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1.
Prostaglandins Other Lipid Mediat ; 150: 106463, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32450304

RESUMO

Low basal endogenous concentrations (<20 pg/mL) of the 5-lipoxygenase (5-LO) pathway biomarker leukotriene E4 (LTE4) in human plasma present a significant analytical challenge. Analytical methods including liquid chromatography-mass spectrometry and enzyme linked immunosorbent assays have been used to quantify plasma LTE4 in the past but have not provided consistent data in the lower pg/mL-range. With our new method, a detection limit (<1 pg/mL plasma) significantly below basal levels of LTE4 was achieved by combining large volume sample purification and enrichment by anion-exchange mixed mode solid phase extraction (SPE) with large volume injection followed by chromatographic separation by ultra performance liquid chromatography (UPLC) and quantification by highly sensitive negative-ion electrospray tandem mass spectrometry (MS/MS). The method was reproducible, accurate and linear between 1 and 120 pg/mL plasma LTE4. The method was used to perform an analysis of plasma samples collected from healthy volunteers in a Phase 1 study with the FLAP (5-lipoxygenase activating protein) inhibitor AZD5718. Basal endogenous LTE4 levels of 5.1 ± 2.7 pg/mL were observed in healthy volunteers (n = 34). In subjects that had been administered a single oral dose of AZD5718, significant suppression (>80%) of plasma LTE4 level was observed, providing pharmacological evidence that endogenous 5-LO pathway activity could be assessed.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Cromatografia Líquida/métodos , Leucotrieno E4/sangue , Pirazóis/administração & dosagem , Espectrometria de Massas em Tandem/métodos , Biomarcadores/sangue , Ensaios Clínicos Fase I como Assunto , Humanos , Inibidores de Lipoxigenase/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Turk J Med Sci ; 50(8): 1786-1791, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-32979900

RESUMO

Background/aim: It is claimed that aberrant immune response has a more important role than the cytopathic effect of the virus in the morbidity and mortality of the coronavirus disease 2019 (COVID-19). We aimed to investigate the possible roles of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway and leukotrienes (LT) in uncontrolled immune response that occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Materials and methods: This study included 25 asymptomatic patients and 35 patients with lung involvement who were diagnosed with COVID-19 as well as 22 healthy volunteers. Lung involvement was determined using computed-tomography. Serum TWEAK, LTE4, and prostaglandin F2α (PGF2α) levels were determined. Results: Compared with the healthy control group, TWEAK, LTE4, and PGF2α levels were higher in the group of SARS-CoV-2 infection without lung involvement. In the group of SARS-CoV-2 infection with lung involvement, age, fibrinogen, sedimentation, C-reactive protein and ferritin, TWEAK, LTE4, and PGF2α levels were higher, and lymphocyte levels were lower compared with the asymptomatic group. Conclusions: In the study, TWEAK and LTE4 levels increased in cases with COVID-19. These results support that TWEAK/Fn14 pathway and LT may involved in the pathology of aberrant immune response against SARS-CoV-2. Inhibition of each of these pathways may be a potential target in the treatment of COVID-19.


Assuntos
COVID-19 , Citocina TWEAK/sangue , Dinoprosta/sangue , Leucotrieno E4/sangue , Pulmão/diagnóstico por imagem , COVID-19/diagnóstico , COVID-19/imunologia , Correlação de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Receptor de TWEAK/metabolismo
3.
J Cell Mol Med ; 23(5): 3441-3450, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30905080

RESUMO

Platelets modulate asthma pathogenesis by forming the platelet-eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE4 ). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28-30 and 42-44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42-44. Mice were assayed for airway hyper-responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all P < 0.05). Levels of interleukin (IL)-4, IL-5, IL-13, platelet factor 4, eosinophil peroxidase and LTE4 increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all P < 0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co-cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE4 (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE4 . Clo/Mon reduced ADP-induced PEA formation and P-selectin expression (P < 0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP-mediated PEA formation.


