leukotriene-c4 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

Basophils are the least common type of granulocyte and they account for less than 1% of peripheral blood leukocytes. Because of this minority status and a phenotype that is similar to mast cells, basophils have often been neglected in immunological studies or considered to have minor, redundant roles in immune responses in vivo. However, recent studies have now defined previously unrecognized roles for basophils in both immune regulation and allergic responses, and have shown that basophils and mast cells have distinct roles in immune responses.

Topics: Anaphylaxis; Animals; Basophils; Dermatitis, Atopic; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Immunologic Memory; Leukotriene C4; Mast Cells; Mice; Th2 Cells

The cytosolic 85 kDa phospholipase A(2) (cPLA(2)) is a unique member of the phospholipase A(2) (PLA(2)) superfamily. Because PLA(2) activity and eicosanoid production are important in normal and pathophysiological states we and the laboratory of Shimizu created a mouse deficient in cPLA(2) (cPLA(2)(-/-) mouse). cPLA(2)(-/-) mice develop normally but the females have severe reproductive defects. cPLA(2)(-/-) mice suffer smaller infarcts and fewer neurological deficits after transient occlusion of the middle cerebral artery and have less injury after administration of a dopaminergic selective neurotoxin. cPLA(2)(-/-) mice have a more rapid recovery from allergen-induced bronchoconstriction and have no airway hyperresponsiveness. Peritoneal macrophages from cPLA(2)(-/-) mice fail to produce prostaglandins, leukotriene B(4) and cysteinyl leukotrienes after stimulation. Bone marrow-derived mast cells from cPLA(2)(-/-) mice fail to produce eicosanoids in either immediate or delayed phase responses. Thus the cPLA(2) knockout mouse has revealed important roles of cPLA(2) in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses. Furthermore the cPLA(2)(-/-) mouse reveals that the many other forms of PLA(2) cannot replace many functions of cPLA(2). The importance of cPLA(2) in inflammation and tissue injury suggests that pharmacological targeting of this enzyme may have important therapeutic benefits.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Airway Resistance; Anaphylaxis; Animals; Brain Injuries; Brain Ischemia; Bronchoconstriction; Cytosol; Female; Gene Deletion; Leukotriene B4; Leukotriene C4; Lipopolysaccharides; Litter Size; Macrophages, Peritoneal; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Cerebral Artery; Models, Animal; Ovalbumin; Phospholipases A; Pregnancy

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

Although anti-IgE antibody (Ab) therapy was recently shown to be effective in patients with bronchial asthma, no study has reported the effect of IgE therapy in the prevention of wasp venom anaphylaxis. In this study, we used a mouse model of wasp venom allergy to investigate the effect of anti-IgE Ab on wasp venom anaphylaxis.. We developed a mouse model of wasp venom allergy by intraperitoneally (i.p.) injecting wasp venom into BALB/c mice twice on experimental day (day) 0 and 7. On day 20, a group of mice received an i.p. injection of mouse anti-IgE Ab as a pretreatment, and another group received rat anti-IgG1 Ab. On day 21, the animals were challenged by i.p. injection of wasp venom, and 30 min later, body temperature was measured and serum levels of leukotriene (LT) B4 and LTC4 were determined using enzyme immunoassay.. The body temperature of mice treated with anti-IgE Ab and controls before and after wasp venom challenge was 37.8±0.2 vs 37.7± 0.3°C before challenge and 37.8±0.2 vs 37.1± 0.3°C after challenge, respectively, showing that anti-IgE Ab treatment significantly prevented body temperature from falling (p <0.05). Furthermore, anti-IgE Ab treatment reduced total serum IgE levels in the treated mice (42.2±15.9 pg/ml), compared with controls (105.9±23.1 pg/ml, p <0.05), and inhibited the secretion of LTC4 in the treated mice (32.0±18.8 pg/ml), but not in the controls (162.4±12.4 pg/ml, p <0.05), following challenge with wasp venom.. The results of the present study indicate that anti-IgE Ab treatment is an effective preventive measure against wasp venom-induced anaphylaxis.

