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1.
Artigo em Inglês | MEDLINE | ID: mdl-33642858

RESUMO

Pulmonary rehabilitation (PR) is effective in reducing symptoms and improving health status, and exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). The coronavirus disease 19 (COVID-19) pandemic has greatly impacted PR programs and their delivery to patients. Owing to fears of viral transmission and resultant outbreaks of COVID-19, institution-based PR programs have been forced to significantly reduce enrolment or in some cases completely shut down during the pandemic. As a majority of COPD patients are elderly and have multiple co-morbidities including cardiovascular disease and diabetes, they are notably susceptible to severe complications of COVID-19. As such, patients have been advised to stay at home and avoid social contact to the maximum extent possible. This has increased patients' vulnerability to physical deconditioning, depression, and social isolation. To address this major gap in care, some traditional hospital or clinic-centered PR programs have converted some or all of their learning contents to home-based telerehabilitation during the pandemic. There are, however, some significant barriers to this approach that have impeded its implementation in the community. These include variable access and use of technology (by patients), a lack of standardization of methods and tools for evaluation of the program, and inadequate training and resources for health professionals in optimally delivering telerehabilitation to patients. There is a pressing need for high-quality studies on these modalities of PR to enable the successful implementation of PR at home and via teleconferencing technologies. Here, we highlight the importance of telerehabilitation of patients with COPD in the post-COVID world and discuss various strategies for clinical implementation.

2.
Respir Res ; 22(1): 75, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653328

RESUMO

BACKGROUND: Asthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor α (IL-4Rα), a critical mediator of Th2 signalling, improved their outcomes. METHODS: Male BALB/c mice were intranasally sensitized with house dust mite antigen (Der p 1) for 2 weeks; the mice were then inoculated intranasally with a single dose of pandemic H1N1 (pH1N1). The mice were administered intraperitoneally anti-IL-4Rα through either a prophylactic or a therapeutic treatment strategy. RESULTS: Infection with pH1N1 of mice sensitized to house dust mite (HDM) led to a 24% loss in weight by day 7 of infection (versus 14% in non-sensitized mice; p < .05). This was accompanied by increased viral load in the airways and a dampened anti-viral host responses to the infection. Treatment of HDM sensitized mice with a monoclonal antibody against IL-4Rα prior to or following pH1N1 infection prevented the excess weight loss, reduced the viral load in the lungs and ameliorated airway eosinophilia and systemic inflammation related to the pH1N1 infection. CONCLUSION: Together, these data implicate allergic asthma as a significant risk factor for H1N1-related morbidity and reveal a potential therapeutic role for IL-4Rα signalling blockade in reducing the severity of influenza infection in those with allergic airway disease.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33603357

RESUMO

Purpose: To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors. Patients and Methods: In this cross-sectional, population-based study, random samples of non-institutionalized adults aged ≥40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV1/FVC <0.70 (fixed ratio, FR) and as FEV1/FVC <5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I2 and Tau2 analyses were used to evaluate heterogeneity. Results: Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0-57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5-17.8) by FR and 11.2% (95% CI, 9.7-12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33-1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42-4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17-2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55-4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau2 analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease. Conclusion: This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.

4.
Hum Genet ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33604698

RESUMO

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (PGWAS < 5 × 10-05). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (PGWAS < 5 × 10-08). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.

5.
Respir Res ; 22(1): 59, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602241

RESUMO

BACKGROUND: Low body weight is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, it is not known whether gender modifies this relationship. METHODS: We pooled data of 8686 COPD patients from 7 studies with a median length of 36-months of follow up. Using a longitudinal natural cubic spline regression model, we examined the dose-response relationship between body mass index (BMI) and the rate of decline in forced expiratory volume in one second (FEV1) in patients with GOLD 1 and 2 disease, stratified by gender and adjusted for age, smoking status, and cohort effects. RESULTS: There was an inverse linear relationship between BMI and the rate of FEV1 decline in GOLD Grades 1 and 2, which was modified by gender (p < 0.001). In male patients, an increase of BMI by 1 kg/m2 reduced FEV1 decline by 1.05 mL/year (95% CI 0.96, 1.14). However, in female patients, BMI status did not have a clinically meaningful impact on FEV1 decline: an increase of baseline BMI by 1 kg/m2 reduced FEV1 decline by 0.16 ml/year (95% CI 0.11, 0.21). These gender-modified relationships were similar between GOLD 1 and 2 patients, and between current and former smokers. CONCLUSION: In mild to moderate COPD, higher BMI was associated with a less rapid decline of FEV1 in male patients whereas this association was minimal in females patients. This gender-specific BMI effect was independent of COPD severity and smoking status.

