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1.
Front Immunol ; 12: 650331, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777047

RESUMO

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Eosinófilos/imunologia , Lectinas/imunologia , Mastócitos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Receptores Toll-Like/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/metabolismo , /prevenção & controle , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Eosinófilos/virologia , Interações Hospedeiro-Patógeno , Humanos , Lectinas/antagonistas & inibidores , Lectinas/genética , Lectinas/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/virologia , Camundongos Transgênicos , Peptídeo Hidrolases/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Receptores Toll-Like/metabolismo
2.
Life Sci ; 267: 118973, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33400932

RESUMO

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.


Assuntos
Eosinófilos/imunologia , Transtornos Respiratórios/imunologia , Doenças Respiratórias/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/fisiopatologia , Doenças Respiratórias/metabolismo , Doenças Respiratórias/fisiopatologia , Células Th2/imunologia , Células Th2/metabolismo
3.
Mol Immunol ; 132: 209-216, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33483086

RESUMO

Epithelial barrier dysfunction is involved in allergic inflammation and asthma, due to increased exposure of sub-epithelial tissues to inhaled allergens and air pollutants. The tight junction proteins claudins (CLDNs) are important regulators of paracellular permeability. CLDN7 is expressed in the alveolar epithelium; however, its contribution to airway barrier function remains unclear. The aim of this study was to assess the effects of TiO2 on epithelial barrier function in asthma. Mice were sensitized and challenged with OVA or exposed to TiO2 on days 21-23. The effect of TiO2 on CLDN7 was assessed by ELISA, immunoblotting, and immunohistochemical analysis. The levels of CLDN7 in the plasma of patients with asthma and healthy individuals were also examined. CLDN7 levels were lower in plasma from patients with asthma compared with healthy individuals. CLDN7 levels were associated with FEV1/FVC and the blood eosinophils (%) in patients with asthma. Although CLDN7 expression was elevated in the lungs of mice with asthma and in NHBE cells treated with HDM extracts, its expression was suppressed by exposure to TiO2. p-AKT and p-ERK was increased in asthmatic mice and decreased in mice with TiO2 treatment. p-AKT and p-ERK was decreased in NHBE cells treated with TiO2 and HDM extracts. Trans-epithelial electrical resistance (TEER) was higher in NHBE cells treated with TiO2 or HDM extracts; however, this was decreased by concurrent TiO2 and HDM extracts treatment. Our data suggest that particulate matter contributes to airway epithelial barrier dysfunction and results in airway inflammation and responsiveness.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Asma/metabolismo , Claudinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Material Particulado/efeitos adversos , Titânio/efeitos adversos , Animais , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Células Epiteliais/metabolismo , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
5.
Methods Mol Biol ; 2223: 101-114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226590

RESUMO

Mouse models of allergic asthma have been utilized to establish the role of T helper type 2 (Th2) cells in driving lung inflammation, airway hyperresponsiveness, and obstruction. Here, we present the allergic asthma models, in which mice are hypersensitized to ovalbumin (OVA) and house dust mite (HDM). These models mimic the major characteristics of human asthma including the eosinophilic inflammation and hyperactivity of the airway, overproduction of Th2 cytokines in the lung, and elevated total and allergen-specific immunoglobulin E (IgE) in serum.


Assuntos
Asma/imunologia , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Ovalbumina/administração & dosagem , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/imunologia , Células Th2/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Alérgenos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Biomarcadores/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Expressão Gênica , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pyroglyphidae/química , Testes de Função Respiratória , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Células Th2/imunologia , Células Th2/patologia
6.
Methods Mol Biol ; 2223: 133-149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226592

RESUMO

Mouse models of allergic conjunctivitis mimic various aspects of human allergic conjunctivitis. They are useful as acute models of allergic conjunctivitis to study immunological aspects of this condition. In this chapter, we will describe ragweed-pollen-induced experimental allergic conjunctivitis (mostly driven by adaptive immunity), and papain-soaked contact lens-induced experimental allergic conjunctivitis (mostly driven by innate immunity). Giemsa staining of histological sections is used for quantification of the number of infiltrating eosinophils, which is useful to evaluate the severity of the allergic inflammation. Immunohistochemical staining and quantitative PCR are used to clarify spatiotemporal expression of proinflammatory molecules in the conjunctival tissue. Flow cytometric analysis of conjunctival tissue is used for the detection of innate lymphoid cell type 2 (ILC2) in the ocular surface tissues.


