RESUMO
The role of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) in alveolar macrophages(AMs) polarization homeostasis is closely associated with airway remodeling in COPD, but the definite mechanism remains unclear. In this study, elevated percentage of M1-type AMs and the expression of functionally cytokines were found in COPD patients and mice, which closely related to the disease severity. PPARγ was markedly up-regulated in M2-type AMs and down-regulated in M1-type AMs, and was associated with disease severity in COPD. Co-cultured with M1- or M2-type AMs promoted the epithelial-mesenchymal transition (EMT) of airway epithelial cells and the proliferation of airway smooth muscle cells. Moreover, airway remodeling and functional damage were observed in both IL4R-/- COPD mice with runaway M1-type AMs polarization and TLR4-/- COPD mice with runaway M2-type AMs polarization. Cigarette extract (CS) or lipopolysaccharide (LPS) stimulated PPARγ-/- AMs showed more serious polarization disorder towards M1, as well as CS induced PPARγ-/- COPD mice, which led to more severe airway inflammation, lung function damage, and airway remodeling. Treatment with PPARγ agonist significantly improved the polarization disorder and function activity in CS/LPS stimulated-AMs by inhibiting the JAK-STAT, MAPK and NF-κB pathways, and alleviated the airway inflammation, restored the lung function and suppressed airway remodeling in CS induced-COPD mice. Our research demonstrates that polarization homeostasis of AMs mediated by PPARγ has the protective effect in airway remodeling, and may be a novel therapeutic target for the intervention and treatment of airway remodeling in COPD.
Assuntos
Macrófagos Alveolares , Doença Pulmonar Obstrutiva Crônica , Camundongos , Animais , Macrófagos Alveolares/metabolismo , PPAR gama/metabolismo , Remodelação das Vias Aéreas , Lipopolissacarídeos/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , HomeostaseRESUMO
Rationale: The etiology of acute respiratory distress syndrome (ARDS) may play an important role in the failure of noninvasive ventilation (NIV). Objectives: To explore the association between ARDS etiology and risk of NIV failure. Methods: A multicenter prospective observational study was performed in 17 intensive care units in China from September 2017 to December 2019. Patients with ARDS who used NIV as a first-line therapy were enrolled. The etiology of ARDS was recorded at study entry. Results: A total of 306 patients were enrolled. Of the patients, 146 were classified as having pulmonary ARDS (ARDSp) and 160 were classified as having extrapulmonary ARDS (ARDSexp). From initiation to 24 hours of NIV, the respiratory rate, heart rate, arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2), and arterial carbon dioxide pressure improved slower in patients with ARDSp than those with ARDSexp. Patients with ARDSp experienced more NIV failure (55% vs. 28%; P < 0.01) and higher 28-day mortality (47% vs. 14%; P < 0.01). The adjusted odds ratios of NIV failure and 28-day mortality were 5.47 (95% confidence interval [CI], 3.04-9.86) and 10.13 (95% CI, 5.01-20.46), respectively. In addition, we combined the presence of ARDSp, presence of septic shock, age, nonpulmonary sequential organ failure assessment score, respiratory rate at 1-2 hours of NIV, and PaO2/FiO2 at 1-2 h of NIV to develop a risk score of NIV failure. With the increase of the risk score, the rate of NIV failure increased. The area under the curve of the receiver operating characteristic was 0.84 (95% CI, 0.79-0.89) and 0.81 (0.69-0.92) in the training and validation cohorts, respectively. Using 5.5 as cutoff value to predict NIV failure, the sensitivity and specificity was good. Conclusions: Among patients with ARDS who used NIV as a first-line therapy, ARDSp was associated with slower improvement, more NIV failure, and higher 28-day mortality than ARDSexp. The risk score combined presence of ARDSp, presence of septic shock, age, nonpulmonary sequential organ failure assessment score, respiratory rate at 1-2 hours of NIV, and PaO2/FiO2 at 1-2 hours of NIV has high accuracy to predict NIV failure among ARDS population.
Assuntos
Ventilação não Invasiva , Síndrome do Desconforto Respiratório , Humanos , Unidades de Terapia Intensiva , Escores de Disfunção Orgânica , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapiaRESUMO
BACKGROUND AND OBJECTIVES: Fractional exhaled nitric oxide (FeNO) has been developed as a useful marker for eosinophilic airway inflammation and is widely used in clinical practice due to its convenience and noninvasiveness. There are two NO analyzers commonly used in China: the Sunvou-CA2122 Analyzer (NOS) and the NIOX VERO Analyzer (NOV). However, the relationships between the two devices have not yet been reported. The aim of our study was to determine the correlation and differences in the FeNO levels measured by the two devices. METHODS: FeNO levels were measured by both NOS and NOV in 107 adult patients with asthma. The asthma control test (ACT) score and lung function were also evaluated. This study was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn). RESULTS: NOS yielded generally higher FeNO values than NOV [median (range): 87.0 (16 â¼ 276) vs 58.0 (9 â¼ 228); p < .001], and the difference increased with increasing FeNO levels. There was a high degree of correlation between FeNO values obtained with both devices (rs = 0.878, p < .001). However, the Bland-Altman plot showed a low degree of agreement, with a mean difference of -0.16 between logFeNONOS and logFeNONOV (95% CI: -0.45 â¼ 0.14). The conversion equation was calculated as follows: logFeNONOS= 0.027 + 0.904× logFeNONOV. CONCLUSION: This was the first report to compare FeNO levels measured by NOS and NOV, showing a strongly positive correlation and a low degree of consistency between the two devices. Further prospective studies are required to verify our conclusions and determine the validity of the equation.