Assuntos
Acetatos/uso terapêutico , Asma/tratamento farmacológico , Clopidogrel/uso terapêutico , Quinolinas/uso terapêutico , Difosfato de Adenosina/farmacologia , Animais , Asma/sangue , Asma/fisiopatologia , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Agregação Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Ciclopropanos , Citocinas/metabolismo , Sinergismo Farmacológico , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Leucotrieno E4/sangue , Leucotrieno E4/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Muco/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/fisiopatologia , Sulfetos , Células Th2/metabolismo
4.
Allergy ; 72(4): 616-626, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27805264

RESUMO

BACKGROUND: Clinical presentation of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease (NERD) is found to be heterogeneous. This study classified phenotypic clusters to determine NERD subtypes. METHODS: We performed two-step cluster analysis using urticaria, chronic rhinosinusitis (CRS), and atopy, in a NERD cohort comprising 302 patients. Asthma exacerbation was defined as receiving at least one burst of intravenous steroid treatment and/or at least two bursts of oral steroid use (≥ 45 mg/3 days) per year. The possession rate of anti-asthmatic medications was estimated during the follow-up period. RESULTS: There were four subtypes: subtype 1 (NERD with CRS/atopy and no urticaria), subtype 2 (NERD with CRS and no urticaria/atopy), subtype 3 (NERD without CRS/urticaria), and subtype 4 (NERD with urticaria). Significant differences were found between the four subtypes in the female proportion, baseline FEV1%, serum total IgE level, and sputum/peripheral eosinophil count. A higher frequency of asthma exacerbations was noted in subtype 1 compared to subtype 3. The possession rates of medium- to high-dose inhaled corticosteroids/long-acting beta2 -agonists showed significant differences among the four subtypes. Metabolomic analysis showed that the four subtypes of NERD had a higher serum leukotriene E4 (LTE4) level than those with aspirin-tolerant asthma. The patients with subtypes 1 and 3 had a higher urine LTE4 level than those with subtype 2. CONCLUSION: We found four distinct subtypes with different clinical/biochemical findings and asthma exacerbations in a NERD cohort. These findings suggest that stratified strategies by applying subtype classification may help achieve better outcomes in the management of NERD.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Fenótipo , Doenças Respiratórias/diagnóstico , Doenças Respiratórias/etiologia , Adulto , Idade de Início , Anti-Inflamatórios não Esteroides/uso terapêutico , Asma/diagnóstico , Asma/epidemiologia , Asma/etiologia , Asma/metabolismo , Biomarcadores , Análise por Conglomerados , Progressão da Doença , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Leucotrieno E4/sangue , Leucotrieno E4/urina , Masculino , Metaboloma , Metabolômica/métodos , Pessoa de Meia-Idade , Testes de Função Respiratória , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/metabolismo
5.
Allergol Immunopathol (Madr) ; 44(1): 59-65, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25982579

RESUMO

BACKGROUND: Urinary leukotriene (LTE4) is an important marker of airway inflammation presence. A relationship between single nucleotide polymorphism in the glucocorticoid receptor (GCR) gene promoter (Bcl I polymorphism), development of asthma and sensitivity to glucocorticoids has been hypothesised. OBJECTIVE: To explore the possible association between the Bcl I polymorphism and baseline levels of urinary LTE4 in preschoolers with recurrent wheezing episodes. We prospectively enrolled and classified 86 preschoolers based on the risk of developing asthma (by the Asthma Predictive Index [API]). METHODS: At admission standardised questionnaires for demographics and respiratory illness characteristics were completed. The Bcl I polymorphism of the GCR was determined by a PCR-RFLP assay from blood samples, and urinary leukotriene was assessed from urine samples by an enzyme immunoassay. RESULTS: We enrolled 86 preschoolers (46 with positive API and 40 with negative API). There were no statistical differences in demographic, respiratory illnesses and wheezing episodes characteristics between both groups. Also, the prevalence of Bcl I polymorphism was similar between positive vs. negative API groups (34.8% vs. 38.9% for homozygote GG, 56.5% vs. 52.8% for heterozygote GC, 8.7% vs. 8.3% for homozygote CC, respectively, p=0.94). However, urinary LTE4 (median [IQR]) was higher in preschoolers with positive than negative API (7.18 [5.57-8.96pg/ml] vs. 6.42 [3.96-8.07pg/ml], p=0.02, respectively). CONCLUSIONS: In our population, wheezing preschoolers with positive API exhibit higher levels of urinary LTE4 than those with negative API; but there were no differences in Bcl I polymorphism of the GCR.


