Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.683
Filtrar
1.
Medicine (Baltimore) ; 99(43): e22351, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120736

RESUMO

Asthma is a chronic inflammatory and multifactorial respiratory tract disease. It affects over 18 million adults and 6 million children in the USA with Puerto Ricans showing the highest prevalence (12%-19%). This airways illness can be triggered by an environmental stimulus such as grass pollen, fungi spores, cockroaches allergens, dust mites metabolic compounds, and importantly, by environmental proteases such as trypsin and tryptase. Because of the pivotal role of proteases in the onset of asthma pathophysiology, we focused this study on the serine Protease Activated Receptor-2 (PAR-2), a G-protein-coupled receptor widely expressed in cells across the respiratory tract. Herein, we measured the activation of PAR-2 on primary pulmonary bronchial/tracheal epithelial cells, human small airway epithelial cells, lung bronchial smooth muscle cells (with and without asthma). We tested human-derived eosinophils from 61 Puerto Rican participants (33 asthmatic and 28 non-asthmatic). As surrogate of PAR-2 activation or inhibition we used intracellular calcium mobilization assay. We hypothesized that following exposure of the PAR-2 agonist (AC264613), the studied human primary cell types will increase the mobilization of intracellular calcium levels. In contrast, we expected a decrease of the intracellular calcium levels upon exposure to a PAR-2 antagonist (FSLLRY-NH2). The Puerto Rican-derived eosinophils were analyzed for the proinflammatory markers MAPK/PI3K using flow cytometry (n = 8). As expected, the PAR-2 agonist significantly increased the activation of PAR-2 on the bronchial/tracheal epithelial cells, bronchial smooth muscle cells and human small airway epithelial cells (P = .01). The PAR-2 antagonist significantly decreased the intracellular calcium levels of these lung primary down to undetectable levels (P = .01). Remarkably, the asthmatic-derived eosinophils showed a striking 300% increase of intracellular calcium mobilization suggesting a severe response to the PAR-2 agonist stimuli in asthmatics. In contrast, there were no significant changes between groups after adding the PAR-2 antagonist. Our outcomes revealed that PAR-2 antagonist effectively inhibited the studied primary cells, expecting to decrease the immune response of eosinophils. Most importantly, our results reveal a promising role for the PAR-2 antagonist in targeting bronchial/tracheal epithelial cells, human small airway epithelial cells and bronchial smooth muscle cells with the potential to oblige an asthma adjuvant therapy.


Assuntos
Asma/tratamento farmacológico , Receptor PAR-2/antagonistas & inibidores , Asma/metabolismo , Biomarcadores/metabolismo , Brônquios/patologia , Cálcio/metabolismo , Sinalização do Cálcio , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Citometria de Fluxo , Humanos , Pulmão/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Receptor PAR-2/agonistas , Receptor PAR-2/metabolismo , Transdução de Sinais , Traqueia/patologia
3.
J Interferon Cytokine Res ; 40(9): 443-445, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32721252

RESUMO

The current pandemic of COVID-19 and the identification of accessible biomarkers of disease progression is of clinical importance in the management of this novel and serious disease. This study was completed to provide information regarding 1 possible uniquely upregulated marker in this illness, eosinophil-derived neurotoxin (EDN-1). A literature search was undertaken to provide medical data regarding EDN-1 as a biomarker in the clinical setting. The literature identified was further analyzed to identify its use in the clinical setting of viral disease and asthma.


Assuntos
Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/patologia , Neurotoxina Derivada de Eosinófilo/metabolismo , Pneumonia Viral/patologia , Betacoronavirus , Biomarcadores/análise , Síndrome da Liberação de Citocina/patologia , Eosinófilos/metabolismo , Humanos , Pandemias , Transcriptoma/genética
4.
Drug Discov Ther ; 14(3): 117-121, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32595179

RESUMO

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Resultado do Tratamento
5.
Nat Commun ; 11(1): 2922, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523103

RESUMO

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis.


Assuntos
Tecido Adiposo/metabolismo , Eosinófilos/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Transdução de Sinais/fisiologia , Adiposidade/genética , Adiposidade/fisiologia , Animais , Células COS , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Citometria de Fluxo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Obesidade/metabolismo , Transdução de Sinais/genética , Software
6.
Clin Sci (Lond) ; 134(11): 1191-1218, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32432676

RESUMO

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.