Topics: Anaphylaxis; Animals; Body Temperature; Disease Models, Animal; Humans; Immunoglobulin E; Leukotriene B4; Leukotriene C4; Mice; Rats; Wasp Venoms

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

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

The role of basophils in an anaphylactic response is well recognized but is usually masked by mast cells, which contain similar mediators for the induction of generalized vasodilatation and laryngeal constriction. The rapid onset of systemic anaphylactic symptoms, particularly in insect stings and ingested food, suggest that basophils, a circulating pool of cells containing histamine and other potent mediators such as leukotrienes, may be more involved in systemic anaphylaxis than originally thought. We wished to examine if secretory phospholipase A2, a systemic allergen found in honey bee venom (HBV-sPLA2) may activate basophils directly leading to rapid systemic mediator release. Basophils were isolated from human blood and stimulated with increasing concentrations of HBV-sPLA2. We found that physiological concentrations of HBV-sPLA2 induce rapid leukotriene C4 production from purified human basophils within 5 min, while interleukin (IL)-4 expression and production was induced at later time-points. Histamine release was not induced, signifying that HBV-sPLA2 did not induce generalized degranulation. Surface expression of CD63, CD69 and CD11b were up-regulated following HBV-sPLA2 treatment. Stimulation of basophils with anti-immunoglobulin E (IgE) following treatment with HBV-sPLA2 did not induce more leukotriene release. To investigate the mechanism of leukotriene production, 9-12 octadecadiynioc acid, a cyclooxygenase-1 (COX-1) and 15-lipoxygenase inhibitor, was used and this abrogated leukotriene production. These results indicate that HBV-sPLA2 can directly activate human basophils in vitro to induce leukotriene production.

Topics: Analysis of Variance; Anaphylaxis; Basophils; Bee Venoms; Cells, Cultured; Cyclooxygenase Inhibitors; Cytokines; Diynes; Enzyme Inhibitors; Fatty Acids, Unsaturated; Flow Cytometry; Histamine Release; Humans; Leukotriene C4; Lipoxygenase Inhibitors; Phospholipases A2, Secretory; Stimulation, Chemical

To ensure the suitable preservation of isolated lungs, a super-cooling system was used to cool water to temperatures as low as -5 degrees C without freezing.. After lung tissues were obtained from patients with lung cancer, they were kept at -5 degrees C or 4 degrees C for as many as 5 days, and then they were histologically and biochemically examined. To evaluate biochemical stability, tissues after storage were passively sensitized with immunoglobulin E and then incubated with anti-immunoglobulin-E antibody.. Although tissues preserved at -5 degrees C for 5 days had an almost normal appearance with intact cilia on bronchial epithelium and normal endothelium, tissues stored at 4 degrees C showed degradation of these structures. Single-stranded DNA, a sign of DNA cleavage, was frequently noted in tissues stored at 4 degrees C, but only rarely observed at -5 degrees C. A significant amount of cysteinyl-leukotrienes was generated from tissues stored at -5 degrees C for 3 days, but there was no response to antibody stimulation from tissues stored at 4 degrees C.. Super-cooling systems may provide useful applications as a novel preserving method.

Topics: Aged; Aged, 80 and over; Anaphylaxis; Antibodies, Anti-Idiotypic; Cryopreservation; DNA, Single-Stranded; Female; Humans; Hypertonic Solutions; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lung; Lung Neoplasms; Lung Transplantation; Male; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pneumonectomy; Refrigeration; Static Electricity; Temperature; Tissue and Organ Harvesting

Topics: Anaphylaxis; Antibodies, Anti-Idiotypic; Cryopreservation; DNA, Single-Stranded; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lung; Lung Transplantation; Organ Preservation; Pneumonectomy; Static Electricity; Tissue and Organ Harvesting; Tissue and Organ Procurement; Transplantation, Homologous

After in vitro allergen-specific stimulation, basophils become activated and release sulfidoleukotrienes LTC4, LTD4 and LTE4. This can be detected by means of the CAST assay. We assessed the positivity criteria and the reliability of antigen-specific sulfidoleukotriene production (CAST) in the in vitro diagnosis of betalactam (BL) allergic patients.. We studied a sample of 67 patients (age 48.94 +/- 15.76 years) who had presented with anaphylaxis or urticaria-angioedema within the first 60 minutes after administration of Amoxicillin (54/67), Penicillin G (7/67), Cefuroxime (5/67) or Cefazoline (1/67). All of them had a positive skin test to at least one of the antigenic determinants of Penicillin. As control group 30 adults with negative skin tests who tolerated BL were included. All of them underwent skin tests, oral provocation tests, specific IgE (CAP-FEIA, Pharmacia) and CAST.. Positivity criteria were established by means of ROC curves: a sLT release induced by Betalactams of at least 100 pg/ml and greater than or equal to 3 times the basal value. The overall sensitivity of CAST is 47.7% and specificity 83.3%. Sensitivity of specific IgE is 37.8% and specificity 83.3%.. We have established validated positivity criteria for the CAST technique in patients allergic to Betalactams. This technique is a useful in vitro diagnostic method in patients with IgE-mediated allergy to Betalactam antibiotics.

