RESUMO
BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.
Assuntos
Proteínas ADAM , Asma/sangue , Asma/genética , Subunidade alfa de Receptor de Interleucina-4 , Proteínas ADAM/sangue , Proteínas ADAM/genética , Adulto , Idoso , Asma/tratamento farmacológico , Seguimentos , Marcadores Genéticos , Humanos , Subunidade alfa de Receptor de Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation. OBJECTIVE: The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium. METHODS: Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules. RESULTS: Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs. CONCLUSIONS: The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.
Assuntos
Interleucina-33/metabolismo , Estresse Oxidativo , Trifosfato de Adenosina/metabolismo , Alérgenos/imunologia , Animais , Antioxidantes/metabolismo , Cálcio/metabolismo , Células Epiteliais/metabolismo , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismoRESUMO
BACKGROUND: Exposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues. METHODS: To investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene-deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms. RESULTS: Naïve BALB/c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata. Expression of IL-5 and IL-33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen-exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti-IL-5 antibody. Mice deficient in the IL-33 receptor ST2 (i.e., Il1rl1(-/-) mice) were unable to increase their serum levels of IL-5 and allergen-induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells (ILC2s) in the lungs showed robust expression of IL-5 after Alternaria exposure. CONCLUSIONS: These finding suggests that lung IL-33, through innate activation of ILC2s and their production of IL-5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions.
Assuntos
Alérgenos/imunologia , Exposição Ambiental/efeitos adversos , Eosinofilia/sangue , Eosinofilia/imunologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Interleucina-33/metabolismo , Mielopoese , Animais , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Eosinofilia/genética , Feminino , Interleucina-5/sangue , Interleucina-5/metabolismo , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/metabolismo , CamundongosRESUMO
BACKGROUND: The mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease. OBJECTIVE: To characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls. METHODS: This was a non-interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post-visit 2 weeks later. The sinonasal outcome test-22 (SNOT-22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis. RESULTS: Both CRSwNP patients and control subjects showed a significant increase in SNOT-22 scores during acute exacerbation. Increased nasal levels of IL-6, IL-5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM-CSF levels were notable and were validated by a conventional analysis. CONCLUSIONS: CRSwNP patients demonstrate distinct immunological changes locally and systemically during acute exacerbation. Growth factors VEGF and GM-CSF may be involved in the immunopathogenesis of subjects with CRS and nasal polyps experiencing exacerbation.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Pólipos Nasais/complicações , Rinite/sangue , Rinite/complicações , Sinusite/sangue , Sinusite/complicações , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Crônica , Análise por Conglomerados , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Estudos Prospectivos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Rinite/diagnóstico , Rinite/imunologia , Sinusite/diagnóstico , Sinusite/imunologia , Adulto JovemRESUMO
BACKGROUND: The mechanisms for producing weals in chronic spontaneous (idiopathic) urticaria (CSU) are incompletely understood. Leucocyte infiltration with vascular leakage and expression of the potent vasoactive agents' calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) are features of late-phase allergic skin reactions, previously proposed as a model of CSU. OBJECTIVE: To measure CGRP and VEGF expression in lesional and non-lesional skin from CSU patients and to compare results with a control group. METHODS: Eight paired biopsies (one from 4-8 h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied by immunohistochemistry and confocal microscopy. RESULTS: Lesional skin in CSU contained significantly more CGRP+ and VEGF+ cells than non-lesional skin. No significant differences were observed in CGRP and VEGF expression between non-lesional skin and controls. In lesional skin, VEGF and CGRP co-localised to UEA-1+ blood vessels. CGRP was also expressed by neutrophils and eosinophils and to a lesser extent by CD90(+) fibroblasts, mast cells, CD3(+) and CD68(+) cells. CGRP and VEGF expression was not related to the duration of disease. CONCLUSION AND CLINICAL RELEVANCE: Increased expression of CGRP and VEGF in lesional, but not uninvolved, skin indicates that these potent vasoactive agents may play a role in wealing and tissue oedema in CSU so representing novel targets in therapy.