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2.
BMC Pulm Med ; 20(1): 269, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066765

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.


Assuntos
Dióxido de Carbono/metabolismo , Infecções por Coronavirus/metabolismo , Eritrócitos/metabolismo , Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Betacoronavirus , Gasometria , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Feminino , Citometria de Fluxo , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pressão Parcial , Projetos Piloto , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Vasodilatação , Adulto Jovem
4.
Cells ; 9(9)2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847034

RESUMO

The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy-lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.


Assuntos
Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Progressão da Doença , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Infecções por Coronavirus/virologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Homeostase , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Lisossomos/metabolismo , Pandemias , Pneumonia Viral/virologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo
5.
Sci Adv ; 6(33): eabb7238, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32851183

RESUMO

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1, which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2. Concomitant partial loss of NF-κB/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.


Assuntos
Células Epiteliais/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Pulmão/metabolismo , Peptidil Dipeptidase A/metabolismo , Fenótipo , Proteínas Inibidoras de STAT Ativados/genética , Doença Pulmonar Obstrutiva Crônica/genética , Ubiquitina-Proteína Ligases/genética , Regulação para Cima/genética , Animais , Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Transdução de Sinais/genética , Fumar/efeitos adversos , Fator de Transcrição RelA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
6.
PLoS One ; 15(6): e0234363, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502184

RESUMO

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease, with oxidative stress and inflammation implicated in its development. Uric acid (UA) could exert anti-oxidative, pro-oxidative or pro-inflammatory effects, depending on the specific context. It was recently shown that soluble UA, and not just its crystals, could activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to interleukin (IL)-1ß secretion. We aimed to assess the differences in blood levels of UA and its ratio with creatinine (UCR) between COPD patients and healthy subjects, as well as their association with disease severity, smoking status, common COPD comorbidities and therapy regimes. The diagnostic characteristics of UA and UCR were also explored. This study included 109 stable COPD patients and 95 controls and measured white blood cells (WBC), C-reactive protein (CRP), fibrinogen (Fbg), IL-1ß, creatinine (CREAT) and UA. All of the parameters were increased in COPD patients, except for CREAT. UA and UCR were positively associated with WBC, CRP and IL-1ß. COPD smokers had lower UA and UCR values. Common COPD therapy did not affect UA or UCR, while patients with cardiovascular diseases (CVD) had higher UA, but not UCR, levels. Patients with higher UCR values showed worse disease-related outcomes (lung function, symptoms, quality of life, history of exacerbations, BODCAT and BODEx). Also, UCR differentiated patients with different severity of airflow limitation as well as symptoms and exacerbations. The great individual predictive potential of UCR and IL-1ß was observed with their odds ratios (OR) being 2.09 and 5.53, respectively. Multiparameter models of UA and UCR that included IL-1ß were able to correctly classify 86% and 90% of cases, respectively. We suggest that UA might be a useful biomarker when combined with IL-1ß, while UCR might be even more informative and useful in overall COPD assessments.


Assuntos
Creatinina/análise , Doença Pulmonar Obstrutiva Crônica/classificação , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ácido Úrico/análise , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Creatinina/sangue , Citocinas/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação , Interleucina-1beta/análise , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Contagem de Leucócitos/métodos , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Índice de Gravidade de Doença , Ácido Úrico/sangue
7.
Arch Biochem Biophys ; 689: 108439, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32504553

RESUMO

Chronic obstructive pulmonary disease (COPD) and lung cancer are a major cause of morbidity and mortality worldwide, with cigarette smoking being the single most important risk factor for both. Emerging evidence indicates alterations in reverse cholesterol transport-mediated removal of excess cholesterol from lung, and intracellular cholesterol overload to be involved in smoke-promoted COPD and lung cancer development. Since there are currently few effective treatments for COPD and lung cancer, it is important to identify food-derived, biologically active compounds, which can protect against COPD and lung cancer development. High intake of the carotenoid lycopene, as one of phytochemicals, is associated with a decreased risk of chronic lung lesions. This review article summarizes and discusses epidemiologic evidence, in vitro and in vivo studies regarding the prevention of smoke-promoted COPD and lung carcinogenesis through dietary lycopene as an effective intervention strategy. We focus on the recent research implying that lycopene preventive effect is through targeting the main genes involved in reverse cholesterol transport. This review also indicates gaps in knowledge about the function of lycopene against COPD and lung cancer, offering directions for further research.