6.
FASEB J ; 35(3): e21376, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33605487

RESUMO

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

7.
Sci Rep ; 11(1): 4333, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619289

RESUMO

Chronic obstructive pulmonary disease (COPD) is a disorder of accelerated lung aging. Multiple pieces of evidence support that the aging biomarker short telomeres, which can be caused by mutations in telomerase reverse transcriptase (TERT), contribute to COPD pathogenesis. We hypothesized that short telomere risk-associated single nucleotide polymorphisms (SNPs) in TERT, while not able to drive COPD development, nonetheless modify the disease presentation. We set out to test the SNP carrying status in a longitudinal study of smokers with COPD and found that rapid decline of FEV1 in lung function was associated with the minor allele of rs61748181 (adjusted odds ratio 2.49, p = 0.038). Biochemical evaluation of ex vivo engineered human cell models revealed that primary cells expressing the minor allele of rs61748181 had suboptimal telomere length maintenance due to reduced telomerase catalytic activity, despite having comparable cell growth kinetics as WT-TERT expressing cells. This ex vivo observation translated clinically in that shorter telomeres were found in minor allele carriers in a sub-population of COPD patients with non-declining lung function, over the 5-year period of the longitudinal study. Collectively, our data suggest that functional TERT SNPs with mild catalytic defects are nonetheless implicated in the clinical presentation of COPD.

8.
Respir Res ; 22(1): 65, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622325

RESUMO

BACKGROUND: Airway inflammation is a key feature of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroids (ICS) remain the main treatment for airway inflammation. Studies have noted the increased efficacy of ICS and long-acting beta 2 agonist (LABA) combination therapy in controlling exacerbations and improving airway inflammation than either monotherapy. Further studies have suggested that LABAs may have inherent anti-inflammatory potential, but this has not been well-studied. OBJECTIVE: We hypothesize that the LABA olodaterol can inhibit airway inflammation resulting from exposure to respiratory syncytial virus (RSV) via its binding receptor, the ß2-adrenergic receptor. METHODS: Human bronchial epithelial brushing from patients with and without COPD were cultured into air-liquid interface (ALI) cultures and treated with or without olodaterol and RSV infection to examine the effect on markers of inflammation including interleukin-8 (IL-8) and mucus secretion. The cell line NCI-H292 was utilized for gene silencing of the ß2-adrenergic receptor via siRNA as well as receptor blocking via ICI 118,551 and butaxamine. RESULTS: At baseline, COPD-ALIs produced greater amounts of IL-8 than control ALIs. Olodaterol reduced RSV-mediated IL-8 secretion in both COPD and control ALIs and also significantly reduced Muc5AC staining in COPD-ALIs infected with RSV. A non-significant reduction was seen in control ALIs. Gene silencing of the ß2-adrenergic receptor in NCI-H292 negated the ability of olodaterol to inhibit IL-8 secretion from both RSV infection and lipopolysaccharide stimulus, as did blocking of the receptor with ICI 118,551 and butaxamine. CONCLUSIONS: Olodaterol exhibits inherent anti-inflammatory properties on the airway epithelium, in addition to its bronchodilation properties, that is mediated through the ß2-adrenergic receptor and independent of ICS usage.