Assuntos
Ambrosia/imunologia , Túnica Conjuntiva/efeitos dos fármacos , Conjuntivite Alérgica/imunologia , Modelos Animais de Doenças , Linfócitos/efeitos dos fármacos , Papaína/administração & dosagem , Imunidade Adaptativa/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Alérgenos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Ambrosia/química , Animais , Biomarcadores/metabolismo , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Conjuntivite Alérgica/induzido quimicamente , Conjuntivite Alérgica/genética , Conjuntivite Alérgica/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Citometria de Fluxo/métodos , Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Interleucinas/genética , Interleucinas/imunologia , Linfócitos/imunologia , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pólen/efeitos adversos , Pólen/imunologia , Reação em Cadeia da Polimerase em Tempo Real/métodos
7.
Lancet Respir Med ; 9(3): 260-274, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33357499

RESUMO

BACKGROUND: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. METHODS: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18-75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per µL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. FINDINGS: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39-0·65; p<0·0001) over the 24-week treatment period and provided clinically meaningful and statistically significant improvement from baseline to week 24 in SGRQ total score versus placebo (least squares mean change from baseline -8·11 (95% CI -11·41 to -4·82; p<0·0001), with similar differences at earlier timepoints. Benralizumab improved FEV1, PEF, ACQ-6, CGI-C, PGI-C, PSIA, and SNOT-22 at week 24 versus placebo, with differences observed early (within weeks 1 to 4). Adverse events were reported for 271 (63%) of 427 patients on benralizumab versus 143 (62%) of 229 patients on placebo. The most commonly reported adverse events for the 427 patients receiving benralizumab (frequency >5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. INTERPRETATION: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. FUNDING: AstraZeneca.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/tratamento farmacológico , Adulto , Antiasmáticos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Eosinófilos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Espirometria
8.
Methods Mol Biol ; 2223: 337-355, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226603

RESUMO

Food allergy has been rising in prevalence over the last two decades, affecting more than 10% of the world population. Current management of IgE-mediated food allergy relies on avoidance and rescue medications; research into treatments that are safer and providing guaranteed and durable curative effects is, therefore, essential. T-cell epitope-based immunotherapy holds the potential for modulating food allergic responses without IgE cross-linking. In this chapter, we describe the methods in evaluating the therapeutic capacities of immunodominant T-cell epitopes in animal models of food allergy. Moreover, we explain in detail the methods to measure the allergen-specific antibody levels, prepare single-cell suspension from spleen, and prepare small intestine for immunohistochemical analysis of eosinophils and Foxp3+ cells.


Assuntos
Alérgenos/administração & dosagem , Dessensibilização Imunológica/métodos , Modelos Animais de Doenças , Hipersensibilidade a Ovo/terapia , Hipersensibilidade a Leite/terapia , Peptídeos/farmacologia , Hipersensibilidade a Frutos do Mar/terapia , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Hidróxido de Alumínio/administração & dosagem , Animais , Toxina da Cólera/administração & dosagem , Hipersensibilidade a Ovo/imunologia , Hipersensibilidade a Ovo/patologia , Ensaio de Imunoadsorção Enzimática/métodos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Imuno-Histoquímica/métodos , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Camundongos Endogâmicos BALB C , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/patologia , Peptídeos/imunologia , Hipersensibilidade a Frutos do Mar/imunologia , Hipersensibilidade a Frutos do Mar/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
9.
Nat Commun ; 11(1): 6396, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328477