Assuntos
Asma/imunologia , Leucotrieno E4/genética , Regiões Promotoras Genéticas/genética , Receptores de Glucocorticoides/genética , Sons Respiratórios/imunologia , Asma/complicações , Asma/tratamento farmacológico , Biomarcadores Farmacológicos/metabolismo , Estudos de Casos e Controles , Pré-Escolar , Análise Mutacional de DNA , Feminino , Glucocorticoides/uso terapêutico , Humanos , Leucotrieno E4/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Recidiva , Sons Respiratórios/etiologia , Sons Respiratórios/genética , Risco , Inquéritos e Questionários
6.
Asian Pac J Allergy Immunol ; 33(2): 99-106, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26141030

RESUMO

BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal airways.Many therapies do not have immediate effects,even which have side-effects.However,the effects of Xingbi gel for the treatment of AR was investigated. OBJECTIVE: We investigated the effects of Xingbi gel on serum levels of leukotriene E4 (LTE4) and immunoglobulin E (IgE), as well as eosinophil counts in the nasal mucosa using a guinea pig model of allergic rhinitis (AR). METHODS: In addition to a healthy control group without AR, guinea pigs with AR were randomly divided into untreated AR control group, low-dose Xingbi gel (0.2483 g/mL) group, high-dose Xingbi gel (0.4966 g/mL) group, and budesonide group. RESULTS: Compared to the healthy controls, untreated AR guinea pigs had significantly higher ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts (p <0.01). Treatments with low-dose Xingbi gel, high-dose Xingbi gel, and budesonide significantly reduced the ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts as compared to untreated AR model guinea pigs (p <0.01). CONCLUSION: Xingbi gel alleviates AR in part through inhibiting LTE4 and IgE production and reducing eosinophilia in the nasal mucosa.


Assuntos
Antialérgicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Eosinofilia/tratamento farmacológico , Imunoglobulina E/sangue , Leucotrieno E4/sangue , Mucosa Nasal/efeitos dos fármacos , Rinite Alérgica/tratamento farmacológico , Administração Intranasal , Animais , Antialérgicos/administração & dosagem , Biomarcadores/sangue , Budesonida/farmacologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Eosinofilia/sangue , Eosinofilia/imunologia , Géis , Cobaias , Imunoglobulina E/imunologia , Leucotrieno E4/imunologia , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Rinite Alérgica/sangue , Rinite Alérgica/imunologia
7.
Allergy ; 69(4): 527-36, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24571371

RESUMO

BACKGROUND: Arachidonic acid metabolites are implicated in the pathogenesis of asthma although only limited information is available on the impact of current smoking history on these metabolites. The aim of the study was to examine the effect of smoking status on urinary, sputum, and plasma eicosanoid concentrations and relevant enzyme transcripts in asthma. METHODS: In 108 smokers and never smokers with asthma and 45 healthy controls [smokers and never smokers], we measured urinary tetranor prostaglandin (PG)D2 (PGDM) and leukotriene (LT)E4 , induced sputum fluid LTB4 , LTE4 , PGD2 , and PGE2 , plasma secretory phospholipase A2 (sPLA2 ), and 11ß prostaglandin F2α (11ßPGF2α ), and, in a subgroup with severe asthma, airway leukocyte and epithelial cell mRNA expression levels of arachidonic acid metabolic enzymes. RESULTS: Smokers with asthma had higher urinary LTE4 ; 83 (59, 130) vs 59 (40, 90) pg/mg creatinine, P = 0.008, and PGDM; 60 (35, 100) vs 41 (28, 59) ng/mg creatinine, P = 0.012 concentrations, respectively, and lower sputum PGE2 concentrations 80 (46, 157) vs 192 (91, 301) pg/ml, P = 0.001 than never smokers with asthma. Sputum LTB4 (P = 0.013), and plasma 11ßPGF2α (P = 0.032), concentrations, respectively, were increased in smokers with asthma compared with healthy smokers. Asthma-specific and smoking-related increases (>1.5-fold expression) in arachidonate 15-lipoxygenase and gamma-glutamyltransferase transcripts were demonstrated. CONCLUSIONS: Several arachidonic acid metabolites and enzyme transcripts involving both lipoxygenase and cyclooxygenase pathways are increased in smokers with asthma and differ from never smokers with asthma. Possibly targeting specific lipoxygenase and cyclooxygenase pathways that are activated by asthma and cigarette smoking may optimize therapeutic responses.