Topics: Amoxicillin; Anaphylaxis; Angioedema; Anti-Bacterial Agents; Cefazolin; Cefuroxime; Drug Hypersensitivity; Female; Humans; Immunoglobulin E; Lactams; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Middle Aged; Penicillin G; Skin Tests; Urticaria

Enteric neuroimmune interactions in gastrointestinal hypersensitivity responses involve antigen detection by mast cells, mast cell degranulation, release of chemical mediators, and modulatory actions of the mediators on the enteric nervous system (ENS). Electrophysiological methods were used to investigate electrical and synaptic behavior of neurons in the stomach and small intestine during exposure to beta-lactoglobulin in guinea pigs sensitized to cow's milk. Application of beta-lactoglobulin to sensitized preparations depolarized the membrane potential and increased neuronal excitability in small intestinal neurons but not in gastric neurons. Effects on membrane potential and excitability in the small intestine were suppressed by the mast cell stabilizing drug ketotifen, the histamine H(2) receptor antagonist cimetidine, the cyclooxygenase inhibitor piroxicam, and the 5-lipoxygenase inhibitor caffeic acid. Unlike small intestinal ganglion cells, gastric myenteric neurons did not respond to histamine applied exogenously. Antigenic exposure suppressed noradrenergic inhibitory neurotransmission in the small intestinal submucosal plexus. The histamine H(3) receptor antagonist thioperamide and piroxicam, but not caffeic acid, prevented the allergic suppression of noradrenergic inhibitory neurotransmission. Antigenic stimulation of neuronal excitability and suppression of synaptic transmission occurred only in milk-sensitized animals. Results suggest that signaling between mast cells and the ENS underlies intestinal, but not gastric, anaphylactic responses associated with food allergies. Histamine, prostaglandins, and leukotrienes are paracrine signals in the communication pathway from mast cells to the small intestinal ENS.

Topics: Anaphylaxis; Animals; Dinoprostone; Electrophysiology; Fluorescent Antibody Technique; Guinea Pigs; Histamine; Histamine Antagonists; Intestine, Small; Lactoglobulins; Leukotriene C4; Mast Cells; Membrane Potentials; Milk; Neuroimmunomodulation; Neurons; Ovalbumin; Serotonin Antagonists; Stomach; Submucous Plexus; Sympathetic Nervous System; Synaptic Transmission

Anaphylactic shock accidents after allergen exposure are frequent. After immunization with ovalbumin (OVA), a common dietary constituent, we evaluated the efficacy of pretreatment with histamine-receptor or serotonin-receptor blockers administered alone or in combination with a nitric oxide synthase inhibitor (L-NAME) on OVA-induced anaphylactic shock in Brown Norway rats. Animals were allocated to the following groups (n = 6 each): control (0.9% saline); diphenydramine (15 mg kg(-1)); cimetidine (20 mg kg(-1)); diphenydramine + cimetidine; dihydroergotamine (50 microg kg(-1)); diphenydramine + cimetidine + dihydroergotamine; L-NAME (100 mg/kg) alone or associated with diphenydramine, cimetidine, diphenydramine + cimetidine, dihydroergotamine, or diphenydramine + cimetidine + dihydroergotamine. Mean arterial blood pressure (MABP), heart rate (HR), and survival time were monitored for 60 min following treatment. The shock was initiated with i.v. OVA. The MABP drop after i.v. OVA was worsened by diphenydramine and was modestly attenuated by cimetidine, dihydroergotamine, or both together. L-NAME potentiated slightly the effects of cimetidine and dihydroergotamine by lessening the initial MABP decrease, but this transient effect was not sufficient to prevent the final collapse or to improve survival time. Decreased vasodilatory (prostaglandins E2), increased vasoconstrictory (thromboxane B2) prostaglandins, and unchanged leukotriene C4 concentrations were contributory to the overall hemodynamic changes. Thus, the combined blockade of vasodilator mediators (histamine, serotonin, and nitric oxide) slowed the MABP drop in anaphylactic shock, but did not improve survival. More studies are needed to understand these discordant effects.