Assuntos
Eosinófilos/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Interleucina-33/farmacologia , Infarto do Miocárdio/fisiopatologia , Sístole/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fragmentação do DNA/efeitos dos fármacos , Diástole/efeitos dos fármacos , Eosinofilia/patologia , Eosinófilos/efeitos dos fármacos , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Mediadores da Inflamação/sangue , Interleucina-33/administração & dosagem , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esplenomegalia/patologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Medicine (Baltimore) ; 99(14): e19625, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243388

RESUMO

Patients with both serous effusion and eosinophilia are rarely reported and geographically distributed; their early diagnosis is difficult.According to the ultimate diagnosis, patients (≤14 years) in West China Second hospital with serous effusion and eosinophilia were divided into two groups including a parasitic group and a non-parasitic group. Clinical data were collected and analyzed between the two groups. Subsequently, significant measurement indicators were evaluated by receiver operating characteristic (ROC) curve to explore the optimal cut-off points for the most appropriate sensitivity and specificity.A total of 884 patients were diagnosed with serous effusion and 61 of them displayed co-morbidity with eosinophilia during enrolled time. Among 61 patients, 34 patients had parasitic infection and 27 had non-parasitic diseases. There were statistical difference in effusion position, the levels of white blood cell count (WBC), eosinophil (EOS), EOS%, C-reactive protein (CRP) between parasitic group and non-parasitic group. ROC curve demonstrated that the areas under the curve of EOS count and EOS% were >80%, and the corresponding optimal cut-off values were 1.71 × 10/L and 25.6% for distinguishing between parasitic and non-parasitic infections in our patients.This study provided a quantified index for potentially quick and convenient indicators of pediatric patients presenting with both eosinophilia and effusion. Eosinophils were helpful to improve the initial diagnosis with awareness of parasitic diseases. For the cases with EOS > 1.71 × 10/L or EOS% > 25.6%, parasitic infection should be considered and serological tests are recommended in our region.


Assuntos
Doenças Parasitárias/diagnóstico , Derrame Pleural/diagnóstico , Eosinofilia Pulmonar/diagnóstico , Proteína C-Reativa/análise , Criança , Pré-Escolar , China , Diagnóstico Diferencial , Diagnóstico Precoce , Eosinófilos/metabolismo , Feminino , Humanos , Pacientes Internados , Contagem de Leucócitos , Masculino , Doenças Parasitárias/sangue , Doenças Parasitárias/complicações , Derrame Pleural/sangue , Derrame Pleural/parasitologia , Eosinofilia Pulmonar/sangue , Eosinofilia Pulmonar/parasitologia , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
8.
Thorax ; 75(7): 600-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32303624

RESUMO

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.


Assuntos
Asma/genética , Eosinófilos/patologia , Regulação da Expressão Gênica , Hipersensibilidade/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , RNA/genética , Animais , Apoptose , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Eosinófilos/metabolismo , Feminino , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Contagem de Leucócitos , Camundongos , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese
9.
Am J Pathol ; 190(6): 1298-1308, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32194050

RESUMO

Eosinophils are a major cause of tissue injury in allergic conjunctivitis. The biological nature of eosinophils in the conjunctiva and the mechanisms that control eosinophils' responses in allergic conjunctivitis are currently not completely understood. This study reports that conjunctival eosinophils comprise two populations-Siglec-Fint and Siglec-Fhi-in different life stages. Siglec-Fint eosinophils partly expressed CD34 and were in the immature (or steady) state. Siglec-Fhi eosinophils did not express CD34, sharply increased in number after short ragweed (SRW) pollen challenge, and were in the mature (or activated) state. Moreover, chemical sympathectomy by 6-hydroxydopamine reduced the recruitment and activation of eosinophils, whereas the activation of the sympathetic nerve system (SNS) with restraint stress accelerated the recruitment and activation of eosinophils in SRW-induced conjunctivitis. It was also found that two eosinophil populations expressed alpha-1a-adrenergic receptors (α1a-ARs); in SRW-induced conjunctivitis, treatment with an α1a-AR antagonist decreased eosinophil responses, whereas treatment with an α1a-AR agonist aggravated eosinophil responses. Thus, eosinophil responses in conjunctivitis are regulated by the SNS via α1a-AR signaling. SNS inputs or α1a-AR function may be potential targets for the treatment of allergic conjunctivitis.