Assuntos
Ácido Araquidônico/metabolismo , Asma/genética , Asma/metabolismo , Fumar , Transcrição Gênica , Adulto , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Estudos Transversais , Feminino , Expressão Gênica , Humanos , Leucócitos/metabolismo , Leucotrieno E4/sangue , Leucotrieno E4/metabolismo , Leucotrieno E4/urina , Masculino , Pessoa de Meia-Idade , Prostaglandinas/sangue , Prostaglandinas/urina , RNA Mensageiro/genética , Testes de Função Respiratória , Mucosa Respiratória/metabolismo , Fatores de Risco , Escarro/metabolismo , Inquéritos e Questionários
8.
Br J Clin Pharmacol ; 75(3): 779-90, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22803688

RESUMO

AIM: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. METHOD: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. RESULTS: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nM and 89 nM in the Western European and Japanese studies, respectively. CONCLUSION: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.


Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase , Indóis , Leucotrieno E4/sangue , Ácidos Pentanoicos , Inibidores da Proteína Ativadora de 5-Lipoxigenase/efeitos adversos , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Povo Asiático , Biomarcadores/sangue , Biomarcadores/urina , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Indóis/farmacologia , Leucotrieno B4/sangue , Leucotrieno B4/urina , Leucotrieno E4/urina , Masculino , Pessoa de Meia-Idade , Ácidos Pentanoicos/efeitos adversos , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , População Branca , Adulto Jovem
10.
Allergol Immunopathol (Madr) ; 40(1): 20-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-21334801

RESUMO

BACKGROUND: The aim of this study was to investigate the influence of exercise training on oxidative stress and markers of lung inflammation in children with asthma. METHODS: Thirty children aged 8-13 years diagnosed with asthma were enrolled in the study as well as 13 healthy children. One group received only pharmacological treatment and the other group was also enrolled in an exercise programme. Venous blood and 24-hour urine samples were obtained from the children enrolled in the study at the beginning and end of the study. Leukotriene E4 and creatinine levels were measured in the urine and matrix metallopeptidase (MMP-9), endothelin-1(ET-1), malnodialdehyde (MDA), IgE and specific IgE levels were measured in blood samples. RESULTS: Leukotriene E4, MDA and MMP9 levels decreased significantly with treatment in both groups (p < 0.001). However, ET-1 levels decreased significant only in the exercise group (26.5 ± 3.6 vs 21.3 ± 2.4 pg/ml respectively, p = 0.001). Moreover, ET-1 levels were found to be significantly lower in the exercise group compared to the only pharmacotherapy group (24.2 ± 3.1 vs 21.3 ± 2.4 pg/ml, p=0.007). CONCLUSIONS: Positive influences of exercise training in children with asthma may be mediated by decrease in ET-1 levels.


Assuntos
Asma/terapia , Terapia por Exercício , Lesão Pulmonar/prevenção & controle , Estresse Oxidativo , Adolescente , Asma/metabolismo , Biomarcadores , Criança , Endotelina-1/sangue , Feminino , Humanos , Leucotrieno E4/sangue , Masculino , Malondialdeído/sangue , Metaloproteinase 9 da Matriz/sangue
11.
Pneumonol Alergol Pol ; 80(2): 120-6, 2012.
Artigo em Polonês | MEDLINE | ID: mdl-22370980

RESUMO

INTRODUCTION: The aim of the study was the evaluation of the concentration of 9α11ß prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. MATERIAL AND METHODS: 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11ß prostaglandin F(2) (9α11ßPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. RESULTS: LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11ßPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11ßPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11ßPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11ßPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. CONCLUSIONS: 9α11ßPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11ßPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11ßPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.