RESUMO

Clinical studies reveal changes in blood eosinophil counts and eosinophil cationic proteins that may serve as risk factors for human coronary heart diseases. Here we report an increase of blood or heart eosinophil counts in humans and mice after myocardial infarction (MI), mostly in the infarct region. Genetic or inducible depletion of eosinophils exacerbates cardiac dysfunction, cell death, and fibrosis post-MI, with concurrent acute increase of heart and chronic increase of splenic neutrophils and monocytes. Mechanistic studies reveal roles of eosinophil IL4 and cationic protein mEar1 in blocking H2O2- and hypoxia-induced mouse and human cardiomyocyte death, TGF-ß-induced cardiac fibroblast Smad2/3 activation, and TNF-α-induced neutrophil adhesion on the heart endothelial cell monolayer. In vitro-cultured eosinophils from WT mice or recombinant mEar1 protein, but not eosinophils from IL4-deficient mice, effectively correct exacerbated cardiac dysfunctions in eosinophil-deficient ∆dblGATA mice. This study establishes a cardioprotective role of eosinophils in post-MI hearts.


Assuntos
Eosinófilos/fisiologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Idoso , Animais , Morte Celular , Toxina Diftérica/toxicidade , Eletrocardiografia , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Feminino , Fibroblastos/patologia , Fibroblastos/fisiologia , Humanos , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/patologia , Ribonucleases/genética , Ribonucleases/metabolismo
10.
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
11.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
12.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L693-L709, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783616

RESUMO

Many mouse models of allergic asthma exhibit eosinophil-predominant cellularity rather than the mixed-granulocytic cytology in steroid-unresponsive severe disease. Therefore, we sought to implement a novel mouse model of antigen-driven, mixed-granulocytic, severe allergic asthma to determine biomarkers of the disease process and potential therapeutic targets. C57BL/6J wild-type, interleukin-6 knockout (IL-6-/-), and IL-6 receptor knockout (IL-6R-/-), mice were injected with an emulsion of complete Freund's adjuvant and house dust mite antigen (CFA/HDM) on day 1. Dexamethasone, a lymphocyte-depleting biological, or anti-IL-17A was administered during the intranasal HDM challenge on days 19-22. On day 23, the CFA/HDM model elicited mixed bronchoalveolar lavage (BAL) cellularity (typically 80% neutrophils and 10% eosinophils), airway hyperresponsiveness (AHR) to methacholine, diffusion impairment, lung damage, body weight loss, corticosteroid resistance, and elevated levels of serum amyloid A (SAA), pro-inflammatory cytokines, and T helper type 1/ T helper type 17 (Th1/Th17) cytokines compared with eosinophilic models of HDM-driven allergic airway disease. BAL cells in IL-6- or IL-6R-deficient mice were predominantly eosinophilic and associated with elevated T helper type 2 (Th2) and reduced Th1/Th17 cytokine production, along with an absence of SAA. Nevertheless, AHR remained in IL-6-deficient mice even when dexamethasone was administered. However, combined administration of anti-IL-17A and systemic corticosteroid significantly attenuated both overall and neutrophilic airway inflammation and also reduced AHR and body weight loss. Inhibition of IL-17A combined with systemic corticosteroid treatment during antigen-driven exacerbations may provide a novel therapeutic approach to prevent the pathological pulmonary and constitutional changes that greatly impact patients with the mixed-granulocytic endotype of severe asthma.


Assuntos
Corticosteroides/farmacologia , Asma/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Alérgenos/efeitos dos fármacos , Alérgenos/imunologia , Animais , Asma/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Hipersensibilidade Respiratória/patologia , Células Th17/imunologia
13.
Phytomedicine ; 78: 153295, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32795904

