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1.
Respir Res ; 23(1): 202, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945604

RESUMO

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.


Assuntos
Anti-Infecciosos , Tratamento Farmacológico da COVID-19 , Complemento C5 , Inativadores do Complemento/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos , SARS-CoV-2 , Resultado do Tratamento
2.
Am J Respir Crit Care Med ; 200(7): 857-868, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31046405

RESUMO

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined.Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care.Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality.Measurements and Main Results: A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal.Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Falha de Tratamento , Administração por Inalação , Agonistas Adrenérgicos beta/uso terapêutico , Idoso , Clindamicina/uso terapêutico , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade , Antagonistas Muscarínicos/uso terapêutico , Readmissão do Paciente , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/uso terapêutico , Capacidade Vital , beta-Lactamas/uso terapêutico
3.
Respir Res ; 20(1): 237, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665017

RESUMO

BACKGROUND: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality. OBJECTIVES: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions. METHODS: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time. RESULTS: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/µL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses. CONCLUSIONS: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy. TRIAL REGISTRATION: ClinicalTrials.gov number. NCT02135354 .


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Progressão da Doença , Readmissão do Paciente/tendências , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Índice de Gravidade de Doença , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Falha de Tratamento
4.
Thorax ; 68(4): 322-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23291349

RESUMO

BACKGROUND: Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. METHODS: We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting ß2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. CONCLUSIONS: Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. CLINICALTRIALS.GOV NUMBER: NCT00760838.


Assuntos
Antibacterianos/uso terapêutico , Asma/tratamento farmacológico , Azitromicina/uso terapêutico , Adulto , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Cell Rep Med ; 3(12): 100833, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36459994

RESUMO

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).


Assuntos
COVID-19 , Macrófagos Alveolares , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Pulmão , Macrófagos
6.
BMJ Open ; 11(11): e051065, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782342

RESUMO

OBJECTIVES: The COVID-19 pandemic has resulted in widespread morbidity and mortality with the consequences expected to be felt for many years. Significant variation exists in the care even of similar patients with COVID-19, including treatment practices within and between institutions. Outcome measures vary among clinical trials on the same therapies. Understanding which therapies are of most value is not possible unless consensus can be reached on which outcomes are most important to measure. Furthermore, consensus on the most important outcomes may enable patients to monitor and track their care, and may help providers to improve the care they offer through quality improvement. To develop a standardised minimum set of outcomes for clinical care, the International Consortium for Health Outcomes Measurement (ICHOM) assembled a working group (WG) of 28 volunteers, including health professionals, patients and patient representatives. DESIGN: A list of outcomes important to patients and professionals was generated from a systematic review of the published literature using the MEDLINE database, from review of outcomes being measured in ongoing clinical trials, from a survey distributed to patients and patient networks, and from previously published ICHOM standard sets in other disease areas. Using an online-modified Delphi process, the WG selected outcomes of greatest importance. RESULTS: The outcomes considered by the WG to be most important were selected and categorised into five domains: (1) functional status and quality of life, (2) mental functioning, (3) social functioning, (4) clinical outcomes and (5) symptoms. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, clinical factors and treatment-related factors. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of care to patients with COVID-19. Their consistent definition and collection could also broaden the implementation of more patient-centric clinical outcomes research.


Assuntos
COVID-19 , Qualidade de Vida , Humanos , Avaliação de Resultados em Cuidados de Saúde , Pandemias , SARS-CoV-2
7.
Lancet Respir Med ; 9(12): 1427-1438, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34756178

RESUMO

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Síndrome da Liberação de Citocina , Insuficiência Respiratória , Idoso , Bélgica , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Ferritinas , Humanos , Hipóxia , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Oxigênio , Estudos Prospectivos , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , SARS-CoV-2 , Resultado do Tratamento
8.
Respir Res ; 11: 35, 2010 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-20307269

