RESUMO
RATIONALE: Biomarkers predicting development of atopic disease are needed for targeted preventive measures and to study if disease pathology may be active before onset of symptoms. OBJECTIVES: To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11ß-prostaglandin (PG) F2α (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life. METHODS: We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11ß-PGF2α (n = 366) in urine from 1-month-old children participating in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Clinical data on development of allergic sensitization, allergic rhinitis, nasal eosinophilia, blood eosinophilia, eczema, troublesome lung symptoms (significant cough or wheeze or dyspnea), and asthma were collected prospectively until age 6 years. Associations between urinary biomarkers and development of atopic traits were investigated using general estimating equations, logistic regression, and Cox regression. MEASUREMENTS AND MAIN RESULTS: Eosinophil protein X in the urine of the asymptomatic 1-month-old neonates was significantly associated with development of allergic sensitization (odds ratio, 1.49; 95% confidence interval [CI], 1.081.89), nasal eosinophilia (odds ratio, 3.2; 95% CI, 1.28.8), and eczema (hazard ratio, 1.4; 95% CI, 1.02.0), but not with allergic rhinitis, asthma, or blood eosinophilia. Neither leukotriene-C4/D4/E4 nor 11ß-PGF2α was associated with any of the atopic phenotypes. CONCLUSIONS: Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life. These findings suggest activation of eosinophil granulocytes early in life before development of atopy-related symptoms.
Assuntos
Neurotoxina Derivada de Eosinófilo/urina , Hipersensibilidade Imediata/urina , Biomarcadores/urina , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Razão de Chances , Prostaglandinas/urina , SRS-A/urinaRESUMO
A 15-year-old male patient presented with mental retardation, mild motor impairment, and partial deafness. Biochemical investigations showed an abnormal urinary profile of leukotrienes. Concentration of leukotriene D(4) (LTD(4)), which is usually not detectable, was highly increased, whereas LTE(4), the major urinary metabolite in humans, was completely absent. These data suggest membrane-bound dipeptidase deficiency, a new defect in leukotriene biosynthesis on the step of LTE(4) synthesis, as underlying defect.
Assuntos
Deficiência Intelectual/metabolismo , Doenças Neuromusculares/metabolismo , SRS-A/biossíntese , SRS-A/urina , Adolescente , Surdez/metabolismo , Humanos , Leucotrieno C4/biossíntese , Leucotrieno C4/urina , Leucotrieno D4/biossíntese , Leucotrieno D4/urina , Leucotrieno E4/biossíntese , Leucotrieno E4/urina , MasculinoRESUMO
In patients with mevalonate kinase deficiency, urinary excretion of the leukotriene LTE4 was found to be elevated. A positive linear relationship between increased urinary excretion of mevalonate and LTE4 (n = 5) suggests that increased cysteinyl leukotriene synthesis is involved in the pathomechanisms of this disease.
Assuntos
Fosfotransferases (Aceptor do Grupo Álcool) , Fosfotransferases/deficiência , SRS-A/análogos & derivados , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Leucotrieno E4 , Masculino , Ácido Mevalônico/urina , SRS-A/urina , Urina/citologiaRESUMO
Synthesis of cysteinyl leukotrienes was assessed in patients with atopic dermatitis (AD; n = 8) and healthy volunteers (n = 8) by measuring urinary excretion of leukotriene E4 (LTE4), the main index metabolite of cysteinyl leukotrienes in man. Using this non-invasive method we demonstrated a significant (P < 0.05) 4.5-fold increase in excretion of LTE4 compared with healthy volunteers. The identity of LTE4 was unequivocally demonstrated by gas chromatography-mass spectrometry/mass spectrometry (GC-MS/MS). LTE4 was routinely measured by radioimmunoassay (RIA), and quantitative measurement of LTE4 by RIA was validated by GC-MS/MS. There was a linear correlation between LTE4 measured by RIA and by GC-MS/MS (r = 0.994). In representative samples, LTE4 was also quantitatively assessed by GC-MS/MS. In these samples, LTE4 values obtained by GC-MS/MS differed < 10% from those obtained by RIA. The present findings suggest that cysteinyl leukotrienes play a role in AD.