Assuntos
Conjuntivite Alérgica/metabolismo , Eosinófilos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervoso Simpático/metabolismo , Animais , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/metabolismo , Conjuntivite Alérgica/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Camundongos , Transdução de Sinais/fisiologia , Sistema Nervoso Simpático/imunologia
10.
Ann Allergy Asthma Immunol ; 124(6): 608-615.e2, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173484

RESUMO

BACKGROUND: Bermuda grass is a prevalent allergen that flourishes in tropical climates. Its exposure is traditionally believed to be low in Ontario due to the colder environment. However, high sensitization rates have been observed in Kingston, Ontario. OBJECTIVE: We sought to investigate whether its allergens can provoke allergic rhinitis (AR) symptoms in sensitized participants from south-eastern Ontario and determine if nasal allergen challenge (NAC) model is appropriate to study Bermuda grass-induced AR. METHODS: Twenty-one participants sensitized to Bermuda grass and 12 nonallergic participants completed a titrated NAC with increasing allergen concentrations at a screening visit. Total nasal symptom score (TNSS) and peak nasal inspiratory flow were collected before allergen exposure and 10 minutes after delivery of each concentration. Twelve participants with a Bermuda grass allergy who met the qualifying criteria (TNSS ≥ 8 and peak nasal inspiratory flow fall ≥ 50%) and 11 nonallergic controls returned for single-dose NAC visit. RESULTS: At titrated NAC, 19 of 21 sensitized participants met the criteria of positive allergic response when challenged. During single-dose NAC, participants with allergy had significantly greater TNSS between 15 minutes and 3 hours after NAC than controls. Likewise, allergic participants had a significantly increased number of nasal lavage eosinophils at both 1 and 6 hours after NAC. Bermuda grass-specific immunoglobulin E was significantly increased in Bermuda grass allergic participants at NAC than screening visit. CONCLUSION: Although Bermuda grass is a non-native allergen in Ontario, it can induce AR symptoms in sensitized participants, and the NAC model is appropriate to study Bermuda grass-induced AR.


Assuntos
Alérgenos/imunologia , Biomarcadores , Cynodon/efeitos adversos , Pólen/imunologia , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/imunologia , Adulto , Estudos de Casos e Controles , Progressão da Doença , Eosinófilos/imunologia , Eosinófilos/metabolismo , Humanos , Imunoglobulina E/imunologia , Contagem de Leucócitos , Pessoa de Meia-Idade , Testes de Provocação Nasal , Fenótipo , Rinite Alérgica Sazonal/sangue , Avaliação de Sintomas
11.
Artigo em Inglês | MEDLINE | ID: mdl-32171907

RESUMO

Eosinophils are important multifaceted effector cells involved in allergic inflammation. Following allergen challenge, eosinophils and other immune cells release secreted phospholipases, generating lysophosphatidylcholines (LPCs). LPCs are potent lipid mediators, and serum levels of LPCs associate with asthma severity, suggesting a regulatory activity of LPCs in asthma development. As of yet, the direct effects of LPCs on eosinophils remain unclear. In the present study, we tested the effects of the major LPC species (16:0, 18:0 and 18:1) on eosinophils isolated from healthy human donors. Addition of saturated LPCs in the presence of albumin rapidly disrupted cholesterol-rich nanodomains on eosinophil cell membranes and suppressed multiple eosinophil effector responses, such as CD11b upregulation, degranulation, chemotaxis, and downstream signaling. Furthermore, we demonstrate in a mouse model of allergic cell recruitment, that LPC treatment markedly reduces immune cell infiltration into the lungs. Our observations suggest a strong modulatory activity of LPCs in the regulation of eosinophilic inflammation in vitro and in vivo.


Assuntos
Quimiotaxia , Eosinófilos/efeitos dos fármacos , Hipersensibilidade/metabolismo , Lisofosfatidilcolinas/farmacologia , Animais , Antígeno CD11b/metabolismo , Células Cultivadas , Eosinófilos/metabolismo , Eosinófilos/fisiologia , Humanos , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
12.
BMC Infect Dis ; 20(1): 85, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000694