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Urticária/imunologia , Urticária/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Antígenos de Superfície/metabolismo , Biópsia , Peptídeo Relacionado com Gene de Calcitonina/genética , Doença Crônica , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Urticária/genética , Urticária/patologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Innate lymphoid cells (ILCs) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILCs (ILC2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC2s and other immune cells. We sought to investigate the capacity of ILC2s to regulate effector functions of T cells. METHODS: We isolated ILC2s from the lungs of naïve mice. We cultured CD4(+) T cells with ILC2s in vitro and examined the functions of these cell types. The mechanisms were investigated using blocking antibodies and cells isolated from cytokine-deficient mice. For the in vivo study, we adoptively transferred ILC2s and CD4(+) T cells into Il7ra(-/-) mice and subsequently exposed the mice to ovalbumin and a cysteine protease. RESULTS: Lung ILC2s enhanced CD4(+) T-cell proliferation and promoted production of type 2 cytokines in vitro. The interaction between ILC2s and CD4(+) T cells involved costimulatory molecule OX40L and cytokine IL-4, which was mainly derived from ILC2s. Adoptive transfer of both ILC2 and CD4(+) T-cell populations, but not each population alone, into Il7ra(-/-) mice resulted in induction of a robust antigen-specific type 2 cytokine response and airway inflammation. CONCLUSION: Lung ILC2s function to promote adaptive immunity in addition to their established roles in innate immunity. This novel function of ILC2s needs to be taken into account when considering the pathophysiology of asthma and other allergic airway diseases.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Transferência Adotiva , Animais , Asma/imunologia , Técnicas de Cocultura , Citocinas/biossíntese , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
Assuntos
Asma/genética , Asma/fisiopatologia , Variação Genética , Receptores de Glucocorticoides/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Idoso , Asma/tratamento farmacológico , Asma/imunologia , Moléculas de Adesão Celular/sangue , Eosinófilos/imunologia , Feminino , Volume Expiratório Forçado , Estudos de Associação Genética , Proteínas de Choque Térmico/genética , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de RiscoRESUMO
BACKGROUND: In chronic spontaneous urticaria (CSU) mast cell activation together with inflammatory changes in the skin are well documented and may play an important role in mechanisms of tissue oedema. OBJECTIVES: To confirm and extend these observations by measuring microvascular markers, leucocytes and mast cell numbers in lesional and uninvolved skin and to compare findings with a control group. METHODS: Paired biopsies (one from 4-8-h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied using immunohistochemistry and confocal microscopy using the lectin Ulex europaeus agglutinin 1 (UEA-1). RESULTS: Lesional skin in CSU contained significantly more CD31+ endothelial cells; CD31+ blood vessels, neutrophils, eosinophils, basophils and macrophages; and CD3+ T cells than nonlesional skin. Increased vascularity was confirmed by confocal imaging using the lectin UEA-1. Uninvolved skin from CSU contained significantly more CD31+ endothelial cells, CD31+ blood vessels and eosinophils compared with the control subjects. There was a threefold increase in mast cell numbers when CSU was compared with controls but no difference was observed between lesional and uninvolved skin. CONCLUSIONS: Increased vascular markers together with eosinophil and neutrophil infiltration are features of lesional skin in CSU and might contribute to tissue oedema. Eosinophils and microvascular changes persist in uninvolved skin, which, together with increased mast cells, suggests that nonlesional skin is primed for further wealing.
Assuntos
Leucocitose/patologia , Mastócitos/patologia , Urticária/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Vasos Sanguíneos/patologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Pele/irrigação sanguínea , Urticária/patologiaRESUMO
PURPOSE: We previously reported that asthmatics had lower anti-serotype-specific pneumococcal polysaccharide antibody levels than non-asthmatics, and the T-helper 2 (Th2) immune profile was associated with suboptimal pneumococcal polysaccharide antibody. Our objective was to determine the influence of asthma status on anti-pneumococcal protein antigen antibody levels. METHODS: We conducted a cross-sectional study, which enrolled 16 children and adults with asthma and 14 subjects without asthma. Asthma was ascertained by predetermined criteria. Serum IgG antibody levels to pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal choline-binding protein A (PcpA), and pneumolysin (PLY) were measured by enzyme-linked immunosorbent assays (ELISA). These antibody levels were compared between asthmatics and non-asthmatics. The Th2 immune profile was determined by IL-5 secretion from PBMCs cultured with house dust mite (HDM) and staphylococcal enterotoxin B (SEB) at day 7. The correlation between the anti-pneumococcal antibody levels and the Th2-HDM and SEB-responsive immune profile was assessed. RESULTS: Of the 30 subjects, 16 (53%) were male and the median age was 26 years. There were no significant differences in anti-PspA, anti-PspC, anti-PcpA, and anti-PLY antibody levels between asthmatics and non-asthmatics. The Th2 immune profile was inversely correlated with the anti-PspC antibody levels (r = -0.53, p = 0.003). This correlation was significantly modified by asthma status (r = -0.74, p = 0.001 for asthmatics vs. r = -0.06, p = 0.83 for non-asthmatics). Other pneumococcal protein antibodies were not correlated with the Th2 immune profile. CONCLUSION: No significant differences in the anti-pneumococcal protein antigen antibody levels between asthmatics and non-asthmatics were found. Asthma status is an important effect modifier determining the negative influence of the Th2 immune profile on anti-PspC antibody levels.
Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Asma/imunologia , Proteínas de Bactérias/imunologia , Streptococcus pneumoniae/imunologia , Adulto , Asma/microbiologia , Estudos de Casos e Controles , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-5/sangue , Leucócitos Mononucleares , Masculino , Estreptolisinas/imunologia , Células Th2/imunologiaRESUMO
We and others have reported that HLA-DRB1*03 is associated with childhood asthma. To extend this observation and to prove this association, we sensitized and challenged either HLA-DR2 (HLA-DRB1*1502) or HLA-DR3 (HLA-DRB1*0301) transgenic mice with house-dust mite extract. Inflammatory cell counts and cytokine levels in the bronchoalveolar lavage (BAL) fluid between HLA-DR3 and DR2 mice were compared. HLA-DR3 transgenic mice had significantly elevated eosinophil counts, Interleukin-4 and Interleukin-13 levels in the BAL fluid but not interferron gamma-γ. Thus, our study suggests that HLA-DRB1*0301 plays an important role in mounting a Th2-predominant immune response to house dust mite and Th2-type inflammation in the lung.
Assuntos
Antígenos HLA-DR/genética , Antígeno HLA-DR2/genética , Antígeno HLA-DR3/genética , Polimorfismo Genético , Pyroglyphidae/genética , Animais , Líquido da Lavagem Broncoalveolar , Cadeias HLA-DRB1 , Humanos , Sistema Imunitário , Inflamação , Interferon gama/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Camundongos , Camundongos Transgênicos , Células Th2RESUMO
OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Eosinofilia/tratamento farmacológico , Esofagite/tratamento farmacológico , Interleucina-5/imunologia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Método Duplo-Cego , Esquema de Medicação , Neurotoxina Derivada de Eosinófilo/metabolismo , Eosinofilia/sangue , Eosinofilia/complicações , Eosinofilia/imunologia , Eosinófilos/patologia , Esofagite/sangue , Esofagite/complicações , Esofagite/imunologia , Esofagoscopia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Resultado do TratamentoRESUMO
We report here the first successful synthesis of planar triphenylborane 1 with the phenyl groups bridged by oxygen and nitrogen atoms via double nucleophilic aromatic substitution reaction. The hetero atom-bridged 1 has excellent planarity. Its structural and photophysical properties are tunable by altering the bridging atoms.
RESUMO
Human peripheral blood eosinophils released eosinophil survival-enhancing activity when stimulated with the calcium ionophore, ionomycin. The release of activity was detected as early as 3 h after stimulation and was inhibited by an immunomodulating agent, cyclosporin A. The survival-enhancing activity was completely abolished by treatment with anti-interleukin 3 (IL-3) and anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies. Moreover, IL-3 and GM-CSF were measurable in ionomycin-stimulated eosinophil supernatants by immunoassay. Eosinophils produced approximately one-half as much IL-3 and one-fifth as much GM-CSF as ionomycin-stimulated mononuclear cells. Neutrophils also produced IL-3 and GM-CSF, but the amounts were less than those produced by eosinophils. These observations suggest a novel role for eosinophils in pathophysiology of allergic inflammation and host defense mechanisms.
Assuntos
Eosinófilos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-3/metabolismo , Neutrófilos/metabolismo , Ribonucleases , Sobrevivência Celular/efeitos dos fármacos , Neurotoxina Derivada de Eosinófilo , Eosinófilos/citologia , Humanos , Técnicas In Vitro , Ionomicina/farmacologia , Neurotoxinas/metabolismo , Neutrófilos/citologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV-related cirrhosis, low platelet count (<==106 000/mm(3)) and splenomegaly (spleen size >==10 cm) underwent splenectomy. Platelet counts significantly increased at 4-8 weeks after splenectomy [pre: 64 200 +/- 6900/mm(3)vs post 209 000 +/- 40 600/mm(3) (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (>==100 KIU/mL), four received combination therapy with pegylated IFNalpha-2b plus ribavirin, and the other four received standard IFNalpha-2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNalpha-2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low-dose long-term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNalpha-based treatment.