RESUMO

BACKGROUND: Dendritic cells (DC) linking innate and adaptive immune responses are present in human lungs, but the characterization of different subsets and their role in COPD pathogenesis remain to be elucidated. The aim of this study is to characterize and quantify pulmonary myeloid DC subsets in small airways of current and ex-smokers with or without COPD. METHODS: Myeloid DC were characterized using flowcytometry on single cell suspensions of digested human lung tissue. Immunohistochemical staining for langerin, BDCA-1, CD1a and DC-SIGN was performed on surgical resection specimens from 85 patients. Expression of factors inducing Langerhans-type DC (LDC) differentiation was evaluated by RT-PCR on total lung RNA. RESULTS: Two segregated subsets of tissue resident pulmonary myeloid DC were identified in single cell suspensions by flowcytometry: the langerin+ LDC and the DC-SIGN+ interstitial-type DC (intDC). LDC partially expressed the markers CD1a and BDCA-1, which are also present on their known blood precursors. In contrast, intDC did not express langerin, CD1a or BDCA-1, but were more closely related to monocytes.Quantification of DC in the small airways by immunohistochemistry revealed a higher number of LDC in current smokers without COPD and in COPD patients compared to never smokers and ex-smokers without COPD. Importantly, there was no difference in the number of LDC between current and ex-smoking COPD patients.In contrast, the number of intDC did not differ between study groups. Interestingly, the number of BDCA-1+ DC was significantly lower in COPD patients compared to never smokers and further decreased with the severity of the disease. In addition, the accumulation of LDC in the small airways significantly correlated with the expression of the LDC inducing differentiation factor activin-A. CONCLUSIONS: Myeloid DC differentiation is altered in small airways of current smokers and COPD patients resulting in a selective accumulation of the LDC subset which correlates with the pulmonary expression of the LDC-inducing differentiation factor activin-A. This study identified the LDC subset as an interesting focus for future research in COPD pathogenesis.


Assuntos
Células de Langerhans/imunologia , Pulmão/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumar/imunologia , Ativinas/genética , Idoso , Antígenos CD/análise , Antígenos CD1/análise , Antígenos de Superfície/análise , Moléculas de Adesão Celular/análise , Diferenciação Celular , Feminino , Citometria de Fluxo , Glicoproteínas , Humanos , Imuno-Histoquímica , Interleucina-15/genética , Peptídeos e Proteínas de Sinalização Intracelular , Lectinas Tipo C/análise , Modelos Lineares , Pulmão/fisiopatologia , Masculino , Lectinas de Ligação a Manose/análise , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ligante RANK/genética , RNA Mensageiro/análise , Receptores de Superfície Celular/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fumar/efeitos adversos , Fumar/genética , Abandono do Hábito de Fumar
9.
Am J Respir Crit Care Med ; 177(11): 1180-6, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18337593

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells responsible for immune homeostasis. In the lung's responses to tissue damage or infection, they initiate and orchestrate innate and adaptive immunity. There are immature and mature states and at least three phenotypic and functional subsets. DCs circulate in the blood and localize to mucosal surfaces in immature form where they act as sentinels, sampling constituents of the external environment that breach the epithelium. With internalization of antigen, they are activated, mature, and migrate to draining lymph nodes to induce the proliferation and regulate the balance of Th1/Th2 T cells or to induce a state of tolerance, the last dependent on maturation status, extent of cell surface costimulatory molecule expression, and cytokine release. Cigarette smoke has modulatory effects varying with species, dose, the location examined within the lung, and the marker or technique used to identify DCs. Healthy smokers (and smokers with asthma) have reduced numbers of large airway mature DCs. In chronic obstructive pulmonary disease, the number of immature DCs is increased in small airways, whereas in smokers with chronic obstructive pulmonary disease, the total number of DCs appears to be reduced in large airways. We hypothesize that the long-term effects of cigarette smoke include reduction of DC maturation and function, changes that favor repeated infection, increased exacerbation frequency, and the altered (CD8(+) T-cell predominant) pattern of inflammation associated with this progressive chronic disease.


Assuntos
Células Dendríticas/fisiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumar/efeitos adversos , Antígenos CD/fisiologia , Células Dendríticas/efeitos dos fármacos , Estimulantes Ganglionares/efeitos adversos , Humanos , Nicotina/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/patologia , Nicotiana/efeitos adversos
10.
Respir Res ; 7: 53, 2006 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-16571143

RESUMO

Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Several mechanisms are involved in the development of the disease: influx of inflammatory cells into the lung (leading to chronic inflammation of the airways), imbalance between proteolytic and anti-proteolytic activity (resulting in the destruction of healthy lung tissue) and oxidative stress. Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD. There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema. Data from animal models suggest a role for Vascular Endothelial Growth Factor (VEGF) in the induction of apoptosis of structural cells in the lung. Other mediators of apoptosis, such as caspase-3 and ceramide, could be interesting targets to prevent apoptosis and the development of emphysema. In this review, recent data on the role of apoptosis in COPD from both animal models as well as from studies on human subjects will be discussed. The aim is to provide an up to date summary on the increasing knowledge on the role of apoptosis in COPD and pulmonary emphysema.