Assuntos
Dermatite Atópica/metabolismo , Leucotrienos/biossíntese , Adulto , Dermatite Atópica/urina , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Leucotrieno E4 , Masculino , Radioimunoensaio , SRS-A/análogos & derivados , SRS-A/urinaRESUMO
ICI 204,219 is a potent and specific leukotriene D4 receptor antagonist that blocks both the early and late responses to allergen challenge in humans when given orally at a dose of 40 mg. Here we report our findings with an inhaled formulation of ICI 204,219 against allergen-induced bronchoconstriction. A group of 10 atopic subjects (mean age 25.6 +/- 4.2; 6 females; FEV1 > 90% of predicted; on inhaled beta 2-agonists only) were studied on 2 separate days 2 to 3 wk apart. In a randomized placebo-controlled trial they inhaled eight puffs of a standard metered dose inhaler containing either ICI 204,219 (200 micrograms/puff, total dose 1,600 micrograms) or propellant alone. They underwent bronchial allergen challenge 30 min later using a single concentration of allergen previously shown to lower the FEV1 by > or = 15%. FEV1 was monitored hourly for 10 h, and urine was collected for LTE4 determination. Inhalation of ICI 204,219 was well tolerated, with no adverse clinical or biochemical effects. There was no significant effect of ICI 204,219 inhalation on basal airway caliber (change in FEV1 30 min after inhalation was -149 +/- 67 ml after placebo versus 3 +/- 38 ml after ICI 204,219; p = 0.08). The early response to allergen was significantly inhibited by ICI 204,219 (the maximum fall in FEV1 was -21.2 +/- 6.1% after ICI 204,219 compared with -38.8 +/- 6.5% on placebo; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alérgenos , Broncoconstrição/efeitos dos fármacos , Receptores Imunológicos/antagonistas & inibidores , Compostos de Tosil/administração & dosagem , Administração por Inalação , Adulto , Análise de Variância , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/metabolismo , Asma/fisiopatologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Indóis , Leucotrieno E4 , Masculino , Fenilcarbamatos , Receptores de Leucotrienos , SRS-A/análogos & derivados , SRS-A/urina , Sulfonamidas , Fatores de Tempo , Compostos de Tosil/sangue , Compostos de Tosil/farmacologiaRESUMO
Allergen challenge is associated with an increased excretion of urinary leukotriene E4. The source of this increase is unknown, although the lack of effect of inhaled beta-agonists and sodium cromoglycate suggests that airway mast cells may not be involved. We investigated this further using a new and topically potent inhaled glucocorticoid, fluticasone propionate (FP). A group of 10 mild atopic asthmatic subjects (6 males; FEV1 > 60% of predicted; PC20 histamine < or = 8 mg/ml; and on inhaled beta 2-agonists only) were studied before and after a 2-wk period of FP (1,000 micrograms/day) or placebo administered by metered-dose inhalers as two puffs twice per day through a large-volume spacer. Treatments were assigned in a double-blind crossover fashion separated by a 3-wk washout period. The PC20 histamine was measured at the start and end of each treatment when subjects also received a bronchial allergen challenge. Urine was collected for 4 h after allergen challenge for determination of LTE4 using HPLC-RIA, and 2 h later the PC20 histamine measurement was repeated. The 2-wk treatment with FP significantly inhibited both early and late responses to allergen: the maximum % fall in FEV1 during the early (0 to 2 h) and late response (2 to 6 h) was 32.6 +/- 3.4 and 19.6 +/- 5.2, respectively, following placebo versus 19.5 +/- 4.5 and 3.6 +/- 2.6 following FP (both p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alérgenos , Androstadienos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Broncoconstrição/efeitos dos fármacos , SRS-A/análogos & derivados , Administração por Inalação , Administração Tópica , Adulto , Asma/tratamento farmacológico , Asma/fisiopatologia , Asma/urina , Testes de Provocação Brônquica/métodos , Broncoconstrição/imunologia , Feminino , Fluticasona , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides , Histamina , Humanos , Leucotrieno E4 , Masculino , SRS-A/urina , Fatores de TempoRESUMO
Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM-CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Leucotrienos/biossíntese , Adulto , Animais , Células CHO/metabolismo , Cricetinae , Escherichia coli/metabolismo , Glicosilação , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacocinética , Humanos , Cinética , Contagem de Leucócitos , Leucotrieno E4 , Masculino , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , SRS-A/análogos & derivados , SRS-A/urinaRESUMO
Peptidoleukotriene metabolism in dogs was investigated to determine the suitability of this species for the development of in vivo biochemical models of asthma and inflammation. Circulatory metabolism of [3H]leukotriene (LT)C4 (0.5 microCi/kg, i.v.) to [3H]LTE4 and subsequent clearance was rapid (T1/2 = 100 sec). After 3 h, the major urinary metabolite was [3H]16-carboxydihydrotetranor LTE4 (identified by radiochromatography), with [3H]LTE4 accruing to a significant 1.7 +/- 0.9% (n = 3) of the original [3H]LTC4 dose. Immunoreactive LTE4 was excreted into canine urine at 1.85 +/- 0.35 to 2.35 +/- 0.57 ng/h (n = 4) over a 6-h period, suggesting that this metabolite may be an index of acute in vivo 5-lipoxygenase activity. MK-0591, a high-affinity ligand for the canine homolog of the human 5-lipoxygenase activating protein, dose-dependently inhibited the systemic generation of peptidoleukotrienes as measured by urinary LTE4 excretion (ED50 1 microgram/kg/min), the time course of disappearance of LTE4 from the urine being similar to that of the clearance of [3H]LTE4. Because the therapeutic improvements in human allergic asthmatics treated with LT synthesis inhibitors and challenged with antigen appear to be related to the degree of in vivo inhibition of LT biosynthesis (measured by urinary LTE4), the dog may be an appropriate species for preclinical assessment of LT inhibitors.
Assuntos
Indóis/farmacologia , Leucotrienos/biossíntese , Quinolinas/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Asma/tratamento farmacológico , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Cães , Indóis/uso terapêutico , Antagonistas de Leucotrienos , Leucotrieno E4 , Leucotrienos/metabolismo , Leucotrienos/urina , Proteínas de Membrana/metabolismo , Quinolinas/uso terapêutico , SRS-A/análogos & derivados , SRS-A/urinaRESUMO
In order to examine the hypothesis that in aspirin-induced asthma (AIA) cyclooxygenase inhibition is associated with enhanced release of leukotrienes (LTs), we measured urinary leukotriene E4 (LTE4) and 11-dehydro-thromboxane B2 (TXB2) (as a measure of cyclooxygenase production) following challenge with oral aspirin or inhaled methacholine, in 10 AIA patients. We also determined serum tryptase and eosinophilic catonic protein (ECP) levels, in order to evaluate mast cell and eosinophil activation. Urinary LTE4 excretion was increased sevenfold 4-6 h after aspirin challenge, while 11-dehydro-TXB2 decreased gradually reaching 50% baseline levels 24 h after challenge (p < 0.05). This was accompanied by a significant fall in blood eosinophil count at 6 h, and a tendency to a rise in ECP. The intensity of both LTE4 and 11-dehydro-TXB2 responses depended on the dose of aspirin used (p < 0.001, analysis of variance (ANOVA)). The accompanying maximum fall in forced expiratory volume in one second (FEV1) was not correlated with peak LTE4 levels. In contrast to aspirin, methacholine challenge producing comparable bronchial obstruction, did not alter eicosanoid excretion or serum tryptase or ECP levels. In a separate