Topics: Anaphylaxis; Animals; Arteries; Cimetidine; Dihydroergotamine; Dinoprostone; Eicosanoids; Enzyme Inhibitors; Heart; Histamine; Hypotension; Leukotriene C4; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Ovalbumin; Pressure; Rats; Rats, Inbred BN; Receptors, Serotonin; Serotonin; Thromboxane B2; Time Factors

We evaluated whether IL-4, a cytokine critical for inducing allergic responses, also contributes to the effector phase of allergy. Pretreatment of mice with IL-4 or the related cytokine, IL-13, rapidly and dramatically increased the severity of anaphylaxis induced by cross-linking Fc(epsilon)RI or FcgammaRIII. This effect was inhibited by endogenously produced IFN-gamma, was T cell-, B cell-, and common gamma-chain-independent, and required IL-4Ralpha and Stat6. IL-4Ralpha signaling also enhanced anaphylaxis in mice infected with a nematode parasite that stimulates IL-4/IL-13 production. IL-4 exacerbated anaphylaxis by acting synergistically with vasoactive mediators to increase vascular permeability. Synergy between IL-4 and vasoactive mediators during the effector phase of allergic inflammation may both contribute to allergic immunopathology and enhance protective immunity against gastrointestinal worms.

Topics: Adjuvants, Immunologic; Anaphylaxis; Animals; Capillary Leak Syndrome; Dose-Response Relationship, Immunologic; Drug Therapy, Combination; Female; Injections, Intravenous; Interleukin-12; Interleukin-13; Interleukin-18; Interleukin-4; Leukotriene C4; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Mice, Transgenic; Platelet Activating Factor; Serotonin; Signal Transduction; STAT6 Transcription Factor; Trans-Activators

Allergy to Hymenoptera venom (VH) effects more and more patients in France. It is manifest in two main forms, which are Loco-regional (RLR) and Systemic reactions (SR). This allergy is detectable amongst others by the techniques of histamine release (HR) and release of leucotrienes C4 (LTC4). The aim of this work has been to fix a threshold that gives differentiation of RLR ad RS by the two techniques. We found in a positive population a threshold histamine release (HR) value of 25% and a concentration of LTC4 of 600 ng/ml. These are the thresholds above which a patient would be at around 70% risk of RS. This study has a predictive value for patients who are suspected of allergy of VH or who have already had clinical reactions and risk sensitization.

Topics: Acetylcholinesterase; Adult; Aged; Allergens; Anaphylaxis; Bee Venoms; Biomarkers; Child; Evaluation Studies as Topic; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Leukotriene C4; Male; Middle Aged; Predictive Value of Tests; Risk; Wasp Venoms

Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.

Topics: Adult; Anaphylaxis; Animals; Antineoplastic Agents; Asparaginase; Bleomycin; Calcimycin; Drug Hypersensitivity; Humans; In Vitro Techniques; Inflammation; Ionophores; Leukotriene C4; Leukotriene E4; Leukotrienes; Lymphoma, Non-Hodgkin; Mast Cells; Mice; Mice, Inbred BALB C; Respiratory Distress Syndrome

Post-anesthesia anaphylactic reactions or those seen during drug provocation tests with a systemic clinical reaction may be confirmed by the sequential release into blood of plasma histamine, tryptase and leukotriene C4 and into urine of urinary methylhistamine and leukotriene E4.

Topics: Acetaminophen; Anaphylaxis; Anesthetics; Aspirin; Biomarkers; Chymases; Drug Hypersensitivity; Histamine; Humans; Leukotriene C4; Leukotriene E4; Postoperative Complications; Serine Endopeptidases; Tryptases

A protocol has been produced for the study of anaphylactic accidents that occur post-operatively that allows definition of the anaphylactic origin, and so reactions that are mediated by IgE in post-operative accidents. This protocol occurs in two stages, the first is done in the minutes and hours that follow the anaphylactic accident, and the second a month or 6 weeks afterwards. At first, we evaluate the sequential study of the liberation of the mediators of anaphylaxis, plasma histamine, serum tryptase, urinary methylhistamine and, more recently, leucotriene E4. The second study is devoted to reactions that are mediated by IgE, essentially, specific serum IgE, tests of activation of basophils by flow cytometry, measurement of leucotriene C4 and skin tests. A study on 16 subjects has evaluated and validated the protocol and shown a significant level of correspondence of results between the sequential measurement of mediators on one hand and on the other the search for IgE-mediated reactions every time that there was an anaphylactic reaction.