Assuntos
Broncoconstrição/fisiologia , Leucotrieno E4/sangue , Leucotrieno E4/urina , Prostaglandina D2/sangue , Prostaglandina D2/urina , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Testes de Função Respiratória , Fatores de Risco , Índice de Gravidade de Doença , Capacidade Vital
12.
PLoS One ; 16(8): e0256237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34437574

RESUMO

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-ß1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-ß1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-ß1 and urinary LTE4. The function of TGF-ß1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-ß1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-ß1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-ß1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-ß1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-ß1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.


Assuntos
Asma Induzida por Aspirina/sangue , Glutationa Transferase/urina , Anormalidades do Sistema Respiratório/sangue , Fator de Crescimento Transformador beta1/sangue , Adulto , Animais , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/patologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Leucotrieno E4/biossíntese , Leucotrieno E4/sangue , Leucotrieno E4/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores de Leucotrienos/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Anormalidades do Sistema Respiratório/induzido quimicamente , Anormalidades do Sistema Respiratório/genética , Anormalidades do Sistema Respiratório/patologia , Fator de Crescimento Transformador beta1/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
13.
Clin Pharmacol Ther ; 81(3): 371-6, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17339866

RESUMO

In this study, prospectively, we aimed to determine the effects of the different treatment alternatives on the oxidant system and inflammatory and clinic determinants during the stable period of 1 month following an asthmatic attack. Thirty-one patients (22 female, nine male) were randomly divided into three groups following the stabilization of an acute asthma attack. The control group that is an additional group to the three patient groups consisted of 10 healthy volunteers (five female, five male). The following protocols were used for 4 weeks: Group I: short-acting inhaler beta2 mimetic as required (treatment A)+800 mug inhaler budesonide (treatment B)+leukotriene receptor antagonist; Group II: treatment A and B; Group III: treatment A and B+vitamin E. The serum levels before and after treatment of eosinophilic cationic protein (ECP), leukotriene E4 (LTE(4)), and malondialdehyde (MDA) were determined. The values before and after treatment were statistically compared both with each other and control values. Pretreatment ECP, LTE(4), and MDA levels for the three groups were significantly higher compared with post-treatment levels (P<0.05 to P<0.001) and the control levels (P<0.01 to P<0.001). However, when post-treatment levels were compared with those of the control group, no significant differences were found (P>0.05). Lack of significant variation was observed when the pre- and post-treatment differences in the three groups were compared for each one of ECP, LTE(4), and MDA levels (P>0.05). Leukotriene receptor antagonist or antioxidant agents added to standard asthma treatment did not make a significant contribution on ECP, LTE(4), and MDA levels and respiratory parameters such as spirometric function tests. Etiologic factors and/or the possible changes in different pathogenetic ways of the inflammation process may have been responsible for nonsignificant intertreatment difference in the biomarker levels. The result confirms that suppressing the inflammation in asthma enables the entire inflammatory pathologic process to be controlled.


Assuntos
Antiasmáticos/uso terapêutico , Antioxidantes/uso terapêutico , Asma/tratamento farmacológico , Asma/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Antagonistas de Leucotrienos/uso terapêutico , Mecânica Respiratória/fisiologia , Adulto , Biomarcadores , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Técnicas Imunoenzimáticas , Leucotrieno E4/sangue , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Oxigênio/sangue , Mecânica Respiratória/efeitos dos fármacos , Espirometria
14.
Artigo em Inglês | MEDLINE | ID: mdl-16757158