Assuntos
Testes Respiratórios/instrumentação , Óxido Nítrico/análise , Adulto , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVES: Airway macrophages represents a central site for the mechanisms involved in the complex interactions between environmental triggers and airway inflammation. Based on anti-inflammatory activity of adiponectin, we hypothesize that adiponectin inhibits the proinflammatory cytokines production and the activation of alveolar macrophages expose to cigarette smoke. MATERIALS AND METHODS: To examine the effects of adiponectin on alveolar macrophages, we used the cigarette smoke-induced the alveolar inflammation model in C57BL/6 mice and the macrophages activation model in vitro, both in the presence or absence of adiponectin, to assess the accumulation of inflammatory cells and the concentration of inflammatory cytokines and chemokines in the bronchoalveolar lavage (BAL), and the proinflammatory cytokines production and M1/2 phenotype in alveolar macrophages. RESULTS: Our results showed that adiponectin improves cigarette smoke-induced airway inflammation in vivo and decreases proinflammatory cytokine production and alveolar macrophages polarization in vitro. Moreover, our study further demonstrates that anti-inflammatory activity of adiponectin depends on the suppression of the proinflammatory cytokine production through TLR2/4 signaling and the inhibition of macrophage polarization vit COX-2/PGE2 signaling. CONCLUSIONS: Our study suggests that the anti-inflammatory activity of adiponectin might contribute to its therapeutic potential in airway inflammation, such as COPD.
Assuntos
Adiponectina/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Inflamação/tratamento farmacológico , Macrófagos Alveolares/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça , NicotianaAssuntos
Hemoptise/complicações , Síndrome de Kartagener/complicações , Síndrome de Kartagener/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Sinusite/tratamento farmacológico , Bronquiectasia/diagnóstico por imagem , Proteína C-Reativa/análise , Tosse/complicações , Feminino , Humanos , Imageamento Tridimensional , Klebsiella , Neutrófilos/citologia , Atelectasia Pulmonar/diagnóstico por imagem , Radiografia Torácica , Sinusite/complicações , Sinusite/diagnóstico por imagem , Situs Inversus/diagnóstico por imagem , Escarro , Tomografia Computadorizada por Raios X , Adulto JovemAssuntos
Empiema/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Abscesso Pulmonar/microbiologia , Micrococcaceae/isolamento & purificação , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Idoso , Antibacterianos/uso terapêutico , Empiema/tratamento farmacológico , Empiema/patologia , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Imunocompetência , Abscesso Pulmonar/tratamento farmacológico , Abscesso Pulmonar/patologia , Masculino , Pneumonia Bacteriana/tratamento farmacológicoAssuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Células Th2/metabolismo , Asma/sangue , Asma/diagnóstico , Asma/imunologia , Biomarcadores/análise , Biomarcadores/metabolismo , Quimiocina CCL17/análise , Quimiocina CCL17/metabolismo , Quimiocina CCL26/análise , Quimiocina CCL26/metabolismo , Eosinófilos/imunologia , Expiração , Humanos , Contagem de Leucócitos , Óxido Nítrico/análise , Células Th2/imunologia , Resultado do TratamentoRESUMO
AIM: Effects of azithromycin on asthma reported in clinical trials are less consistent. We aimed to further clarify the efficacy and safety of azithromycin in treatment of asthma. METHODS: The protocol registration number was CRD42017074318 (http://www.crd.york.ac.uk/Prospero). We searched PubMed, EMBASE, Cochrane databases, China National Knowledge Internet (CNKI), and Wanfang databases for the randomized controlled trials (RCTs) with prolonged treatment of azithromycin for more than 3 weeks. Random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference (MD) for dichotomous and continuous data respectively. RESULTS: A total of eight studies were included for analysis. The pooled result of adjunctive azithromycin therapy in asthma showed a small, but statistically significant increase in forced expiratory volume in one second (FEV1) (MDâ=â0.06, 95% confidence interval [CI]: 0.01-0.12, Pâ=â.02), but no significant differences in exacerbation frequency (MDâ=â-0.42, 95%CI: -1.13 to 0.30, Pâ=â.25) and peak expiratory flow (PEF) (MDâ=â0.20, 95% CI: -0.05 to 0.44, Pâ=â.12), fractional exhaled nitric oxide (FeNO) (MDâ=â4.12, 95% CI: -2.06 to 10.30, Pâ=â.19), asthma quality of life questionnaire (AQLQ) (MD: 0.05, 95% CI: -0.17 to 0.28, Pâ=â.65), asthma control questionnaire (ACQ) (MD: -0.03, 95% CI: -0.21 to 0.15, Pâ=â.75). The subgroup analysis revealed that azithromycin could decrease FeNO among Asian asthma (MDâ=â15.04, 95% CI: 6.18-23.90, Pâ=â.0009). CONCLUSIONS: Add-on therapy of azithromycin in asthma patients could improve the FEV1, but failed to improve asthma exacerbations, PEF, ACQ, AQLQ, and FeNO. Subgroup analysis indicated that azithromycin could improve FeNO in Asian group asthmatics.