Topics: Adolescent; Adult; Aged; Anaphylaxis; Anesthetics; Basophils; Child; Chymases; Clinical Protocols; Creatine; Drug Hypersensitivity; Female; Gelatin; Histamine Release; Humans; Immunoglobulin E; Leukotriene C4; Leukotriene E4; Male; Methylhistamines; Middle Aged; Muscle Relaxants, Central; Plasma Substitutes; Postoperative Complications; Serine Endopeptidases; Skin Tests; Succinates; Tryptases

Ws/Ws rats are deficient in both mucosal- and connective tissue-type mast cells. To study the role of mast cells in active anaphylaxis, changes in vascular permeability in the trachea upon intravenous antigen challenge with Evans blue dye were examined in Ws/Ws, heterogenic Ws/+, and normal +/ + rats sensitized with the nematode Nippostrongylus brasiliensis. Antigen challenge resulted in fatal anaphylactic shock in some +/+ and Ws/+ rats, but not in Ws/Ws rats. Marked dye leakage developed within 30 min in the trachea of +/+ and Ws/+ rats, while Ws/Ws rats showed no substantial increases in the levels of vascular permeability. Ex vivo stimulation of sensitized lung fragments from +/+ animals with specific antigen induced significant releases of histamine and leukotriene (LT) C4, while sensitized Ws/Ws rat-lung fragments did not. In Ws/Ws rats, levels of nematode-specific IgE, IgG1 and IgG2a antibodies as well as levels of lung eosinophilia were not significantly different from those in +/+ rats. These results show that mast cell-deficient Ws/Ws rats fail to develop active anaphylaxis, and this is mediated probably by the lack of mast cell-derived mediators required for initiation of the reaction.

Topics: Anaphylaxis; Animals; Antibodies, Helminth; Antigens, Helminth; Capillary Permeability; Cell Count; Histamine Release; Immunization; Leukotriene C4; Lung; Mast Cells; Nippostrongylus; Rats; Rats, Mutant Strains; Strongylida Infections; Trachea

Persistent diarrhea, vomiting, and dehydration are symptoms often seen in patients suffering from food allergy after chronic antigen exposure; however, the precise mechanisms involved have not been well defined. In an effort to clarify the mechanisms of the chronic intestinal changes attributable to genuine IgE-mediated anaphylactic reactions induced by orally administered antigen, a mouse model was established by s.c. implantation of a murine hybridoma capable of producing monoclonal anti-trinitrophenyl IgE antibody, and the morphologic and immunologic changes occurring in the intestine upon chronic antigen exposure were investigated. In the early stage after ingestion of the antigen, diarrhea and noticeable infiltration of mast cells as well as eosinophils into the lamina propria were observed. A substantial increase in serum histamine levels as well as an increase in leukotriene C4 synthesis in the jejunal mucosa were observed 1 h after antigen challenge. Also, the synthesis of leukotriene B4 was significantly elevated for up to 9 h after antigen challenge. The expression of both intercellular adhesion molecule-1 (ICAM-1) on mucosal vascular endothelial cells and IAd on epithelial cells was markedly enhanced, and noticeable infiltration of eosinophils and lymphocytes was also confirmed in the mouse model after chronic antigen exposure. These findings suggest that oral antigen exposure induces anaphylactic reactions in the intestine mediated by mast cells and eosinophils in response to the IgE-antigen complex in the early phase, and also induces lymphocyte migration after chronic antigen exposure.

Topics: Administration, Oral; Anaphylaxis; Animals; Calcimycin; Chemotaxis, Leukocyte; Female; Haptens; Immunoglobulin E; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Ionophores; Leukotriene B4; Leukotriene C4; Mice; Mice, Inbred BALB C; Serum Albumin, Bovine; Trinitrobenzenes

A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC50s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtho l (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.

Topics: Anaphylaxis; Animals; Blood Platelets; Bronchial Hyperreactivity; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene C4; Lipoxygenase Inhibitors; Male; Naphthols; Neutrophils; Optical Rotation; Quinolines; Rats; Rats, Sprague-Dawley; SRS-A; Stereoisomerism