RESUMO

To evaluate the levels of leukotrienes (LTs), interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma) in patients with eczema and observe the effects inversed by mizolastine. Serum LTB4, LTC4, IL-2, IL-4, IFN-gamma and urinary LTE4 levels were detected by enzyme-linked immunosorbent assay (ELISA) and LTB4, LTC4, LTE4 concentrations of cutis tissue were measured by reverse-phase high-pressure liquid chromatography (RP-HPLC) in 10 eczema patients and 10 healthy volunteers. Eczema patients received mizolastine 10 mg once a day for 5 days, respectively, for comparison between before and after treatment. The above markers were assayed again after treatment. Serum LTB4, LTC4, IL-2, IFN-gamma and urinary LTE4 and skin tissue LTB4, LTC4, LTE4 levels in patients are higher than those in healthy volunteers significantly (P < 0.05). But serum IL-4 level did not show significant difference between patients and normal controls (P > 0.05). Mizolastine significantly reduced serum LTB4 and IFN-gamma levels as well as skin lesion LTB4, LTC4, LTE4 concentrations. LTs are involved in the pathogenesis of eczema. Mizolastine clearly reduces LTs levels in skin lesion.


Assuntos
Benzimidazóis/administração & dosagem , Eczema/tratamento farmacológico , Leucotrienos/análise , Pele/química , Adolescente , Adulto , Benzimidazóis/farmacologia , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/análise , Interleucina-2/análise , Interleucina-4/análise , Leucotrieno B4/análise , Leucotrieno B4/sangue , Leucotrieno C4/análise , Leucotrieno C4/sangue , Leucotrieno E4/análise , Leucotrieno E4/sangue , Leucotrienos/sangue , Masculino , Pessoa de Meia-Idade , Pele/patologia , Resultado do Tratamento
15.
Respir Med ; 99(5): 519-23, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15823446

RESUMO

To further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant-antioxidant balance in 12 asthmatic patients (age, 25+/-3[SEM] yr; FEV1, 95+/-10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design. Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant-antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45 min after PAF and L-PAF (18 microg each) bronchoprovocation. Urinary leukotriene E4 (uLTE4) elimination was measured 120 min after challenge. Compared with baseline, as expected, PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible. We conclude that there is no systemic oxidant-antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma.


Assuntos
Asma/sangue , Estresse Oxidativo , Fator de Ativação de Plaquetas/análogos & derivados , Administração por Inalação , Adulto , Análise de Variância , Antioxidantes/metabolismo , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Testes de Provocação Brônquica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação , Leucotrieno E4/sangue , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Testes de Função Respiratória
16.
Biochem Pharmacol ; 55(1): 101-4, 1998 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9413936

RESUMO

Estrogens have a beneficial effect on atherosclerosis and osteoporosis after menopause, but their exact mechanism of action is still unknown. The aim of the present study was to investigate the effects of estradiol and its metabolites catechol estrogens on arachidonic acid metabolism in vitro. Estradiol had no effect on arachidonic acid metabolism up to 33 microM in A23187-stimulated human whole blood. All catechol estrogens (2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol and 4-hydroxyestrone) had similar kinds of actions on arachidonic acid metabolism, being over ten times more potent inhibitors of leukotriene synthesis (IC50 values 0.044-0.16 microM) than thromboxane (IC50 values 0.99-2.1 microM) and prostaglandin E2 synthesis (IC50 values 0.84-5.5 microM). It is suggested that some of the protective actions of estrogens--e.g., on atherosclerosis and osteoporosis--may be related to the inhibition of leukotriene synthesis by catechol estrogens.


Assuntos
Inibidores Enzimáticos/farmacologia , Estrogênios de Catecol/farmacologia , Leucotrienos/biossíntese , Araquidonato 5-Lipoxigenase/sangue , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Araquidônico/sangue , Ácido Araquidônico/metabolismo , Calcimicina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/biossíntese , Dinoprostona/sangue , Estradiol/sangue , Estradiol/metabolismo , Estradiol/farmacologia , Humanos , Ionóforos/farmacologia , Leucotrieno E4/biossíntese , Leucotrieno E4/sangue , Leucotrienos/sangue , Inibidores de Lipoxigenase/farmacologia , Prostaglandina-Endoperóxido Sintases/sangue , Prostaglandina-Endoperóxido Sintases/metabolismo , Estimulação Química , Tromboxano B2/biossíntese , Tromboxano B2/sangue
17.
Chest ; 105(4): 1038-41, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8162721