study, lysine-aspirin inhalation challenge was performed in seven AIA patients, four of whom had responded with a rise in serum tryptase to oral aspirin challenge. Challenge with inhaled aspirin led to similar bronchoconstriction as with oral challenge, but non-respiratory symptoms such as scarlet flush or rhinorrhea were absent, and serum tryptase levels remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Aspirina/efeitos adversos , Asma/induzido quimicamente , Broncoconstrição/efeitos dos fármacos , Mastócitos/imunologia , Ribonucleases , SRS-A/análogos & derivados , Tromboxano B2/análogos & derivados , Adulto , Asma/imunologia , Asma/metabolismo , Proteínas Sanguíneas/análise , Testes de Provocação Brônquica , Quimases , Proteínas Granulares de Eosinófilos , Eosinófilos/imunologia , Feminino , Humanos , Leucotrieno E4 , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , SRS-A/urina , Serina Endopeptidases/sangue , Tromboxano B2/urina , TriptasesRESUMO
Tissue distribution, elimination, and metabolism of [3H]-leukotriene C4 were studied at 2.5 hours after injection in the conscious and anesthetized American bullfrog, Rana catesbeiana. Conscious frogs were injected via the dorsal lymph sac or the sciatic vein. Anesthetized frogs were injected via the abdominal vein. The organs containing the greatest percent of injected radioactivity at 2.5 hours after injection were liver, small intestine and kidney. Route of injection and anesthesia appears to alter distribution and elimination of leukotrienes. [3H]-leukotrienes were eliminated into bladder water and bile. In addition, 7.8 +/- 2.2 and 5.2 +/- 2.5 percent of the injected radioactivity was found in the pan water bathing the ventral surface of the venously and dorsally injected conscious frogs, respectively, suggesting transfer of radioactivity across the skin. At 2.5 hours, polar metabolites represented 50% of the radioactivity found in liver, bile, and bladder water. These polar metabolites were determined to be 18-carboxy-19,20-dinor-leukotriene E4, 20-carboxy-leukotriene E4, and 20-hydroxy-leukotriene E4. Of the non-oxidized leukotrienes, bile contained mainly LTD4 while bladder water contained primarily LTE4. N-acetyl LTE4 was not detected in any samples. The tissue distribution, elimination and metabolism of leukotrienes in the bullfrog was similar to mammalian studies and suggests evolutionary conservation of leukotriene processing.
Assuntos
SRS-A/farmacocinética , Animais , Evolução Biológica , Feminino , Masculino , Rana catesbeiana , SRS-A/metabolismo , SRS-A/urina , Distribuição Tecidual/fisiologia , TrítioRESUMO
In humans, dietary n-3 fatty acids ameliorate some chronic inflammatory diseases. In contrast, however, dietary n-3 fatty acids had no effect in patients with bronchial asthma. In bronchial asthma, the cysteinyl-leukotrienes C4, D4, and E4, formed from arachidonic acid, are considered important mediators. They are as vasoconstrictive and bronchoconstrictive as leukotrienes C5, D5, and E5, cysteinyl-leukotrienes derived from eicosapentaenoic acid. Whether and how n-3 fatty acids affect human cysteinyl-leukotriene metabolism is largely unknown. We therefore investigated human cysteinyl-leukotriene metabolism in vitro, ex vivo, and in vivo in the absence and presence of dietary n-3 fatty acids. We demonstrate formation of leukotrienes C5, D5, and E5 from eicosapentaenoic acid in vitro and ex vivo in stimulated human granulocytes. Proof of formation relies on cochromatography with authentic standards on reverse-phase high-performance liquid chromatography, ultraviolet-absorbance spectra, and radioactive tracer studies. In vitro, amounts of leukotrienes C5, D5, and E5 formed depended on the amount of exogenous eicosapentaenoic acid; leukotrienes C4, D4, and E4 formed from endogenous arachidonic acid, however, remained unaltered. A randomized, controlled, observer-blind