RESUMO

BACKGROUND: Little is known about the potential use of the eosinophil count as a predictive marker of bloodstream infection. In this study, we aimed to assess the reliability of eosinopenia as a predictive marker of bloodstream infection. METHODS: This retrospective cohort study was performed in the outpatient department and general internal medicine department of a tertiary university hospital in Japan. A total of 189 adult patients with at least 2 sets of blood cultures obtained during the period January 1-December 31, 2018, were included; those with the use of antibiotic therapy within 2 weeks prior to blood culture, steroid therapy, or a history of haematological cancer were excluded. The diagnostic accuracies of each univariate variable and the multivariable logistic regression models were assessed by calculating the areas under the receiver operating characteristic curves (AUROCs). The primary outcome was a positive blood culture indicating bloodstream infection. RESULTS: Severe eosinopenia (< 24.4 cells/mm3) alone yielded small but statistically significant overall predictive ability (AUROC: 0.648, 95% confidence interval (CI): 0.547-0.748, P < 0.05), and only moderate sensitivity (68, 95% CI: 46-85%) and specificity (62, 95% CI: 54-69%). The model comprising baseline variables (age, sex), the C-reactive protein level, and neutrophil count yielded an AUROC of 0.729, and further addition of eosinopenia yielded a slight improvement, with an AUROC of 0.758 (P < 0.05) and a statistically significant net reclassification improvement (NRI) (P = 0.003). However, the integrated discrimination index (IDI) (P = 0.284) remained non-significant. CONCLUSIONS: Severe eosinopenia can be considered an inexpensive marker of bloodstream infection, although of limited diagnostic accuracy, in a general internal medicine setting.


Assuntos
Agranulocitose , Bacteriemia/sangue , Bacteriemia/diagnóstico , Eosinófilos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Confiabilidade dos Dados , Feminino , Hospitais Universitários , Humanos , Japão , Contagem de Leucócitos/métodos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade
13.
Lancet Respir Med ; 8(5): 461-474, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32066536

RESUMO

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per µL or more (including no more than 30% patients with an eosinophil count <400 cells/µL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per µL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per µL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/µL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/tratamento farmacológico , Administração Oral , Adulto , Asma/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eosinofilia/tratamento farmacológico , Eosinófilos/metabolismo , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Glucocorticoides/administração & dosagem , Humanos , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Índice de Gravidade de Doença
14.
Am J Respir Cell Mol Biol ; 63(1): 25-35, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32101465

RESUMO

Diisocyanates are well-recognized causes of asthma. However, sensitized workers frequently lack diisocyanate-specific IgE, which complicates diagnosis and suggests the disease involves IgE-independent mechanisms. We used a mouse model of methylene diphenyl diisocyanate (MDI) asthma to identify biological pathways that may contribute to asthma pathogenesis. MDI sensitization and respiratory tract exposure were performed in Balb/c, transgenic B-cell (e.g., IgE)-deficient mice and a genetic background (C57BL/6)-matched strain. Eosinophils in airway fluid were quantitated by flow cytometry. Lung tissue gene expression was assessed using whole-genome mRNA microarrays. Informatic software was used to identify biological pathways affected by respiratory tract exposure and potential targets for disease intervention. Airway eosinophilia and changes (>1.5-fold; P value < 0.05) in expression of 192 genes occurred in all three mouse strains tested, with enrichment in chemokines and a pattern associated with alternatively activated monocytes/macrophages. CLCA1 (calcium-activated chloride channel regulator 1) was the most upregulated gene transcript (>100-fold) in all exposed mouse lungs versus controls, followed closely by SLC26A4, another transcript involved in Cl- conductance. Crofelemer, a U.S. Food and Drug Administration-approved Cl- channel inhibitor, reduced MDI exposure induction of airway eosinophilia, mucus, CLCA1, and other asthma-associated gene transcripts. Expression changes in a core set of genes occurs independent of IgE in a mouse model of chemical-induced airway eosinophilia. In addition to chemokines and alternatively activated monocytes/macrophages, the data suggest a crucial role for Cl- channels in diisocyanate asthma pathology and as a possible target for intervention.


Assuntos
Asma/metabolismo , Asma/patologia , Canais de Cloreto/metabolismo , Eosinofilia/metabolismo , Eosinófilos/metabolismo , Expressão Gênica/fisiologia , Pulmão/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Eosinofilia/induzido quimicamente , Eosinófilos/patologia , Expressão Gênica/efeitos dos fármacos , Imunoglobulina E/metabolismo , Isocianatos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo
15.
J Immunol ; 204(6): 1650-1660, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060135

RESUMO

Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.e., Scnn1b-Tg-positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33KO) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33HET) Tg+ mice. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clca1, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33HET/Tg+ mice, although the IL-33KO/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33KO/Tg+ mice compared with IL-33HET/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.