Assuntos
Apoptose/fisiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Animais , Caspase 3 , Caspases/fisiologia , Proliferação de Células , Ceramidas/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Endotélio/enzimologia , Endotélio/patologia , Endotélio/fisiopatologia , Humanos , Pulmão/enzimologia , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estresse Oxidativo/fisiologia , Peptídeo Hidrolases/fisiologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/patologia , Mucosa Respiratória/enzimologia , Mucosa Respiratória/patologia , Mucosa Respiratória/fisiopatologia , Fumar/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/fisiologia
11.
Curr Opin Pharmacol ; 5(3): 257-63, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15907912

RESUMO

Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent, chronic inflammatory lung diseases that lead to significant morbidity and mortality. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes that play a critical role in normal development and physiological tissue remodeling and repair. In addition, they play an important role in the regulation of the kinetics and function of inflammatory cells. There is increasing evidence that MMPs are involved in the pathogenesis of both asthma and COPD, and several MMPs are possible therapeutic targets in these common chronic airway diseases.


Assuntos
Asma , Metaloproteinases da Matriz , Inibidores de Proteases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica , Inibidor Tecidual de Metaloproteinase-1/uso terapêutico , Asma/tratamento farmacológico , Asma/enzimologia , Asma/etiologia , Humanos , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/efeitos adversos , Metaloproteinases da Matriz/fisiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-27099485

RESUMO

BACKGROUND: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions. METHODS/DESIGN: Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge. DISCUSSION: We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Aguda , Progressão da Doença , Método Duplo-Cego , Hospitalização , Humanos , Projetos de Pesquisa
13.
Respir Res ; 6: 147, 2005 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-16359546

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease is associated with a chronic inflammatory response of the host to chronic exposure to inhaled toxic gases and particles. Although inflammatory cells of both the innate and adaptive immune system infiltrate the lungs in pulmonary emphysema and form lymphoid follicles around the small airways, the exact role of the acquired immune system in the pathogenesis of emphysema is not known. METHODS: In this study, wild type Balb/c mice and immunodeficient scid mice--which lack functional B- and T-cells--were exposed to mainstream cigarette smoke (CS) for 5 weeks or 6 months. RESULTS: Subacute CS-exposure for 5 weeks significantly increased innate inflammatory cells (neutrophils, macrophages and dendritic cells) in the bronchoalveolar lavage (BAL) fluid of wild type mice and scid mice, which correlated with the CS-induced upregulation of the chemokines Monocyte Chemotactic Protein-1, Macrophage Inflammatory Protein-3alpha and KC (= mouse Interleukin-8). Chronic CS-exposure for 6 months significantly increased the number of neutrophils, macrophages, dendritic cells, CD4+ and CD8+ T-lymphocytes in BAL fluid and lungs of wild type mice compared to air-exposed littermates, and augmented the size and number of peribronchial lymphoid follicles. In contrast, neither B-lymphocytes, nor T-lymphocytes, nor lymphoid follicles could be discerned in the lungs of air- or CS-exposed scid mice. Importantly, chronic CS-exposure induced pulmonary emphysema in both wild type animals and scid mice, as evidenced by a significant increase in the mean linear intercept and the destructive index of CS-exposed versus air-exposed animals. The CS-induced emphysema was associated with increased mRNA expression of matrix metalloproteinase-12 in the lungs and increased protein levels of Tumor Necrosis Factor-alpha in the BAL fluid of CS-exposed Balb/c and scid mice compared to air-exposed littermates. CONCLUSION: This study suggests that the adaptive immune system is not required per se to develop pulmonary emphysema in response to chronic CS-exposure, since emphysema can be induced in scid mice, which lack lymphoid follicles as well as functional B- and T-cells.