Assuntos
Anticarcinógenos/uso terapêutico , Antioxidantes/uso terapêutico , Fumar Cigarros/efeitos adversos , Neoplasias Pulmonares/prevenção & controle , Licopeno/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Animais , Anticarcinógenos/metabolismo , Antioxidantes/metabolismo , Colesterol/metabolismo , Suplementos Nutricionais , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Licopeno/metabolismo , Lycopersicon esculentum/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia
8.
Am J Respir Crit Care Med ; 202(7): 983-995, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32515984

RESUMO

Rationale: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2α (hypoxia-inducible factor-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations. These findings suggest that decreased HIF-2α expression is important in the development of emphysema.Objectives: The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2α in the pathogenesis of emphysema in mice.Methods: Mouse lungs were examined for emphysema after either the loss or the overexpression of EC Hif-2α. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2α expression.Measurements and Main Results: EC Hif-2α deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC Hif-2α-knockout mice developed more severe emphysema, whereas EC Hif-2α-overexpressing mice were protected. EC Hif-2α-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2α expression.Conclusions: Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2α and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2α may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2α may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Endoteliais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/metabolismo , Enfisema Pulmonar/genética , Inibidores da Angiogênese/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Desferroxamina/farmacologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Indóis/toxicidade , Quelantes de Ferro/farmacologia , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microvasos , Pericitos/metabolismo , Circulação Pulmonar , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Pirróis/toxicidade , Fumaça/efeitos adversos
9.
Am J Med Sci ; 360(2): 166-175, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32536416

RESUMO

BACKGROUND: Fraction of exhaled nitric oxide (FeNO) is a noninvasive indicator of eosinophilic airway inflammation and has been used for the diagnosis and treatment of asthma. The levels of FeNO are controversial in patients with stable chronic obstructive pulmonary disease (COPD). Accordingly, this study aimed to assess FeNO levels in patients with stable COPD. MATERIALS AND METHODS: A search of the Medline, Embase, Web of Science, ClinicalTrials.gov and The Cochrane Library databases was performed in August 2019. The literature search was restricted to articles published in English. Studies were included if they reported data addressing FeNO levels in patients with stable COPD and healthy controls. Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis. RESULTS: A total of 19 studies were included. Analysis revealed that FeNO levels in patients with stable COPD were higher than those in the healthy control group (mean difference [MD] 2.49 [95% confidence interval {CI} 0.99-4.00]; P < 0.05), those in nonsmoking patients with stable COPD were higher than those in the healthy control group (MD 5.04 [95% CI 2.19-7.89]; P < 0.05) and those in smoking patients with stable COPD were not higher than those in the healthy control group (MD 0.30 [95% CI -2.81 to 3.41]; P = 0.85). FeNO measured using a chemiluminescence analyzer in nonsmoking patients with stable COPD was higher than those in the healthy control group (MD 4.84 [95% CI 1.83-7.86]; P < 0.05). CONCLUSIONS: Findings suggested that FeNO levels in patients with stable COPD were elevated, and that smokers exhibited decreased levels.


Assuntos
Eosinofilia/metabolismo , Óxido Nítrico/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Testes Respiratórios , Estudos de Casos e Controles , Humanos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doenças Respiratórias/metabolismo
10.
Respir Investig ; 58(5): 387-394, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32381453

RESUMO

BACKGROUND: The data on smoking cessation treatment outcomes for smokers with chronic obstructive pulmonary disease (COPD) are limited. The present study assessed the effectiveness of smoking cessation interventions at our clinic. METHODS: Data from a prospective registry of a 3-month smoking cessation program were evaluated. The primary outcome, smoking cessation, was defined as the complete abstinence from smoking between the 8-week and 12-week clinic visits. Pulmonary function and health-related quality of life using St. George's Respiratory Questionnaire (SGRQ) were assessed at baseline and at the end of the program. RESULTS: Out of the 155 COPD patients with nicotine dependence (female/male = 39/116; mean age, 67.2 ± 9.8 years; mean forced expiratory volume in 1 s (FEV1), 59.7 ± 21.1% predicted), 107 participants completed the program. Among the completers, 74 achieved smoking cessation. In the multivariate analysis, mental disorders (odds ratio [OR] 3.678, 95% confidence interval [CI]: 1.182, 11.445), higher exhaled carbon monoxide (CO) level (OR 1.080, 95% CI: 1.013, 1.151) and lower FEV1/forced vital capacity (FVC) (OR 0.958, 95% CI: 0.923, 0.995) were negatively associated with successful smoking termination. Significant changes in pulmonary function were found in quitters but not in continuous smokers (increases in FEV1 by 0.09 L/s [95% CI: 0.03, 0.15] and peak expiratory flow by 0.23 L/s [95% CI: 0.01, 0.44]). SGRQ total scores improved significantly in both quitters (-5.4 [95% CI: -8.4, -2.5]) and continuous smokers (-7.0 [95% CI: -11.6, -2.5]). CONCLUSION: In the program completers, the exhaled CO levels, FEV1/FVC ratio, and presence of mental disorders were significantly associated with program success or failure in COPD patients with nicotine dependence.