Assuntos
Antibacterianos/uso terapêutico , Asma/tratamento farmacológico , Azitromicina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are novel agents for asthma but with controversial efficacies in clinical trials. Therefore, we conducted a meta-analysis to determine the roles of CRTH2 antagonists in asthma. METHODS: We searched in major databases for RCTs comparing CRTH2 antagonists with placebo in asthma. Fixed- or random-effects model was performed to calculate mean differences (MD), risk ratio (RR) or risk difference (RD) and 95% confidence interval (CI). RESULTS: A total of 14 trails with 4671 participants were included in our final analysis. Instead of add-on treatment of CRTH2 antagonists to corticosteroids, CRTH2 antagonist monotherapy significantly improved pre-bronchodilator FEV1 (MD = 0.09, 95% CI 0.04 to 0.15, P = 0.0005), FEV1% predicted (MD = 3.65, 95% CI 1.15 to 6.14, P = 0.004), and AQLQ (MD = 0.25, 95% CI 0.09 to 0.41, P = 0.002), and reduced asthma exacerbations (RR = 0.45, 95% CI 0.23 to 0.85, P = 0.01). Rescue use of SABA was significantly decreased in both CRTH2 antagonist monotherapy (MD = - 0.04, 95% CI -0.05 to - 0.03, P < 0.00001) and as add-on to corticosteroids (MD = - 0.78, 95% CI -1.47 to - 0.09, P = 0.03). Adverse events were similar between the intervention and placebo groups. CONCLUSIONS: CRTH2 antagonist monotherapy can safely improve lung function and quality of life, and reduce asthma exacerbations and SABA use in asthmatics.
Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Asma/metabolismo , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/biossíntese , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/biossíntese , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , Resultado do TratamentoRESUMO
Activation of alveolar macrophages (AMs) and the release of cytokines play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the mechanisms of AM activation. miRNAs have recently emerged as key regulators of inflammation and as mediators of macrophage activation and polarization. We identified potential miRNAs related to AM activation using miRNA microarray analysis, which showed that miR-27-3p expression was up-regulated in AMs and the lung tissues of mice exposed to cigarette smoke (CS)/lipopolysaccharide (LPS), and found that miR-27-3p regulated proinflammatory cytokine production and AM polarization depending on TLR2/4 intracellular signaling in AMs. We also found that miR-27-3p controlled TLR2/4 signaling in AMs via targetting the 3'-UTR sequences of peroxisome proliferator-activated receptor γ (PPARγ) and inhibiting PPARγ activation. Moreover, we found that PPARγ activation not only inhibited CS/LPS-induced TLR2/4 expression and miR-27-3p-mediated TLR2/4 signaling cascades involving the nuclear factor-κB (NF-κB), c-Jun NH2-terminal kinase (JNK)/p38, and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways in AMs but also ameliorated CS/LPS-induced AM activation and pulmonary inflammation. Our study revealed that miR-27-3p mediated AM activation by the inhibition of PPARγ activation and sensitization of TLR signaling.
Assuntos
Ativação de Macrófagos , Macrófagos Alveolares/metabolismo , MicroRNAs/metabolismo , PPAR gama/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Animais , Fumar Cigarros/efeitos adversos , Citocinas/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases (1946-2016) using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included. Random or fixed-effects models were used to calculate odds ratios (OR) and mean differences between the two treatment groups. Statistical analyses were conducted using Mann-Whitney U-tests and Cochrane systematic review software, Review Manager. Seventeen studies were included in the systematic review, of which 14 studies were included in the meta-analysis. Except for significant statistical heterogeneity in pre- and post-challenge predicted percentage of forced expiratory volume in 1 s (FEV1 %; I2 = 72%, χ2 = 3.35, P = 0.06), there was no heterogeneity in outcome measures. Roflumilast (500 µg) significantly improved FEV1 (mean difference: 0.05, 95% CI: 0.01-0.09, Z = 2.50, P = 0.01), peak expiratory flow, asthma control and exacerbations, but showed variable effects on airway responsiveness to methacholine and a 20% fall in FEV1 .Of note, PDE4 inhibitors were accompanied with significantly higher adverse events such as headache (OR: 3.99, 95% CI: 1.65-9.66, Z = 3.07, P = 0.002) and nausea (OR: 5.53, 95% CI: 1.38-22.17, Z = 2.41, P = 0.02). In patients with mild asthma, oral PDE4 inhibitors can be considered as an alternative treatment to regular bronchodilators and inhaled controllers.