Assuntos
Enfisema/etiologia , Enfisema/imunologia , Imunidade Inata/imunologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Enfisema/patologia , Sistema Imunitário/imunologia , Masculino , Camundongos , Camundongos SCID
14.
Inflamm Allergy Drug Targets ; 6(2): 75-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17692030

RESUMO

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and disability in the world, with a prevalence that is expected to increase in the next decades. The disease is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke. The molecular and cellular mechanisms that lead to this exaggerated influx of cells belonging to both the innate and adaptive immune system are not yet completely unravelled. However, there is now growing evidence that the recruitment of these inflammatory cells in response to cigarette smoke is largely regulated by chemokines acting as ligands for chemokine receptors. Several of these receptors, which fall mainly in the CC- or CXC-category, have been implicated in the pathogenesis of COPD. In this review we will focus mainly on the CC-family, as the involvement of CXC-receptors in COPD has already been extensively reviewed. In patients with COPD, several CC-chemokines like MIP-1alpha, MIP-3alpha, RANTES and MCP-1 are upregulated, suggesting the contribution of their respective receptor in the pathogenesis of the disease. Using knock out mice, this contribution has been further confirmed for CCR5 and CCR6, evidenced by an attenuated accumulation of inflammatory cells like macrophages, dendritic cells, neutrophils and CD8(+) T-lymphocytes upon cigarette smoke-exposure. Moreover, mice deficient for CCR5 or CCR6 are partially protected from the development of pulmonary emphysema, another hallmark of COPD. These data suggest that chemokine receptors are potential therapeutic targets to reduce the chronic inflammation and parenchymal destruction in COPD.


Assuntos
Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptores de Quimiocinas/fisiologia , Animais , Antagonistas dos Receptores CCR5 , Humanos , Camundongos , Camundongos Knockout , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/imunologia , Receptores CCR5/genética , Receptores CCR5/fisiologia , Receptores CCR6 , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/genética
15.
Am J Respir Crit Care Med ; 175(10): 998-1005, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17332482

RESUMO

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. It is unclear if dendritic cells (DC) participate in this inflammatory process. OBJECTIVES: To evaluate the presence of DC in small airways of patients with COPD. METHODS: We evaluated DC infiltration in small airways by immunohistochemistry in patients with COPD (stage I-IV), never-smokers, and smokers without COPD. Chemokine ligand 20 (CCL20, the most potent chemokine in attracting DC) was determined in total lung by RT-PCR and in induced sputum by enzyme-linked immunsorbent assay. Chemokine receptor 6 (CCR6, the receptor for CCL20) expression on human pulmonary DC was evaluated by RT-PCR and flow cytometry. MEASUREMENTS AND MAIN RESULTS: There is a significant increase in DC number in the epithelium (p = 0.007) and adventitia (p = 0.009) of small airways of patients with COPD compared with never-smokers and smokers without COPD. DC number in epithelium and adventitia increases along with disease severity. CCL20 mRNA expression in total lung and CCL20 protein levels in induced sputum are significantly higher in patients with COPD compared with never-smokers (p = 0.034 for CCL20 mRNA and p = 0.0008 for CCL20 protein) and smokers without COPD (p = 0.016 for CCL20 mRNA and p = 0.001 for CCL20 protein). DC isolated from human lung express CCR6 both at mRNA and at protein level. CONCLUSIONS: This is the first description of airway infiltration by DC in COPD. Moreover, interaction between CCL20 and CCR6 provides a possible mechanism for accumulation of DC in the lungs in COPD.


Assuntos
Quimiocinas CC/metabolismo , Células Dendríticas/imunologia , Pulmão/imunologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Idoso , Quimiocina CCL20 , Quimiocinas CC/análise , Quimiocinas CC/genética , Feminino , Humanos , Pulmão/patologia , Proteínas Inflamatórias de Macrófagos/análise , Proteínas Inflamatórias de Macrófagos/genética , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores CCR6 , Receptores de Quimiocinas/análise , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Escarro/química , Escarro/imunologia
16.
Am J Respir Cell Mol Biol ; 35(3): 387-93, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16627825

RESUMO

Dendritic cells (DC) have a central role in the initiation of adequate immune responses. They recognize pathogens by means of Toll-like receptors (TLR) and link innate to adaptive immune responses by releasing proinflammatory cytokines and inducing T cell proliferation. We conducted this study to evaluate the expression and function of TLR on human lung DC subsets and to study their T cell stimulatory capacity. TLR gene expression by human pulmonary DC was evaluated by RT-PCR, while protein expression was analyzed by flow cytometry. We investigated cytokine release by DC in response to different TLR ligands. T cell stimulatory capacity was evaluated by mixed leukocyte reactions of purified lung DC with allogeneic T cells. Myeloid dendritic cells type 1 (mDC1) and myeloid dendritic cells type 2 (mDC2) express mRNA transcripts for TLR1, TLR2, TLR3, TLR4, TLR6, and TLR8. Flow cytometric analysis demonstrated high TLR2 protein expression for mDC1 and moderate TLR4 expression for mDC2. mDC1 and mDC2 release proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) in response to TLR2 and TLR4 ligands. TLR3 ligands induce cytokine release in mDC1, but not in mDC2. Plasmacytoid DC (pDC) express TLR7 and TLR9 and release proinflammatory cytokines in response to imiquimod and IFN-alpha in response to CpG oligonucleotides. mDC1 are strong inducers of T cell proliferation, while pDC hardly induce any T cell proliferation. mDC2 have an intermediate T cell-stimulatory capacity. Our results show divergent roles for the different human lung DC subsets, both in innate and adaptive immune responses.