Assuntos
Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Abandono do Hábito de Fumar , Tabagismo/complicações , Tabagismo/terapia , Idoso , Monóxido de Carbono/metabolismo , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Qualidade de Vida , Inquéritos e Questionários , Tabagismo/metabolismo , Tabagismo/fisiopatologia , Capacidade Vital
11.
Clin Sci (Lond) ; 134(10): 1107-1125, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32400877

RESUMO

There is little information on mucins versus potential regulatory factors in the peripheral airway lumen of long-term smokers with (LTS+) and without (LTS-) chronic obstructive pulmonary disease (COPD). We explored these matters in bronchoalveolar lavage (BAL) samples from two study materials, both including LTS+ and LTS- with a very similar historic exposure to tobacco smoke, and healthy non-smokers (HNSs; n=4-20/group). Utilizing slot blot and immunodetection of processed (filtered and centrifuged), as well as unprocessed BAL samples from one of the materials, we compared the quantity and fraction of large complexes of mucins. All LTS displayed an enhanced (median) level of MUC5AC compared with HNS. LTS- displayed a higher level of large MUC5AC complexes than HNS while LTS+ displayed a similar trend. In all LTS, total MUC5AC correlated with blood leukocytes, BAL neutrophil elastase and net gelatinase activity. Large mucin complexes accounted for most MUC5B, without clear group differences. In all LTS, total MUC5B correlated with total MUC5AC and local bacteria. In the same groups, large MUC5B complexes correlated with serum cotinine. MUC1 was increased and correlated with BAL leukocytes in all LTS whereas MUC2 was very low and without clear group differences. Thus, the main part of MUC5AC and MUC5B is present as large complexes in the peripheral airway lumen and historic as well as current exposure to tobacco smoke emerge as potential regulatory factors, regardless of COPD per se. Bacteria, leukocytes and proteinases also constitute potential regulatory factors, of interest for future therapeutic strategies.


Assuntos
Pulmão/metabolismo , Mucina-5AC/metabolismo , Mucina-1/metabolismo , Complexos Multiproteicos/metabolismo , Fumantes , Fumar/metabolismo , Bactérias/crescimento & desenvolvimento , Lavagem Broncoalveolar , Difusão , Feminino , Gases/metabolismo , Humanos , Pulmão/microbiologia , Masculino , Viabilidade Microbiana , Mucina-2/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fatores de Tempo
13.
Ann Allergy Asthma Immunol ; 125(3): 294-303.e1, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32304877

RESUMO

BACKGROUND: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS). OBJECTIVE: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019. RESULTS: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS. CONCLUSION: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/metabolismo , Feminino , Humanos , Imunoglobulina E/metabolismo , Interleucina-5/metabolismo , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adulto Jovem
14.
Clin Sci (Lond) ; 134(7): 751-763, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32227160

RESUMO

The numbers of macrophages are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. COPD lung macrophages have reduced ability to phagocytose microbes and efferocytose apoptotic cells. Inhaled corticosteroids (ICSs) are widely used anti-inflammatory drugs in COPD; however, their role beyond suppression of cytokine release has not been explored in COPD macrophages. We have examined the effects of corticosteroids on COPD lung macrophage phenotype and function. Lung macrophages from controls and COPD patients were treated with corticosteroids; effects on gene and protein expression of CD163, CD164, CD206, MERTK, CD64, CD80 and CD86 were studied. We also examined the effect of corticosteroids on the function of CD163, MERTK and cluster of differentiation 64 (CD64). Corticosteroid increased CD163, CD164, CD206 and MERTK expression and reduced CD64, CD80 and CD86 expression. We also observed an increase in the uptake of the haemoglobin-haptoglobin complex (CD163) from 59 up to 81% and an increase in efferocytosis of apoptotic neutrophils (MERTK) from 15 up to 28% following corticosteroid treatment. We observed no effect on bacterial phagocytosis. Corticosteroids alter the phenotype and function of COPD lung macrophages. Our findings suggest mechanisms by which corticosteroids exert therapeutic benefit in COPD, reducing iron available for bacterial growth and enhancing efferocytosis.


Assuntos
Corticosteroides/farmacologia , Dexametasona/farmacologia , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Feminino , Regulação da Expressão Gênica , Humanos , Ferro/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Fenótipo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Transdução de Sinais , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
15.
PLoS One ; 15(4): e0231072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275684

RESUMO

A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.