study in 14 human volunteers, seven of whom supplemented their diet with 7 gm/day of an 85% n-3 fatty acid concentrate for 6 weeks was subsequently performed. Ex vivo, levels of leukotriene E5 almost equaled those of leukotriene E4. Moreover, urinary excretion of leukotriene E4 was assessed to estimate formation of cysteinyl leukotrienes from arachidonic acid in vivo. Urinary excretion of leukotriene E4 was reduced by 35% after dietary supplementation with n-3 fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ácidos Graxos/metabolismo , Granulócitos/metabolismo , SRS-A/análogos & derivados , SRS-A/metabolismo , Adulto , Humanos , Leucotrieno E4 , Fosfolipídeos/metabolismo , SRS-A/urinaRESUMO
The FEV1 and urinary leukotriene E4 (LTE4) concentrations were determined in six aspirin-sensitive and six non-aspirin-sensitive asthmatic subjects before and after inhalation challenge with lysine-aspirin or placebo solution. Lysine-aspirin produced a mean fall in FEV1 of 26.7 +/- 4.9% (mean +/- SEM) in subjects with aspirin sensitivity and of 8.5 +/- 6.5% (mean +/- SEM) in non-aspirin-sensitive asthmatic subjects. The mean baseline urinary LTE4 concentration of 83 pg/mg creatinine (geometric mean [GM], range 15 to 326 pg/mg creatinine) in aspirin-sensitive subjects was significantly higher than the 33.8 pg/mg creatinine (GM, range 10 to 111 pg/mg creatinine) in non-aspirin-sensitive subjects (p = 0.02). In aspirin-sensitive subjects, inhalation challenge with lysine-aspirin produced a significant increase in urinary LTE4 concentration to 240 pg/mg creatinine (GM, range 60 to 1,113 pg/mg creatine), which was not observed after placebo challenge. There was no significant change in urinary LTE4 concentration after inhalation challenge with either lysine-aspirin or placebo solution in non-aspirin-sensitive asthmatic subjects. Thus, sulfidopeptide leukotrienes are released after inhalation of lysine-aspirin in aspirin-sensitive asthmatic patients.
Assuntos
Aspirina/análogos & derivados , Asma/urina , Lisina/análogos & derivados , SRS-A/análogos & derivados , Administração por Inalação , Adulto , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Asma/fisiopatologia , Testes de Provocação Brônquica , Broncoconstrição/efeitos dos fármacos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Leucotrieno E4 , Lisina/administração & dosagem , Masculino , Pessoa de Meia-Idade , SRS-A/urinaRESUMO
Leukotriene (LT) E4 represents the major LT metabolite in man, and its urinary excretion can be used as an indirect marker of systemic LTC4 and/or LTD4 synthesis and release. In the present study LTE4 excretion was monitored for 24 h in 12 atopic patients with mild asthma undergoing antigen bronchoprovocation as part of a double-blind, placebo-controlled, two-period cross-over study of the aerosol-delivered LTD4 antagonist, L-648,051. Urinary LTE4 excretion was also studied separately in six of the patients after inhaling only diluent. Urine was sampled before, and serially after antigen challenge, at intervals corresponding to the immediate (0-3 h postchallenge) and late (3-6, 6-12, 12-24 h postchallenge) asthmatic reactions. LTE4 was determined by reversed-phase HPLC and radioimmunoassay. Forced expiratory volume in 1 s (FEV1) was recorded serially through 8 h after inhalation of antigen and diluent. Compared to base-line measurements, antigen bronchoprovocation induced significant increases in mean LTE4 excretion rates 0-3 h postchallenge (i.e. during the immediate asthmatic response) after treatment with both placebo (P < 0.01) and L-648,051 (P < 0.05). These mean LTE4 excretion rates in the immediate phase were also significantly higher than the mean rates in the late phase (3-6 h and beyond); the excretion rates of LTE4 at these later time intervals were similar to base-line values. After inhalation of diluent, the LTE4 excretion rates in the intervals 0-3, 3-6, 6-12 and 12-24 h were unchanged from base-line values.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Cetoácidos/uso terapêutico , SRS-A/análogos & derivados , Sulfonas/uso terapêutico , Administração por Inalação , Adulto , Testes de Provocação Brônquica , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Leucotrieno E4 , Masculino , SRS-A/urinaRESUMO