We have investigated the antigen-stimulated release of calcitonin gene-related peptide (CGRP) from ovalbumin-sensitized guinea-pig isolated hearts and the interaction with other mediators of anaphylaxis released concomitantly. It was found that antigen challenge caused a significant increase of CGRP release (from basal 31.2 +/- 2.9 to 51.6 +/- 4.9 fmol/5 min). Anaphylactic CGRP release was significantly attenuated in the presence of the cyclooxygenase inhibitor indomethacin while the 5-lipoxygenase inhibitor Bay-X1005 ((R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid) had no significant effect. Combined treatment with the histamine receptor (H1,H2) antagonists mepyramine and cimetidine also significantly attenuated anaphylactic release of CGRP. Under control conditions antigen injection increased release of cysteinyl-leukotrienes (LT), thromboxane (TXB2) and 6-keto-prostaglandin (PG)F1 alpha from basal values of 0.96 +/- 0.09, 2.7 +/- 0.7 and 3.4 +/- 0.28 ng/5 min respectively, to 5.9 +/- 0.9, 48.4 +/- 3.4 and 6.9 +/- 1.4 ng/5 min. Indomethacin abolished the release of cyclooxygenase products of arachidonate metabolism and simultaneously increased cysteinyl-LT release significantly (8.8 +/- 1.4 ng/5 min). Conversely Bay-X1005 completely abolished cysteinyl-LT release and had no significant effect on anaphylactic release of TXB2 and 6-keto-PGF1 alpha. Simultaneous blockade of H1 and H2 receptors abolished release of 6-keto-PGF1 alpha, while release of TXB2 and cysteinyl-LT was not significantly affected. The results indicate that CGRP is not a primary mediator of the immediate hypersensitivity reaction of the heart, but is in turn released by arachidonic acid metabolites of the cyclooxygenase pathway and histamine. In contrast, LT obviously do not contribute to anaphylactic CGRP release. CGRP is a potent coronary vasodilator and could act as endogenous functional antagonist of vasoconstrictor mediators also released during cardiac anaphylaxis such as cysteinyl-LT, platelet activating factor and TXA2.

Topics: 6-Ketoprostaglandin F1 alpha; Anaphylaxis; Animals; Calcitonin Gene-Related Peptide; Cimetidine; Coronary Circulation; Cyclooxygenase Inhibitors; Guinea Pigs; Heart; Histamine H1 Antagonists; Histamine H2 Antagonists; In Vitro Techniques; Indomethacin; Leukotriene C4; Lipoxygenase Inhibitors; Myocardium; Ovalbumin; Pyrilamine; Quinolines; Thromboxane B2

Anaphylaxis to paracetamol exists and perhaps nowadays diagnosis is not confined to clinical evidence of: The repeatability of clinical symptoms. Skin tests. Provocation tests. But also by immuno-biological evidence. Application of the test of Activation of basophils by Flow Cytometry and measurement of leukotriene C4 have been nowadays largely validated and constitute irrefutable proof of the responsibility of the drug as the origin of the clinical symptoms.

Topics: Acetaminophen; Adult; Anaphylaxis; Basophil Degranulation Test; CD4-Positive T-Lymphocytes; Drug Eruptions; Female; Humans; Leukotriene C4; Middle Aged; Skin Tests; Urticaria

With regard to an observation of anaphylaxis after a mosquito bite, we have shown by new immunobiological parameters and clinical investigations: Skin tests, specific IgE, Tests of Activation of basophils by flow cytometry (on basophils and total blood) and measurement of Leucotriene LTC4, the objective reality of the mechanism of IgE-dependent hypersensitivity (HS). This observation is correlated with rare work in support of true IgE-mediated allergy to mosquito 9 authors having used skin tests, PK in 1984 and immunoblot.

Topics: Adult; Anaphylaxis; Animals; Basophils; Culicidae; Humans; Immunoglobulin E; Insect Bites and Stings; Leukotriene C4; Mice; Skin Tests

Leukotrienes have been implicated in the regulation of immune responses, including inflammation and immediate hypersensitivity reactions. Here, we describe the phenotypic analysis of leukotriene-deficient mice generated by inactivation of the 5-lipoxygenase (5LO) gene. These 5LO(-/-) mice were unable to synthesize detectable levels of leukotrienes and were more resistant to lethal anaphylaxis induced by platelet-activating factor. The intensity of an acute inflammatory response induced by arachidonic acid was similar in 5LO(-/-) mice and controls. However, the response in 5LO(-/-) mice, but not in controls, could be virtually eliminated by a cyclooxygenase inhibitor. These data suggest that inflammatory responses are modulated by arachidonic acid metabolites through a variety of interconnected mechanisms. This has important implications for understanding the early events of an inflammatory response and for designing drugs for use in therapeutic intervention.

Topics: Anaphylaxis; Animals; Arachidonate 5-Lipoxygenase; Chemotaxis, Leukocyte; Dinoprostone; Edema; Inflammation; Leukotriene C4; Leukotrienes; Macrophages; Mice; Mice, Knockout; Neutrophils; Platelet Activating Factor; Thromboxane B2