RESUMO

To investigate the relationship between circulating leukotriene E4 and bronchial asthma, we tried to measure the concentration of leukotriene E4 during the clinical course of bronchial asthma with or without oral prednisolone treatment. Additionally, we investigated the relationship between the LTE4 levels and FEV1 (percent predicted) and PaCO2 (mm Hg) concomitantly. Two milliliters of blood were drawn from the femoral artery of eight patients on three occasions: (1) during remission; (2) during an attack treated without prednisolone; and (3) during an attack treated with prednisolone. Leukotriene E4 was detected by high-pressure liquid chromatography and radioimmunoassay. In eight asthmatic patients, mean (SD) leukotriene E4 levels on the three occasions were 11.8 (2.61), 48.4 (18.2), and 32.6 (8.28) pg/ml, respectively. In contrast, the mean leukotriene E4 level of ten normal control subjects was 11.8 (4.49) pg/ml. Leukotriene E4 levels differed significantly between remission and attack treated without prednisolone, and between attacks treated with and without prednisolone. Mean FEV1 values were 85.5 (3.07), 50.5 (9.58), and 65.9 (7.44) on the three occasions, respectively; corresponding mean PaCO2 values were 31.7 (2.74), 55.5 (5.81), 48.9 (2.56), respectively. Leukotriene E4 was significantly correlated with FEV1 and relatively with PaCO2 during an attack without prednisolone. We suggest that leukotriene E4 levels in arterial blood reflect the severity of asthmatic attacks and orally administered prednisolone may affect the leukotriene E4 levels.


Assuntos
Asma/sangue , Leucotrieno E4/sangue , Prednisolona/administração & dosagem , Administração Oral , Adulto , Asma/tratamento farmacológico , Asma/fisiopatologia , Dióxido de Carbono/sangue , Cromatografia Líquida de Alta Pressão , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Radioimunoensaio
18.
J Appl Physiol (1985) ; 93(1): 116-26, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12070194

RESUMO

We examined whether lung inflammatory mediators are increased during exercise and whether pharmacological blockade can prevent exercise-induced arterial hypoxemia (EIAH) in young athletes. Seventeen healthy athletes (9 men, 8 women; age 23 +/- 3 yr) with varying degrees of EIAH completed maximal incremental treadmill exercise tests after administration of fexofenadine, zileuton, and nedocromil sodium or placebo in a randomized double-blind crossover study. Lung function, arterial blood gases, and inflammatory metabolites in plasma, urine, and induced sputum were assessed. Drug administration did not improve EIAH or gas exchange during exercise. At maximal exercise, oxygen saturation fell to 91.4 +/- 2.6% (drug trial) and 91.9 +/- 2.1% (placebo trial) and alveolar-arterial oxygen difference widened to 28.1 +/- 6.3 Torr (drug trial) and 29.3 +/- 5.7 Torr (placebo trial). Oxygen consumption, ventilation, and other exercise variables were similarly unaffected by drug treatment. Although plasma histamine increased with exercise, values did not differ between trials, and urinary leukotriene E(4) and 11beta-prostaglandin F(2alpha) levels were unchanged after exercise. Postexercise sputum revealed no significant changes in markers of inflammation. These results demonstrate that EIAH in young athletes is not attenuated with acute administration of drugs targeting histamine and bioactive lipids. We conclude that airway inflammation is of insufficient magnitude to cause impairments in gas exchange and does not appear to be linked to EIAH in healthy young athletes.