Increased thromboxane (TX) production and modified aspirin sensitivity has been detected in vitro in platelets isolated from patients with polycythemia vera. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo and its suppression by oral aspirin, we have investigated the urinary excretion of major enzymatic metabolites of TXB2 in 17 patients with polycythemia vera and 23 gender- and age-matched controls. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. In addition, urinary immunoreactive leukotriene (LT) E4 was measured to explore the 5-lipoxygenase pathway of arachidonate metabolism. Polycythemic patients had significantly (P < .001) higher excretion rates of both 11-dehydro-TXB2 (1,033 +/- 1,050 v 117 +/- 45 pmol/mmol creatinine; mean +/- SD) and 2,3-dinor-TXB2 (725 +/- 676 v 82 +/- 43 pmol/mmol creatinine) than controls. In contrast, urinary LTE4 was not significantly different. Enhanced metabolite excretion did not correlate with the platelet count or with the hematocrit value, and was not related to the current treatment or to a clinical history of thrombotic complications. Platelet TX receptor studies did not show any significant changes in the binding characteristics of two different ligands. A platelet-selective regimen of aspirin therapy (50 mg/d for 7 to 14 days) was associated with greater than 80% suppression in metabolite excretion in nine patients. These results are consistent with abnormal stimuli operating in polycythemia vera to induce a selective enhancement in the platelet biosynthesis of TXA2 without changes in receptor binding. This in vivo abnormality in platelet biochemistry can be largely suppressed by low doses of aspirin.
Assuntos
Aspirina/farmacologia , Plaquetas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Policitemia Vera/sangue , Tromboxano A2/biossíntese , Adulto , Idoso , Plaquetas/efeitos dos fármacos , Feminino , Humanos , Cinética , Leucotrieno E4 , Masculino , Pessoa de Meia-Idade , SRS-A/análogos & derivados , SRS-A/urina , Tromboxano B2/análogos & derivados , Tromboxano B2/urinaRESUMO
Recent evidence suggests that the cysteinyl-leukotrienes (LTC4, LTD4, and LTE4) may be important in the pathogenesis of exercise-induced asthma. To evaluate the role of these mediators further, nine asthmatic subjects with exercise-induced bronchoconstriction were studied on two occasions. On visit 1, subjects performed 6 min of treadmill exercise; the mean maximal percent fall in FEV1 was 38.0 +/- 5.3%. On visit 2, maximal bronchoconstriction observed after exercise was matched with aerosolized methacholine. Urine was collected in two 90-min fractions (0-90 and 90-180 min) after challenges and analyzed by high-performance liquid chromatography-radioimmunoassay for LTE4. There were no significant differences in urinary LTE4 excretion between exercise and methacholine challenges for the periods 0-90 min (16.9 +/- 5.4 vs. 20.4 +/- 4.2 ng/mmol urinary creatinine), 90-180 min (24.9 +/- 8.2 vs. 20.1 +/- 5.5), or 0-180 min (21.5 +/- 6.5 vs. 18.8 +/- 4.1). Thus in contrast to allergen-induced bronchoconstriction, there is little evidence for enhanced cysteinyl-leukotriene generation in exercise-induced bronchoconstriction as assessed by urinary LTE4. If local release and subsequent participation of functionally active cysteinyl-leukotrienes in the pathways that ultimately lead to bronchoconstriction after exercise challenge do occur, these are of insufficient magnitude to perturb urinary LTE4 excretion.