RESUMO

BACKGROUND AND PURPOSE: Asthma is a chronic respiratory disease orchestrated by immune and structural cells. Identification of novel therapeutic strategies are needed for asthma due to the limitations of existing therapies. We have validated the anti-inflammatory, anti-asthmatic and immunomodulatory therapeutic properties of herbal decoction, Divya-Swasari-Kwath (DSK) using mouse model of ovalbumin (OVA) induced allergic asthma. METHODS AND RESULTS: HPLC analysis identified the presence of Rutin, Glycyrrchzin, Gallic acid, Cinnamic acid, Chlorogenic acid, Caffeic acid and Piperine as bioactive herbal metabolites in DSK. Therapeutic treatment with herbal decoction DSK significantly alleviated the pathological features of allergic asthma including inflammatory cell accumulation in Broncho-Alveolar Lavage (BAL) fluids, specifically lymphocytes and eosinophils, lung inflammation, oxidative stress, airway remodelling, and pro-inflammatory cytokine levels. H&E analysis of lung tissue sections identified attenuated inflammatory cell infiltration and thickening of bronchial epithelium by DSK. PAS staining and MT staining identified decrease in OVA-induced mucus hyper secretion and peri-bronchial collagen deposition respectively, upon DSK treatment. Treatment with DSK increased the mRNA expression of antioxidative defence gene Nrf-2 and its downstream target genes HO-1 and NQO-1. In the same line, biochemical analysis for the markers of oxidative/antioxidant system confirmed the restoration of activity of Catalase, GPx, SOD and EPO and the levels of GSH, GSSG, MDA and Nitrite in whole lungs. In line with PAS staining, DSK treatment decreased the OVA-induced expression of Muc5AC and Muc5B genes. DSK treatment reduced the steady state mRNA expression levels of IL-6, IL-1ß, TNF-α, IL-4, -5, -33, IFN-γ in whole lung; and IL-6, TNF-α and IL-1ß protein levels in BALF. CONCLUSION: Collectively, our results suggest that herbal decoction DSK is effective in protecting against allergic airway inflammation and remodelling by regulating anti-oxidant mechanisms. We postulate that DSK could be the potential therapeutic option for allergic asthma management.


Assuntos
Antiasmáticos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Asma/tratamento farmacológico , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Antiasmáticos/química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/metabolismo , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Hipersensibilidade/tratamento farmacológico , Fatores Imunológicos/farmacologia , Pulmão/patologia , Masculino , Medicina Ayurvédica , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Ovalbumina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/tratamento farmacológico
14.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L683-L692, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726138

RESUMO

Nicotine of unprecedented concentrations and purity is being inhaled by those using commercially available electronic nicotine delivery systems (ENDS). The consequences of this route of self-administration on the immunological response to inhaled allergens are not known. In mice, sensitization and inhalation challenge with the common environmental house dust mite (HDM) allergen is an experimental model of this response. When mice were exposed to aerosolized nicotine base (aeroNic) twice daily, 5 days/wk for 8 wk, the HDM-induced recruitment of eosinophils (EOS) was substantially reduced as measured in bronchial alveolar lavage fluid (BALF). Oral nicotine administration had no effect. HDM challenge in the presence of nicotinic receptor subtype α7 (α7)-specific type-1 positive allosteric modulators (PAMs) was alone sufficient to suppress EOS. RNA analysis of alveolar macrophages (AM) collected from BALF after HDM challenge of aeroNic revealed that α7 activation strongly suppresses initiation of Ccl24 (eotaxin 2) transcription. To examine possible cellular signaling mechanisms coupling α7 to Ccl24 transcription, an AM culture model system was used. In AM cultures of freshly collected BALF, Ccl24 transcription was robustly activated by a mixture of IL-4 and IL-10, and this was suppressed by coapplication of type-1 PAMs through a pathway that requires p38MAPK but is independent of Jak2. These results suggest that the EOS response to HDM inhaled allergen is subject to modulation through activation of the α7 receptor and suggest that the allergic response may be substantially modified in ENDS users.


Assuntos
Antígenos de Dermatophagoides/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nicotina/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Eosinófilos/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Pulmão/metabolismo , Camundongos , Ácaros , Nicotina/metabolismo , Pyroglyphidae/efeitos dos fármacos , Pyroglyphidae/imunologia
17.
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
18.
Microbes Infect ; 22(9): 403-404, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32599077

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Síndrome Respiratória Aguda Grave/prevenção & controle , Vacinas Virais/administração & dosagem , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Eosinófilos/virologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Vacinas Virais/efeitos adversos
20.
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
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