a reliable marker of endogenous production of inflammatory mediators associated with anaphylaxis.

Topics: Adolescent; Adult; Anaphylaxis; Asthma; Cysteine; Dinoprost; Female; Humans; Inflammation Mediators; Leukotriene E4; Leukotrienes; Male; Mast Cells; Middle Aged; Prostaglandin D2; Young Adult

Patients with systemic mastocytosis have increased numbers of mast cells in the bone marrow and other organs, such as the liver, spleen, gastrointestinal tract and skin. Symptoms result from the local and remote effects of mediator release from mast cells and from the local effects of increased mast cell numbers in various organs. Patients with mast cell activation experience many of the same clinical symptoms as do patients with systemic mastocytosis from chronic or spontaneous release of mast cell mediators. We report 4 patients with mast cell activation symptoms from selective release of prostaglandin (PG) D(2), but not histamine, and their improvement with aspirin therapy.. Bone marrow biopsy specimens obtained from 4 patients with symptoms suggestive of mastocytosis were examined by tryptase immunostaining. Baseline levels of serum tryptase and urinary 11beta-PGF(2)(alpha) and N-methylhistamine were obtained. In 2 of the 4 patients, urinary 11beta-PGF(2)(alpha) and N-methylhistamine samples were also measured during acute symptoms.. Baseline increase in urinary excretion of the PGD(2) metabolite 11beta-PGF(2)(alpha) was found in 2 patients. In the remaining 2 patients, baseline levels of urinary 11beta-PGF(2)(alpha) and N-methylhistamine were normal, but during acute symptoms, the excretion of 11beta-PGF(2)(alpha) increased markedly. Treatment with aspirin resulted in normalization of 11beta-PGF(2)(alpha) excretion in the 2 patients with elevated baseline levels and in prevention of symptoms in all 4 patients.. These results suggest that mast cell activation may be manifested by a selective excessive release of PGD(2). These patients respond to administration of aspirin but not to antihistamines.

Topics: Adult; Anaphylaxis; Aspirin; Female; Histamine Release; Humans; Male; Mast Cells; Mastocytosis; Middle Aged; Prostaglandin D2; Tryptases

Human mast cells, by elaborating vasoactive mediators and cytokines, are the primary effector cells of anaphylaxis. A body of evidence implicates human heart mast cells (HHMCs) in anaphylaxis. These cells have been identified perivascularly, in dose proximity to myocytes and in the arterial intima in human heart tissue. The membrane surface of mast cells from human heart tissue of patients undergoing cardiac transplantation expresses the high affinity receptors for IgE (FcepsilonRI) and C5a receptors. Activation of HHMCs in vitro with anti-IgE or anti-FcepsilonRI induced the release of preformed mediators (histamine, tryptase and chymase) and the de novo synthesis of LTC4 (approximately equal to 18 ng/10(6) cells) and PGD2 (approximately equal to 18 ng/10(6) cells). Complement activation and anaphylatoxin formation occur during anaphylaxis in human. C5a caused rapid release of histamine and tryptase from HHMCs. These cells are activated in vitro by therapeutic (general anaesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.) that may cause non-IgE-mediated anaphylactic reactions. Administration of low concentrations of histamine and cysteinyl leukotrienes in subjects undergoing diagnostic catheterization caused significant systemic and coronary haemodynamic effects. Taken together, these results indicate that the human heart can be both the site and the target of anaphylactic reactions.

Topics: Anaphylaxis; Atracurium; Autoantibodies; Cytokines; Heart; Histamine; Humans; Immunoglobulin E; Leukotrienes; Mast Cells; Myocardium; Propofol; Prostaglandin D2; Receptors, Histamine H1; Receptors, IgE

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.

Topics: Anaphylaxis; Animals; Antigens; Dinoprost; Diphenhydramine; Glycopeptides; Guinea Pigs; Histamine; In Vitro Techniques; Indazoles; Leukotriene D4; Muscle Contraction; Muscle, Smooth; Neprilysin; Prostaglandin D2; SRS-A; Trachea

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.