Assuntos
Asma Induzida por Exercício/urina , SRS-A/análogos & derivados , Adulto , Volume Expiratório Forçado/fisiologia , Humanos , Leucotrieno E4 , Masculino , Compostos de Metacolina , SRS-A/urinaRESUMO
We have tested the hypothesis that leukotriene D4 (LTD4) receptor activation is involved in the development of antigen-induced bronchoconstriction. In two studies, patients with asthma received infusions of placebo or MK-571, a potent and specific LTD4 receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV1 was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE4; plasma samples were drawn repeatedly for assay of MK-571. MK-571 infusions inhibited both immediate (0 to 3 hours) and late (3 to 10 hours) asthmatic responses. For the high MK-571 dose, the extent of inhibition, as assessed by the area under the curve of FEV1 versus time was 88% (p = 0.01) and 63% (p = 0.01), for immediate and late responses, respectively. The low MK-571 dose also inhibited both responses but to a minor extent. Mean urinary LTE4 excretion was elevated after antigen challenge and was unaffected by administration of the LTD4 receptor antagonist. The present study demonstrates that MK-571 inhibits antigen-induced asthma in a dose-related fashion; it had not effect on antigen-induced increases in urinary LTE4 excretions. The results suggest that LTD4 receptor activation plays an important role in antigen-induced asthma.
Assuntos
Antígenos/imunologia , Broncoconstrição/imunologia , Receptores Imunológicos/metabolismo , SRS-A/antagonistas & inibidores , Administração por Inalação , Adulto , Asma/imunologia , Asma/fisiopatologia , Creatinina/urina , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Leucotrieno E4 , Masculino , Propionatos/sangue , Propionatos/farmacologia , Quinolinas/sangue , Quinolinas/farmacologia , Receptores de Leucotrienos , SRS-A/análogos & derivados , SRS-A/urinaRESUMO
We measured the excretion of a major urinary metabolite of leukotriene (LT) C4, i.e., LTE4, during the infusion of exogenous LTC4 to enable estimation of the rate of entry of endogenous LTC4 into the bloodstream. Four healthy volunteers received 2-h intravenous infusions of vehicle alone and LTC4 at 0.063, 0.32, 1.6, and 2.9 pmol.kg-1.min-1 in random order. Urinary LTE4 was measured before, during, and up to 24 h after the infusions. The fractional elimination of LTE4 was independent of the rate of LTC4 infusion and averaged 4.3 +/- 0.9%. Calculation of the mean rate of entry of LTC4 into the circulation was found to be 0.06 pmol.kg-1.min-1. In addition, we characterized further metabolism of [14C]LTC4. The two major urinary metabolites were the omega- and beta-oxidation products (16-COOH-LTE4 and 14-COOH-LTE3), which accounted for 6-8% of the total infused amount of [14C]LTC4. We conclude that 1) LTC4 is produced at a low rate under physiological circumstances and is rapidly converted in the vasculature to LTE4, 2) changes in the urinary excretion of the latter may reliably reflect short-term changes in the rate of secretion of LTC4, and 3) measurement of the omega- and beta-oxidation products may reflect chronic changes in cysteinyl leukotriene biosynthesis.
Assuntos
SRS-A/farmacocinética , Adulto , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucotrieno E4 , Leucotrienos/urina , Masculino , Pessoa de Meia-Idade , Valores de Referência , SRS-A/análogos & derivados , SRS-A/sangue , SRS-A/urinaRESUMO
The urinary excretion of leukotriene E4 (LTE4) was measured in subjects presenting for emergency treatment of airway obstruction. A total of 72 subjects presenting with airway obstruction performed peak flow determinations before and after three treatments with nebulized albuterol given at 20-min intervals. Of these subjects, 22 more than doubled their peak flow rates, while 19 failed to increase their peak flow rates more than 25% during the treatment period. These groups were designated "responders" and "nonresponders," respectively. Urinary LTE4 excretion was determined in 16 of the 22 responders and 12 of the 19 nonresponders as well as 13 normal subjects by precolumn extraction, analytic reversed-phase high-performance liquid chromatography, and enzyme immunoassay. In the normal subjects the urinary LTE4 excretion was significantly (p less than 0.0001) less than the urinary LTE4 measured in the responder subjects, but not less than the urinary LTE4 excretion in the nonresponder group (p = 0.071). The enhanced recovery of LTE4 from the urine of subjects with acutely reversible airway narrowing is consistent with a bronchoconstrictor role for the cysteinyl leukotrienes in spontaneous acute asthma.