Assuntos
Hipertrigliceridemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Índice de Massa Corporal , Colesterol/sangue , Feminino , Homeostase/genética , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Insulina/metabolismo , Resistência à Insulina/genética , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco
17.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L1056-L1062, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32233789

RESUMO

Air-liquid interface (ALI) cultures are ex vivo models that are used extensively to study the epithelium of patients with chronic respiratory diseases. However, the in vitro conditions impose a milieu different from that encountered in the patient in vivo, and the degree to which this alters gene expression remains unclear. In this study we employed RNA sequencing to compare the transcriptome of fresh brushings of nasal epithelial cells with that of ALI-cultured epithelial cells from the same patients. We observed a strong correlation between cells cultured at the ALI and cells obtained from the brushed nasal epithelia: 96% of expressed genes showed similar expression profiles, although there was greater similarity between the brushed samples. We observed that while the ALI model provides an excellent representation of the in vivo airway epithelial transcriptome for mechanistic studies, several pathways are affected by the change in milieu.


Assuntos
Mucosa Nasal/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Mucosa Respiratória/metabolismo , Transcriptoma , Idoso , Ar , Fumar Cigarros/efeitos adversos , Meios de Cultura/química , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Anotação de Sequência Molecular , Mucosa Nasal/patologia , Cultura Primária de Células , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia , Análise de Sequência de RNA , Conchas Nasais/metabolismo , Conchas Nasais/patologia
18.
Med Sci Monit ; 26: e920793, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32201430

RESUMO

BACKGROUND Chronic obstructive pulmonary disease (COPD), a general airway disease, is featured by progressive and chronic immunoreaction in the lung. Increasing evidences have showed that cigarette smoking is the main reason in the COPD progression, and human pulmonary microvascular endothelial cell (HPMEC) apoptosis often be observed in COPD, while its pathogenesis is not yet fully described. Upregulation of long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) was observed in COPD patients, but the specific mechanism of lncRNA MEG3 in COPD remains unknown. The objective of this research was to explore the role of lncRNA MEG3 in cigarette smoke extract (CSE)-induced HPMECs. MATERIAL AND METHODS HPMECs were induced by a series of concentrations of CSE (0%, 0.1%, 1%, and 10%). Then cell apoptosis was analyzed by flow cytometry. Cell apoptosis related proteins were tested using western blot assay. Finally, we applied knockdown and over-expression system to explore the lncRNA MEG3 functions in CSE-induced HPMECs. RESULTS Our results indicated that various concentrations of CSE (0%, 0.1%, 1%, and 10%) significantly promoted cell apoptosis, augmented caspase-3 activity, upregulated Bax expression, decreased Bcl-2 expression, and enhanced lncRNA MEG3 level in HPMECs. LncRNA MEG3-plasmid transfection resulted in the upregulation of lncRNA MEG3, more apoptotic HPMECs, and higher caspase-3 activity. While lncRNA MEG3 knockdown presented the opposite effects. Further investigation suggested that all the effects of CSE treatment on HPMECs were markedly reversed by lncRNA MEG3-shRNA (short hairpin RNA). CONCLUSIONS Our study illustrated a protective effect of lncRNA MEG3-shRNA on CSE-induced HPMECs, indicting lncRNA MEG3 can be a new therapeutic approach for COPD treatment.


Assuntos
Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Longo não Codificante , Transdução de Sinais/fisiologia , Tabaco/efeitos adversos , Apoptose/fisiologia , Células Cultivadas , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Fumaça/efeitos adversos
19.
Respir Res ; 21(1): 72, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197620

RESUMO

BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 µg and placebo twice daily (BID) in a randomised crossover study. RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 µg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.


Assuntos
Bronquite Crônica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Escarro/citologia , Administração por Inalação , Idoso , Anti-Inflamatórios/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Bronquite Crônica/metabolismo , Estudos Cross-Over , Feminino , Humanos , Mediadores da Inflamação , Masculino , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/metabolismo , Sulfonamidas , Transcriptoma , para-Aminobenzoatos
20.
Am J Respir Crit Care Med ; 202(3): 371-382, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186892

RESUMO

Rationale: Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions.Objectives: To determine whether vitamin D metabolism is altered in asthma or COPD.Methods: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D3, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.Measurements and Main Results: The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L; P = 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both presupplementation and postsupplementation (P ≤ 0.005). Intergroup differences in 1α,25(OH)2D3-inducible gene expression signatures were modest and variable if statistically significant.Conclusions: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.


Assuntos
Asma/metabolismo , Calcifediol/metabolismo , Calcitriol/metabolismo , Colecalciferol/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Vitaminas/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Estudos de Casos e Controles , Colecalciferol/farmacocinética , Colestanotriol 26-Mono-Oxigenase/genética , Citocromo P-450 CYP3A/genética , Família 2 do Citocromo P450/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteína de Ligação a Vitamina D/genética , Vitamina D3 24-Hidroxilase/genética , Vitaminas/farmacocinética
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