Assuntos
Células Dendríticas/imunologia , Pulmão/imunologia , Linfócitos T/imunologia , Receptores Toll-Like/metabolismo , Técnicas de Cocultura , Citocinas/metabolismo , Humanos , Imunidade Inata/genética , Ativação Linfocitária , Transporte Proteico , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores Toll-Like/genética , Transcrição Gênica
17.
Int Arch Allergy Immunol ; 141(4): 354-68, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16940747

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. We investigated whether Toll-like receptor 4 (TLR4) is implicated in cigarette smoke (CS)-induced pulmonary inflammation in a murine model of COPD. METHODS: C3H/HeOuJ (Tlr4(WT)) and C3H/HeJ (Tlr4(defective)) mice were exposed to air or CS for 5 weeks (subacute) and 26 weeks (chronic), and pulmonary inflammation was evaluated. RESULTS: In Tlr4(WT) mice, subacute and chronic CS exposure induced a substantial pulmonary infiltration of macrophages, neutrophils, lymphocytes and dendritic cells (DCs), that was absent in air-exposed mice. CS exposure increased the costimulatory marker expression on DCs, the levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage (BAL) fluid and induced the pulmonary expression of matrix metalloproteinase-12 (MMP-12), TLR4 and TLR2. In contrast, after subacute CS exposure, Tlr4(defective) mice showed a limited (5-fold lower) increase of DCs and lymphocytes in BAL fluid, lower costimulatory marker expression on DCs and lower MCP-1 and TNF-alpha levels in BAL fluid compared to Tlr4(WT) animals. After chronic CS exposure, however, the difference in pulmonary inflammation between Tlr4(WT) and Tlr4(defective) mice was less pronounced and both strains showed similar MCP-1 and TNF-alpha levels in BAL and similar pulmonary MMP-12, TLR4 and TLR2 expression. CONCLUSIONS: We demonstrated that the TLR4 mutation in C3H/HeJ mice is protective against CS-induced pulmonary influx of neutrophils, DCs and lymphocytes upon subacute CS exposure. However, TLR4 is only of minor importance in chronic CS-induced inflammation in mice.


Assuntos
Inflamação/etiologia , Pulmão/patologia , Nicotiana/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumaça/efeitos adversos , Receptor 4 Toll-Like/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Antígeno CD11c/análise , Quimiocina CCL2/biossíntese , Células Dendríticas/fisiologia , Masculino , Metaloproteinase 12 da Matriz/biossíntese , Camundongos , Camundongos Endogâmicos C3H , Receptor 2 Toll-Like/biossíntese , Fator de Necrose Tumoral alfa/biossíntese
18.
J Immunol ; 177(7): 4350-9, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16982869

RESUMO

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3alpha/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8(+) T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3alpha/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3alpha contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.


Assuntos
Pulmão/imunologia , Pneumonia/imunologia , Enfisema Pulmonar/imunologia , Receptores de Quimiocinas/imunologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocina CCL20 , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Granulócitos/imunologia , Pulmão/patologia , Proteínas Inflamatórias de Macrófagos/imunologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Metaloproteinase 12 da Matriz , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Knockout , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/patologia , Receptores CCR6 , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fumar/efeitos adversos , Linfócitos T/imunologia , Fatores de Tempo
19.
Am J Respir Cell Mol Biol ; 32(3): 177-84, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15576669

RESUMO

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.


Assuntos
Células Dendríticas/fisiologia , Pulmão/citologia , Antígenos CD1/imunologia , Biomarcadores , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Humanos , Imuno-Histoquímica , Pulmão/imunologia , Pulmão/fisiologia , Macrófagos/fisiologia
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