Assuntos
Asma/urina , SRS-A/análogos & derivados , Doença Aguda , Adulto , Idoso , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Asma/fisiopatologia , Feminino , Humanos , Leucotrieno E4 , Masculino , Pessoa de Meia-Idade , Pico do Fluxo Expiratório , SRS-A/urinaRESUMO
In vivo production of thromboxane (TX) A2 and the cysteinyl-containing leukotrienes (LT) C4, D4, and E4 in correlation to airway responses was studied. Bronchial provocation with specific allergen in atopic asthmatics was followed by a significant increase in urinary concentration of immunoreactive LTE4 (34 +/- 6 before versus 56 +/- 7 ng/mmol creatinine after allergen challenge; n = 5) and 11-dehydro-TXB2 (164 +/- 29 versus 238 +/- 25 ng/mmol creatinine). In the presence of the leukotriene-antagonist ICI-204,219, which significantly increased the PD20 for allergen, the increment in urinary excretion of LTE4 was even higher (60 +/- 8 versus 288 +/- 128 ng/mmol creatinine; n = 5). In contrast, provocation with histamine (n = 5) did not provoke release of leukotrienes or thromboxane, nor was inhalation of LTD4 (n = 7) associated with increased urinary concentration of 11-dehydro-TXB2. Furthermore, bronchoconstriction induced by inhalation of lysine-aspirin in aspirin-sensitive asthmatics (n = 4) was followed by increased levels of LTE4 in the urine, whereas the levels of 11-dehydro-TXB2 remained the same. Finally, the basal levels of LTE4 in the urine of nine aspirin-sensitive asthmatics were elevated as compared with 15 other asthmatics (112 +/- 54 versus 38 +/- 20 ng/mmol creatinine; p less than 0.001). The findings support that the cysteinyl-leukotrienes are potential mediators of allergen-induced asthma and that the release of LTE4 and 11-dehydro-TXB2 into the urine appeared to be a direct and dose-dependent effect of the antigen-antibody reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Asma/urina , Testes de Provocação Brônquica , SRS-A/análogos & derivados , Tromboxano B2/análogos & derivados , Adulto , Alérgenos/administração & dosagem , Aspirina/administração & dosagem , Asma/fisiopatologia , Feminino , Histamina , Humanos , Leucotrieno E4 , Masculino , Pessoa de Meia-Idade , SRS-A/administração & dosagem , SRS-A/urina , Tromboxano B2/urinaRESUMO
Cysteinyl leukotriene synthesis was investigated in patients with psoriasis. A non-invasive test requiring no stimulation was employed by measuring the major index metabolite of LTC4, which appears in urine. The presence of this metabolite, LTE4, was shown unequivocally by gas chromatography-mass spectrometry. Routinely LTE4 was quantitated by specific radio immunoassay after its isolation by reversed-phase high-performance liquid chromatography. Furthermore, in representative samples amounts of LTE4 obtained by radioimmunoassay were validated by gas chromatography-mass spectrometry. We demonstrate a significant (p less than 0.01) more than fourfold increase of urinary LTE4 in psoriasis compared to healthy volunteers. Urinary LTE4 was log normally distributed with geometric mean values (95% confidence intervals) of 11 (9-14) nmol LTE4/mol creatinine in healthy volunteers (n = 11) and 51 (28-95) nmol LTE4/mol creatinine in psoriasis (n = 9). The present study shows that cysteinyl leukotriene synthesis is enhanced in patients with psoriasis and that measurement of urinary LTE4 is a useful parameter to monitor its rate of synthesis.