Topics: Anaphylaxis; Dinoprost; Drug Stability; Drug Storage; Female; Humans; Kinetics; Male; Mastocytosis; Niacin; Prostaglandin D2; Prostaglandins D; Time Factors; Urticaria Pigmentosa

One hundred thirty-eight patients with a previous anaphylactic reaction to a yellow jacket or a honeybee sting, as well as eight volunteers, were subjected to an in-hospital sting challenge. Plasma levels of histamine, tryptase, and prostaglandin D2 (PGD2) during sting challenge were studied in relation to clinical symptoms. Prechallenge levels (mean +/- SD) of histamine, tryptase, and PGD2 were 2 +/- 1 nmol/L, 0.3 +/- 0.3 U/L, and 320 +/- 223 ng/L, respectively. In the volunteers and in none except for one of the nonreacting patients, these levels did not change significantly after challenge. In contrast, mean increases in the group of 18 patients with a mild reaction were significant for histamine and tryptase at one or more time points after the challenge. (Five patients demonstrated no increase in histamine; nine demonstrated no increase in tryptase.) Except for histamine levels in one patient, these increases were considerably more in all 17 patients with a severe reaction, starting from the first anaphylactic symptoms. Fifteen minutes later, peak values were reached of 1275 +/- 2994 nmol of histamine per liter (range, 3 to 12800 nmol/L; median, 11 nmol/L) and 406 +/- 1062 U of tryptase per liter (range, 1.8 to 4400 U/L; median, 17 U/L). This rise in levels inversely correlated with the mean arterial pressure. Plasma levels of PGD2 in severely reacting patients did not differ significantly from those in patients with a mild or no reaction. In conclusion, only 28% of patients with a history of Hymenoptera anaphylaxis developed an anaphylactic reaction after an in-hospital challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anaphylaxis; Animals; Bees; Clemastine; Epinephrine; Histamine; Humans; Immunoglobulin E; Immunoglobulin G; Insect Bites and Stings; Mast Cells; Peptide Hydrolases; Prospective Studies; Prostaglandin D2; Time Factors; Wasps

The release of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), and histamine induced by antigen and compound 48/80 was studied using an in vitro model of anaphylaxis in guinea pig skin. Abdominal skin from ovalbumin-sensitized guinea pigs was cut into 0.5-1.0 mm-thick slices which were incubated in Tyrode solution at 37 degrees C with or without either ovalbumin or 48/80. Released PGD2 and PGE2 were measured by radioimmunoassay and gas chromatography-mass spectrometry, respectively. Release of PGD2 was detectable at 2 min after challenge (50 micrograms/ml ovalbumin), reaching a maximum at about 15 min. Histamine release was more rapid, achieving 50% of maximum at about 4 min compared to about 7 min for PGD2. In 11 experiments incubation with ovalbumin (50 micrograms/ml for 10 min) induced a significant 6-fold increase in PGD2 compared to unchallenged controls (399 +/- 53 and 67 +/- 19 ng/g dry weight skin, respectively; mean +/- SEM) and a net 47.2% histamine release. In contrast, a smaller (27%) rise in PGE2 was found. Indomethacin (14 microns) completely suppressed evoked PGD2 and PGE2 synthesis without evident effect on histamine release, suggesting that the release of histamine in this model is not dependent on prostaglandin production. The mast cell degranulating agent compound 48/80 (50 micrograms/ml) released significant amounts of PGD2 (340 +/- 86 ng/g skin compared to 89 +/- 30 ng/g for control skin, n = 5) but had no appreciable effect on PGE2. These results show that guinea pig skin can synthesize significant quantities of PGD2 in anaphylactic reactions. Prostaglandin D2 produced in acute allergic reactions in skin in vivo may contribute to the inflammatory reaction, either directly or in synergism with other mediators.

Topics: Anaphylaxis; Animals; Antigens; Dinoprostone; Guinea Pigs; Histamine Release; Indomethacin; Mast Cells; Ovalbumin; p-Methoxy-N-methylphenethylamine; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Skin

The immunopathogenesis of the anaphylactoid Mazzotti reactions has been studied by comparing physiologic and immunologic aspects of diethylcarbamazine-induced shock in Dirofilaria immitis infected dogs with antigen induced anaphylaxis in infected and uninfected controls. Filarial antigen, specific host IgG antibody, and C1 and C3 complement levels were quantitatively measured over time in relation to the levels of histamine and prostaglandin D2 in the blood and changes in mean blood pressure. D. immitis antigen injected into uninfected dogs having no detectable IgG antibody to D. immitis or Toxocara canis produced a rapid drop in blood pressure that paralleled a drop in C1 and C3 levels and an increase in prostaglandin D2. Antigen injected into infected dogs with IgG antibody produced a similar drop in blood pressure and complement and increase in prostaglandin D2 which differed from the uninfected group only in the slower clearance of antigen from the blood. Diethylcarbamazine alone produced no measurable changes in blood pressure or complement in uninfected hosts. Diethylcarbamazine, however, administered into skin test positive infected dogs, produced a temporally slower but quantitatively similar loss in blood pressure, drop in complement, and increase in prostaglandin D2 and histamine to that induced by antigen injection. Complement activation and immune complex formation are initiated by antigen release, and subsequent vasoactive mediator release leads to shock with prostaglandin D2 being quantitatively higher in blood than is histamine.