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Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Esplenectomia , Esplenomegalia/cirurgia , Trombocitopenia/terapia , Idoso , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Ribavirina/uso terapêutico , Resultado do Tratamento , Carga ViralRESUMO
The relationship between allergic airway inflammation and pneumococcal pneumonia is not well understood. We assessed susceptibility to experimental pneumococcal pneumonia in mice with and without allergic airway inflammation. Susceptibility to pneumococcal pneumonia was evaluated by challenging mice with a bioluminescent Streptococcus pneumoniae strain after sensitization with ovalbumin (OVA), with subsequent monitoring of pneumococcal infection using real-time photonic imaging. Of 46 OVA-sensitized mice challenged with pneumococci, 13 (28%) developed imaging findings consistent with pneumococcal pneumonia. In comparison, 28 (57%) of 49 non-sensitized control mice developed pneumococcal pneumonia (P = 0.005). While none of the control group developed meningitis (0%, none of 28), two mice in the OVA-sensitized group developed meningitis (15.4%, two of 13) (P = 0.09). The mean bacterial count in the lung was significantly lower in the OVA-sensitized than the non-sensitized group (8.26 +/- 0.69 versus 9.21 +/- 0.67 log(10) colony-forming units (CFU)/g, P = 0.002). There was a trend towards the mean bacterial count in the spleen being higher in the OVA-sensitized versus the non-sensitized group (8.14 +/- 0.89 versus 7.45 +/- 1.07 log(10) CFU/g, P = 0.071). A high level of interleukin (IL)-4 in lung homogenates was associated with risk of pneumococcal infection independent of sensitization with OVA (odds ratio: 49.7, 95% confidence interval 2.92-846.5, per increment of 1.0 pg/ml). In the murine model studied, acute allergic airway inflammation reduced susceptibility to pneumococcal pneumonia. IL-4 may increase the risk of pneumococcal pneumonia independently of allergic airway inflammation.
Assuntos
Infecções Oportunistas/complicações , Pneumonia Pneumocócica/complicações , Hipersensibilidade Respiratória/complicações , Animais , Contagem de Colônia Microbiana , Citocinas/análise , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Cavidade Nasal/microbiologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/patologia , Ovalbumina/imunologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/patologia , Hipersensibilidade Respiratória/imunologia , Streptococcus pneumoniae/isolamento & purificação , Células Th2/imunologiaAssuntos
Adenocarcinoma Mucinoso/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Endoscopia do Sistema Digestório/métodos , Neoplasias Pancreáticas/diagnóstico , Idoso , Biópsia , Colangiopancreatografia por Ressonância Magnética , Diagnóstico Diferencial , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
We analyzed 8 patients with unresectable locally advanced non-small cell lung cancer who responded to chemotherapy or chemoradiotherapy and underwent complete resection between June 2003 and June 2005. The patients were all male with a mean age of 61 years (range, 42 to 72 years). Histological subtypes included adenocarcinoma in 4 patients and squamous cell carcinoma in 4 patients. Clinical staging included T2N2M0 in 3 patients, T2N3M0 in 2 patients, and 1 patient each for T3N2M0, T4N2M0, and T4N3M0. Preoperative treatment included chemotherapy in 5 patients and chemoradiotherapy in 3 patients, all of whom had a partial response. Surgical procedures included lobectomy in 6 patients and pneumonectomy in 2 patients. In addition, all of the patients underwent mediastinal lymph node dissection (ND2a). Pathological effect included Ef. 0 in 1 patient, Ef. 1 in 2 patients, Ef. 2 in 2 patients, Ef. 3 in 3 patients. The median survival time from initial treatment (or surgery) was 16 (14) months in all cases, 22 (19) for ycN0, 12 (8) for ycN2, 31 (27) for Ef. 3, 13 (9) for Ef. 0-2, 27 (23) for pN0, 13 (9) for pN1-3, 31 (27) for chemoradiotherapy, 16 (13) for chemotherapy, 24 (21) for adenocarcinoma, and 15 (11) for squamous cell carcinoma. Multimodality treatment, including surgery, is beneficial for patients with unresectable locally advanced non-small cell lung cancer who respond to chemotherapy or chemoradiotherapy, especially those patients with ycN0 or pN0.