Assuntos
Exercício Físico/fisiologia , Hidroxiureia/análogos & derivados , Hipóxia/sangue , Mediadores da Inflamação/metabolismo , Pulmão/fisiologia , Esportes/fisiologia , Terfenadina/análogos & derivados , Adulto , Contagem de Células , Feminino , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Hidroxiureia/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Antagonistas de Leucotrienos/farmacologia , Leucotrieno E4/sangue , Masculino , Consumo de Oxigênio/fisiologia , Troca Gasosa Pulmonar/fisiologia , Testes de Função Respiratória , Escarro/química , Escarro/citologia , Terfenadina/farmacologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-9089801

RESUMO

We investigated the relationship between circulating leukotriene E4 (LTE4) and chronic obstructive pulmonary disease (COPD) by measuring plasma levels of leukotriene E4 in patients with COPD and 10 normal controls. We also investigated the relationship between LTE4 levels and FEV1 and PaO2. Leukotriene E4 was measured by high performance liquid chromatography (HPLC) and radioimmunoassay. The mean leukotriene E4 level in patients with COPD during remission, during acute exacerbation before and after prednisolone treatment were 16.8[4.02], 41.7[21.9], and 19.5[3.78] pg/ml (mean[SD]), respectively. In contrast, the mean leukotriene E4 level of 10 normal controls was 11.8[4.49] pg/ml. Thus, the mean LTE4 level during an acute exacerbation of COPD was significantly lower in patients after prednisolone treatment than in patients before prednisolone treatment. The mean LTE4 level in patients after prednisolone treatment did not significantly differ from that in patients during remission and in normal controls (Scheffe F-test, P < 0.05) (Fig. 1). Mean FEV1 (% predict) values were 51.4[9.02] (mean[SD]), 38.0[4.82], and 44.2[4.48] on the three occasions, respectively; corresponding mean PaO2 values (mmHg) were 84.0[5.01] (mean[SD]), 61.3[1.66], and 80.6[5.30], respectively. Leukotriene E4 levels were significantly correlated with PaO2 and relatively with FEV1 in the patients during acute exacerbation before prednisolone treatment. Thus, we suggest that leukotriene E4 levels in arterial blood reflect the severity of COPD lung and oral prednisolone reduces the plasma levels of leukotriene E4 in patients with COPD.


Assuntos
Leucotrieno E4/sangue , Pneumopatias Obstrutivas/sangue , Adulto , Idoso , Estudos de Casos e Controles , Volume Expiratório Forçado , Glucocorticoides/uso terapêutico , Humanos , Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio/fisiologia , Prednisolona/uso terapêutico
20.
Eur J Pharmacol ; 353(1): 87-92, 1998 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-9721044

RESUMO

The effects of (-)-nicotine (0.0005-500 microM), (+)-nicotine (0.0005-50 microM) and (-)-cotinine (0.0005-500 microM) on arachidonic acid metabolism were investigated in Ca2+ ionophore A23187 (calcimycin)-stimulated human whole blood in vitro. (-)-Nicotine and (-)-cotinine stimulated prostaglandin E2 but inhibited thromboxane B2 synthesis, as has been observed previously in A23187-stimulated polymorphonuclear leukocytes and platelet-rich plasma [Saareks, V., Riutta, A., Mucha, I., Alanko, J., Vapaatalo, H., 1993. Nicotine and cotinine modulate eicosanoid production in human leukocytes and platelet rich plasma. Eur. J. Pharmacol., 248, 345-349.]. (+)-Nicotine also stimulated prostaglandin E2 but inhibited thromboxane B2 synthesis. High concentrations of (-)-nicotine and (-)-cotinine and even nanomolar concentrations of (+)-nicotine inhibited leukotriene E4 synthesis. These results indicate that (-)-nicotine and (-)-cotinine stimulate cyclooxygenase but inhibit thromboxane synthase and 5-lipoxygenase in whole blood in vitro. (+)-Nicotine is capable of affecting in the same direction as well.


Assuntos
Cotinina/farmacologia , Dinoprostona/biossíntese , Leucotrieno E4/biossíntese , Nicotina/farmacologia , Tromboxano B2/biossíntese , Adulto , Araquidonato 5-Lipoxigenase/sangue , Ácido Araquidônico/metabolismo , Calcimicina/farmacologia , Dinoprostona/sangue , Humanos , Técnicas In Vitro , Ionóforos/farmacologia , Leucotrieno E4/sangue , Pessoa de Meia-Idade , Nicotina/química , Prostaglandina-Endoperóxido Sintases/sangue , Estereoisomerismo , Tromboxano B2/sangue
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