Topics: Airway Resistance; Anaphylaxis; Animals; Antigens, Helminth; Blood Pressure; Complement Activation; Complement C1; Complement C3; Diethylcarbamazine; Dirofilaria immitis; Dirofilariasis; Dogs; Histamine; Immunoglobulin G; Prostaglandin D2; Prostaglandins D

The relative activities of three bronchoconstrictive mediators of anaphylaxis, prostaglandin (PG) D2, PGF2 alpha and histamine, were investigated in anesthetized dogs using two different measures of peripheral lung reactivity: resistance to flow through collateral airways (Rcoll) and dynamic lung compliance (Cdyn). In the collateral system, the three agonists exhibited approximately 3-fold differences in their relative activities when administered by rapid injection into the superior vena cava, with PGD2 greater than PGF2 alpha greater than histamine. PGD2 was approximately three times more active than PGF2 alpha in reducing Cdyn, whereas responses to PGF2 alpha and histamine were equivalent. These relationships were unchanged in vagotomized animals. Pretreatment with atropine (1 mg/kg) significantly attenuated changes in Rcoll, but had only small and inconsistent effects on changes in Cdyn. Although the time to initial response in both measures of peripheral airways reactivity was similar, the time to maximal response in Rcoll was approximately twice that of Cdyn. In lung parenchymal strips, the rank order of contractile activity of the three mediators was opposite that observed in the peripheral airways in vivo. These data demonstrate that airflow through the collateral system can be modulated by mediators of anaphylaxis in the pulmonary circulation and suggest that such mediators may influence ventilation/perfusion relationships in the lung periphery through their differential effects on peripheral airways and other parenchymal contractile elements. The present study also indicates that the determinants of flow through the collateral system exhibit certain basic pharmacologic and physiologic differences from those of Cdyn and suggests that these two measures of peripheral airways reactivity are not equivalent.

Topics: Airway Resistance; Anaphylaxis; Animals; Dinoprost; Dogs; Dose-Response Relationship, Drug; Female; Histamine; In Vitro Techniques; Lung; Lung Compliance; Male; Muscle Contraction; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Respiration; Vagotomy

Proteolytic digestion of human lung tissue dispersed a population of cells (HDLC) containing 1 to 8% mast cells but which were free from bronchial and vascular smooth muscle. Incubation of HDLC with anti-human IgE, which released a net 24.8 + 4.3% of mast cell-derived histamine, stimulated a 14-fold increase in the generation of PGD2, a seven-fold increase in TXB2, and less than a twofold increase in PGF2 alpha, immunoreactive PGE, (i-PGE) and 6-keto-PGF1 alpha. A similar profile of prostanoid release was observed when cells were challenged with epsilon-specific anti-IgE, indicating that the response was specific to the coupling of IgE Fc receptors. The calcium ionophore A23187 also released prostanoids from HDLC in approximately the same proportions as anti-IgE. This stimulus, however, released only 50% as much PGD2 per nanogram histamine than did IgE-dependent activation, thereby showing a fundamental difference in the mechanisms by which the two agents activate mast cells and liberate arachidonic acid for oxidative metabolism. In concentration-response and time course experiments, both secretory stimuli released prostanoids and histamine in parallel. After separation of lung cells by isopyknic centrifugation, challenge with anti-IgE or A23187 released PGD2 only from those fractions containing mast cells, the amount released corresponding closely to both the mast cell concentration and net histamine release. On pooling data from all experiments, the closest correlation was found between release of PGD2 and histamine when cells were stimulated with either anti-IgE (r = 0.813, p less than 0.001) or A23187 (r = 0.763, p less than 0.001), supporting a mast cell origin for PGD2. The release of other prostanoids in fractions not containing mast cells demonstrates that macrophages, monocytes, and lymphocytes have the capacity to generate TXB2, PGF2 alpha, and i-PGE both in the absence and presence of mast cells. Thus, although mast cells are likely to be the major source of PGD2 generated upon IgE-dependent stimulation of HDLC, other cells dispersed from lung tissue have the capacity to generate prostanoids directly after activation of their IgE-Fc receptors and, indirectly after the secretion of mast cell mediators.

Topics: Anaphylaxis; Calcium; Cell Separation; Centrifugation, Density Gradient; Histamine Release; Humans; Kinetics; Lung; Mast Cells; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; Thromboxane B2