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Adenocarcinoma/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Evidence suggests that eosinophils contribute to inflammation in bronchial asthma by releasing chemical mediators and cytotoxic granule proteins. To investigate the mechanism of eosinophil degranulation in asthma, we established an in vitro model of allergen-induced degranulation. We treated tissue culture plates with short ragweed pollen (SRW) extract and sera from either normal donors or SRW-sensitive patients with asthma. Eosinophils were incubated in the wells and degranulation was assessed by measurement of eosinophil-derived neurotoxin in supernatants. We detected degranulation only when sera from SRW-sensitive patients were reacted with SRW. Anti-IgG and anti-Fc gamma RII mAb, but not anti-IgE or anti-Fc epsilon RII mAb, abolished the degranulation. IgG-depleted serum did not induce degranulation; IgE-depleted serum triggered as much degranulation as untreated serum. Furthermore, serum levels of SRW-specific IgG1 or IgG3 correlated with the amounts of released eosinophil-derived neurotoxin. When eosinophils were cultured in wells coated with purified IgG or IgE, eosinophil degranulation was observed only with IgG. Finally, human IgG1 and IgG3, and less consistently IgG2, but not IgG4, induced degranulation. Thus, sera from patients with SRW-sensitive asthma induce eosinophil degranulation in vitro through antigen-specific IgG1 and IgG3 antibodies. These antibodies may be responsible for degranulation of eosinophils in inflammatory reactions, such as bronchial asthma.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Eosinófilos/imunologia , Imunoglobulina G/imunologia , Receptores de IgG/imunologia , Degranulação Celular/efeitos dos fármacos , Humanos , Imunoglobulina E/imunologia , Técnicas In Vitro , Interleucina-5/farmacologia , PólenRESUMO
Malignant pleural mesothelioma is an uncommon neoplasm that caused 647 deaths in Japan in 2004. The incidence of the disease is increasing and is estimated to reach its peak in 2025. We reviewed the clinical features in 11 consecutive patients with pathologically confirmed diffuse malignant pleural mesothelioma in our institution from January 1997 to December 2002. Of the 11 patients, 9 were male and 2 were female with a mean age of 66 (range, 55 to 90) years. Symptoms included dyspnea in 4 patients, chest pain in 3, dyspnea plus chest pain in 2, and cough in 2. Median period between symptom onset and presentation was 1 (range, 0 to 6) month. A history of asbestos exposure was identified in 3 patients and suspected in 5. A definitive diagnosis was made by closed pleural biopsy in 8 patients, pleural fluid cytology in 2, and autopsy in 1. Histological subtypes included epithelioid in 6 patients, sarcomatoid in 2, biphasic in 1, and unknown in 2. International Mesothelioma Interest Group (IMIG) staging included stage II in 6 patients, stage III in 3, and stage IV in 2. Median period between presentation and diagnosis was 1 (range, 0 to 22) month. Treatment included intrapleural chemotherapy in 4 patients, extrapleural pneumonectomy in 3, pleural drainage in 2, and best supportive care in 2. During the follow-up period, 9 patients died and 2 survived. Median survival time after diagnosis was 3 (range, 0 to 51) months. Of the 11 patients, 7 (64%) died within 6 months after the first presentation, and only 1 (9%) lived longer than 2 years after diagnosis.
Assuntos
Mesotelioma , Neoplasias Pleurais , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mesotelioma/terapia , Pessoa de Meia-Idade , Neoplasias Pleurais/terapiaRESUMO
Benign endobronchial tumors are rare, and among these endobronchial neurinoma is extremely rare. We describe a case of endobronchial neurinoma successfully treated with left lower lobectomy. A 58-year-old man presented with an 8-month history of cough. During this period he was repeatedly treated with antibiotics for pneumonia of the left lower lobe. Chest X-ray showed atelectasis of the left lower lobe. Computed tomography (CT) of the chest showed a mass in the left main and lower lobe bronchi. Bronchoscopy revealed the mass almost completely obstructing the left main bronchus. Although transbronchial biopsy was inconclusive and yielded necrotic tissue with Aspergillus hyphae, lung cancer was highly suspected based on clinical and radiographic findings. He underwent left lower lobectomy and was discharged 14 days after surgery in good condition. Pathological diagnosis was an endobronchial neurinoma 4 cm in size arising from the left basal bronchus. On immunohistochemical staining, the tumor was positive for S-100 protein and negative for a-smooth muscle actin. He took itraconazole at a daily dose of 200 mg orally for 6 months. He remains well 52 months after surgery without any evidence of recurrence.