Assuntos
Fibrose Cística/imunologia , Interleucina-33/metabolismo , Pulmão/patologia , Mucina-5AC/metabolismo , Células Th2/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/patologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Canais Epiteliais de Sódio/genética , Humanos , Interleucina-33/genética , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Muco/imunologia , Muco/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Células Th2/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-31918007

RESUMO

Trihydroxyoctadecenoic acids (TriHOMEs) are linoleic acid-derived lipid mediators reported to be dysregulated in obstructive lung disease. In contrast to many other oxylipins, TriHOME biosynthesis in humans is still poorly understood. The association of TriHOMEs with inflammation prompted the current investigation into the ability of human granulocytes to synthesize the 16 different 9,10,13-TriHOME and 9,12,13-TriHOME isomers and of the TriHOME biosynthetic pathway. Following incubation with linoleic acid, eosinophils and (to a lesser extent) the mast cell line LAD2, but not neutrophils, formed TriHOMEs. Stereochemical analysis revealed that TriHOMEs produced by eosinophils predominantly evidenced the 13(S) configuration, suggesting 15-lipoxygenase (15-LOX)-mediated synthesis. TriHOME formation was blocked following incubation with the 15-LOX inhibitor BLX-3887 and was shown to be largely independent of soluble epoxide hydrolase and cytochrome P450 activities. TriHOME synthesis was abolished when linoleic acid was replaced with 13-HODE, but increased in incubations with 13-HpODE, indicating the intermediary role of epoxy alcohols in TriHOME formation. In contrast to eosinophils, LAD2 cells formed TriHOMEs having predominantly the 13(R) configuration, demonstrating that there are multiple synthetic routes for TriHOME formation. These findings provide for the first-time insight into the synthetic route of TriHOMEs in humans and expand our understanding of their formation in inflammatory diseases.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Eosinófilos/metabolismo , Hidroxiácidos/metabolismo , Ácidos Oleicos/metabolismo , Vias Biossintéticas , Linhagem Celular , Células Cultivadas , Eosinófilos/química , Humanos , Hidroxiácidos/análise , Isomerismo , Ácido Linoleico/análise , Ácido Linoleico/metabolismo , Ácidos Oleicos/análise
18.
J Leukoc Biol ; 107(3): 363-365, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31985092

RESUMO

Discussion of the neutrophil marker Ly6G/Gr1, which is readily detectable on mouse eosinophils, and is expressed in higher levels in the presence of IL-5.


Assuntos
Antígenos Ly/metabolismo , Eosinófilos/metabolismo , Animais , Aspergillus fumigatus/fisiologia , Microambiente Celular , Interleucina-5/metabolismo , Camundongos , Modelos Biológicos
19.
Immunol Lett ; 218: 40-43, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31901376

RESUMO

Chronic cough is a common symptom of various chronic diseases. However, the vast majority of individuals with conditions that are commonly associated with cough, such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. It is known that in the pathogenesis of cough, the nervous system plays a vital role. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature. The aim of this article is to review the most recent data about the role of the immune system in the pathogenesis of chronic cough.


Assuntos
Tosse/etiologia , Suscetibilidade a Doenças/imunologia , Sistema Imunitário/imunologia , Biomarcadores , Doença Crônica , Tosse/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Humanos , Sistema Imunitário/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/metabolismo
20.
Lab Invest ; 100(5): 751-761, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31925326

RESUMO

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Nax is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Nax using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Nax knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Nax knockdown. In addition, expression of COX-2, IL-1ß, IL-8, and S100A9, which are downstream genes of Nax and are involved in dermatitis pathogenesis, were also decreased by Nax knockdown. Our data show that knockdown of Nax relieved dermatitis symptoms in vivo and indicate that Nax is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.


Assuntos
Dermatite Atópica , Pele , Canais de Sódio Disparados por Voltagem , Animais , Proliferação de Células/genética , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Regulação para Baixo/genética , Eosinófilos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/patologia , Ceratose/fisiopatologia , Mastócitos/metabolismo , Coelhos , Pele/citologia , Pele/patologia , Pele/fisiopatologia , Canais de Sódio Disparados por Voltagem/genética , Canais de Sódio Disparados por Voltagem/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA