leukotriene-d4 and Drug-Hypersensitivity

Leukotriene (LT) E(4) mediates many of the principal features of bronchial asthma, such as bronchial constriction, hyperresponsiveness, eosinophilia, and increased vascular permeability. Furthermore, it is the most stable of the cysteinyl leukotrienes (CysLTs) and can be active at the site of release for a prolonged time after its synthesis. There might be several reasons why LTE(4) has been forgotten. LTE(4) demonstrated low affinity for CysLT(1) and CysLT(2) receptors in equilibrium competition assays. It was less potent than other CysLTs in functional assays, such as calcium flux, in cells transfected with CysLT(1) and CysLT(2). The introduction of CysLT(1) antagonists into clinical practice diverted interest into CysLT(1)-related mechanisms, which were mediated mainly by LTD(4). However, experiments with animal models and human studies have revealed that LTE(4) has unique characteristics that cannot be explained by the current knowledge of CysLT(1) and CysLT(2). These activities include its potency relative to other CysLTs to increase airway responsiveness to histamine, to enhance eosinophilic recruitment, and to increase vascular permeability. Asthmatic airways also demonstrate marked in vivo relative hyperresponsiveness to LTE(4), especially in patients with aspirin-sensitive respiratory disease. This has stimulated a search for additional LT receptors that would respond preferentially to LTE(4) stimulation.

Topics: Animals; Aspirin; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Histamine; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Methacholine Chloride; Receptors, Leukotriene; Skin

Aspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic, aspirin is being increasingly used in the prophylaxis of ischemic heart disease and strokes. The prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the asthmatic population is sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis, sinusitis, and asthma when exposed to the offending drugs. This syndrome is referred to as aspirin-induced asthma (AIA). The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E(2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC(4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. LT-modifying drugs are effective in blocking the bronchoconstriction provoked by aspirin and are used in the treatment of this condition. Aspirin desensitization has a role in the management of AIA, especially in patients who need prophylaxis from thromboembolic diseases, myocardial infarction, and stroke. This review covers the latest understanding of pathogenesis, clinical features, and management of AIA.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Asthma; Bronchial Hyperreactivity; Cyclooxygenase Inhibitors; Desensitization, Immunologic; Dinoprostone; Drug Hypersensitivity; Glutathione Transferase; Humans; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase; Rhinitis; Sinusitis

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

Leukotrienes (LTs) are important in asthma, and LT modifiers modulate antigen-induced asthma. Overproduction of LT by suppression of cyclooxygenase activity is involved in patients with aspirin-intolerant asthma (AIA).. House dust mite (HDM) inhalation provocation tests were performed in HDM-sensitive asthmatic inpatients without AIA (HDM group; n = 6), and aspirin oral provocation tests were performed in AIA patients (ASA group; n = 7). Tests were repeated using the same regimen after 7 days of treatment with pranlukast, an LT receptor antagonist (LTRA). The effects of pranlukast on changes in sputum LTC(4)-LTD(4), eosinophil cationic protein (ECP), eosinophil count, urinary LTE(4)/creatinine, 11-dehydrothromboxane B(2) (11-dhTXB(2))/creatinine, serum LTC(4)-LTD(4), ECP, and peripheral blood eosinophil count, during immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) in the HDM group and during IAR in the ASA group for each test, were compared in each group.. In the HDM group, IAR and LAR were observed. Sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine increased significantly both during IAR and LAR. Sputum ECP increased during IAR and further increased during LAR. Eosinophil count in the sputum did not increase during IAR but significantly increased during LAR. Pranlukast suppressed the fall in FEV(1) both during IAR and LAR (73.8% and 51.9%, respectively) and inhibited the increase in sputum eosinophil count during LAR and sputum ECP during IAR and LAR. In the ASA group, aspirin-induced IAR was associated with a fall in urinary 11-dhTXB(2)/creatinine, increased the levels of sputum LTC(4)-LTD(4) and ECP and urinary LTE(4)/creatinine. Pranlukast suppressed IAR and inhibited the increase of the level of sputum ECP, but failed to change aspirin-induced LT production in the sputum and urine. The levels of sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine in the stable phase in the ASA group were significantly greater than those in the HDM group.. Our results indicated that HDM-provoked asthma is associated with overproduction of LT with an antigen-antibody reaction, while AIA is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade. LTRA may be useful against both types of asthma through inhibition of LT activity and eosinophilic inflammation of the airways.

Topics: Adult; Anti-Asthmatic Agents; Aspirin; Asthma; Blood Proteins; Bronchial Provocation Tests; Chromones; Drug Hypersensitivity; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Leukotriene D4; Leukotriene E4; Male; Middle Aged; Ribonucleases; Thromboxane B2

Topics: Aspirin; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Humans; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Rhinitis, Allergic, Perennial; Sensitivity and Specificity; Sinusitis

To determine the role of leukotriene (LT)-degrading enzymes in allergic reactions, we studied the effects of inhibitors of gamma-glutamyl transpeptidase (gamma-GTP) and dipeptidases on increases in pulmonary insufflation pressure (PIP) and vascular permeability induced by ovalbumin (OA) antigen in guinea pigs sensitized to OA antigen in vivo. Vascular permeability was assessed by the amount of extravasated Evans blue dye from the trachea, main bronchi, and segmental bronchi. An intravenous (i.v.) administration of OA antigen (200 micrograms/kg) caused increases in PIP and extravasated Evans blue dye, and OA antigen-induced effects were potentiated by gamma-GTP inhibitor L-serine borate (3 x 10(-5) M/kg, i.v.) (P < 0.05) and an inhibitor of dipeptidases, L-cysteine (3 x 10(-5) M/kg, i.v.) (P < 0.01). OA antigen-induced increases in PIP and Evans blue dye extravasation were in part inhibited by LT-receptor antagonist ONO-1078 (10(-4) M/kg, i.v.). Guinea-pig tracheal tissues contained gamma-GTP and microsomal dipeptidase activities. Histochemical and immunohistochemical studies indicate that gamma-GTP-like activity existed in the epithelium and smooth muscle, and an activity of microsomal dipeptidase was observed in the endothelial cells of microvessels and epithelium. These results suggest that LT-degrading enzymes have an important role in regulating allergic reaction in the airway in vivo.

Topics: Animals; Capillary Permeability; Dipeptidases; Dose-Response Relationship, Drug; Drug Hypersensitivity; Evans Blue; gamma-Glutamyltransferase; Glycosylphosphatidylinositols; GPI-Linked Proteins; Guinea Pigs; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Lung; Male; Muscle, Smooth; Ovalbumin; Trachea

Pseudo-allergic reactions (PAR) are caused by a variety of drugs, of particular interest by acetylsalicylic acid (ASA) and other nonsteroidal antiinflammatory drugs. The clinical symptoms often resemble immediate type hypersensitivity reactions and consist of bronchospasm, urticaria, angioedema and even anaphylactic shock. Antigen specific immune mechanisms, however, are not involved. In general, skin tests are not reliable and the diagnosis of PAR is based mainly on risky provocation tests. Therefore, the purpose of this study was to establish procedures for in vitro diagnosis of PAR to ASA. A controlled study was performed including patients with PAR to ASA based on history and positive oral provocation test and non-atopic as well as atopic controls. In this in vitro study the production of sulfidoleukotrienes (sLT) by isolated leukocytes was measured by cellular allergen stimulation test (CAST), which is based on detection of LTC4, LTD4 and LTE4 by a monoclonal antibody. Accordingly, the direct effect of ASA as well as the modulatory effect of ASA on C5a-induced production of sLT in leukocytes in vitro was investigated. In patients with PAR to ASA, C5a-induced generation of sLT was significantly increased as compared to normal controls. In contrast, there was no difference in the spontaneous release of sLT in vitro in patients and controls. Preincubation of leukocytes with ASA did not exert a significant modulatory effect on the spontaneous or the C5a-induced production of sLT in patients and controls. In summary, the present study provides a novel in vitro test system for the diagnosis of PAR to ASA by measurement of sLT release in leukocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antigen-Antibody Reactions; Aspirin; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Humans; In Vitro Techniques; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Middle Aged

The ovalbumin (OA)-sensitized Brown Norway rat (BN) demonstrates early-response (ER) and late-response (LR) allergic bronchoconstriction. To determine whether these responses could be replicated in vitro, we studied lung explants from 8-wk-old male BN rats (wt: 239 +/- 28 g), of which 19 were sensitized to OA (test) and 16 served as controls. Two weeks after sensitization, the animals' lungs were removed, filled with a 1% (wt/vol) agarose-containing solution at 37 degrees C, and cooled to 4 degrees C. Transverse slices (0.5 to 1.0 mm thick) were cut and cultured overnight. Airways were visualized with an inverted microscope and baseline images were obtained with a video camera. To study the ER, 40 airways from 15 test rats and 29 airways from 10 control rats were challenged with 2 micrograms OA and imaged each minute for 10 min. To study the LR, 40 airways from 12 test rats and 44 airways from 12 control rats were challenged with 2 micrograms OA and imaged each hour for 8 h. The maximal response (MR) for each airway was defined as the percent of airway closure. The ER and LR were both defined as an MR > or = mean + 2 SD of the controls. An ER occurred in 38 of 40 test and 2 of 29 control airways (mean MR: 42 +/- 24% versus 4 +/- 3%, p < 0.001), and was completely blocked by methysergide pretreatment in 13 airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Constriction, Pathologic; Disease Models, Animal; Drug Hypersensitivity; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunoglobulin E; In Vitro Techniques; Leukotriene D4; Male; Methysergide; Ovalbumin; Premedication; Propionates; Quinolines; Rats; Serotonin; Time Factors