9.
Curr Opin Pulm Med ; 27(2): 125-131, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33332878

RESUMO

PURPOSE OF REVIEW: Several observational studies have suggested that ß-blockers, especially cardioselective ones, are well tolerated and associated with a lower risk of acute exacerbations and death in patients with chronic obstructive pulmonary disease (COPD). However, there are dissenting studies. This review provides an update on the use of ß-blockers in COPD, focusing on results of recent prospective studies and randomized controlled trials. RECENT FINDINGS: In totality, cohort studies indicate that ß-blockers are generally well tolerated and effective in COPD patients who also have a clear cardiovascular indication for these medications. Although ß-blockers on average reduce lung function acutely in COPD patients, the absolute decrease is relatively small, especially if cardioselective ß-blockers are used. The results of two large randomized controlled trials suggest that ß-blocker use does not reduce the therapeutic benefits of inhaled bronchodilators in COPD patients. The use of ß-blockers in COPD patients, who do not have overt cardiovascular disease, does not prevent COPD exacerbations and may paradoxically increase the risk of COPD-related hospitalization and mortality. SUMMARY: The use of ß-blockers is generally well tolerated and effective in COPD patients, who also have a clear cardiovascular indication for these drugs. However, they should not be used in patients who do not have overt cardiovascular disease as ß-blockers can reduce lung function, worsen health status and increase the risk of COPD-related hospitalization.

10.
ERJ Open Res ; 6(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33263033

RESUMO

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A-4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66-0.68) for GOLD 2015 and 0.65 (95% CI 0.63-0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.

11.
Eur Respir J ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303555

RESUMO

INTRODUCTION: The aim of this study was to examine the association between blood eosinophil (EOS) levels and the decline in lung function in individuals over the age of 40 from the general population. METHODS: The study evaluated the EOS counts from thawed blood in 1120 participants (mean age 65 years) from the prospective population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. Participants answered interviewer-administered respiratory questionnaires and performed pre-/post-bronchodilator spirometric tests at 18-month intervals; computed tomography (CT) imaging was performed at baseline. Statistical analyses to describe the relationship between EOS levels and decline in forced expiratory volume in 1 s (FEV1) were performed using random mixed effects regression models with adjustments for demographics, smoking, baseline FEV1, ever-asthma and history of exacerbations in the previous 12 months. CT measurements were compared between EOS subgroups using an analysis of variance. RESULTS: Participants who had a peripheral EOS count of ≥300 cells·µL-1 (n=273) had a greater decline in FEV1 compared with those with EOS counts of <150 cells·µL-1 (n=430) [p=0.003] (reference group) and 150 to <300 cells·µL-1 (n=417) [p=0.003]. The absolute change in FEV1 was -32.99 mL·year-1 for participants with EOS counts <150 cells·µL-1; -38.78 mL·year-1 for those with 150 to <300 cells·µL-1; and -67.30 mL·year-1 for participants with ≥300 cells·µL-1. In COPD, higher EOS count was associated with quantitative CT measurements reflecting both small and large airway abnormalities. CONCLUSION: A blood EOS count of ≥300 cells·µL-1 is an independent risk factor for accelerated lung function decline in older adults and is related to undetected structural airway abnormalities.

12.
Lancet Digit Health ; 2(5): e259-e267, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-33328058

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the community. Thoracic CT scans are widely used for diagnostic and screening purposes for lung cancer. In this proof-of-concept study, we aimed to evaluate a software pipeline for the automated detection of COPD, based on deep learning and a dataset of low-dose CTs that were performed for early detection of lung cancer. METHODS: We examined the use of deep residual networks, a type of artificial residual network, for the automated detection of COPD. Three versions of the residual networks were independently trained to perform COPD diagnosis using random subsets of CT scans collected from the PanCan study, which enrolled ex-smokers and current smokers at high risk of lung cancer, and evaluated the networks using three-fold cross-validation experiments. External validation was performed using 2153 CT scans acquired from a separate cohort of individuals with COPD in the ECLIPSE study. Spirometric data were used to define COPD, with stages defined according to the GOLD criteria. FINDINGS: The best performing networks achieved an area under the receiver operating characteristic curve (AUC) of 0·889 (SD 0·017) in three-fold cross-validation experiments. When the same set of networks was applied to the ECLIPSE cohort without any modifications to the trained models, they achieved an AUC of 0·886 (0·017), a positive predictive value of 0·847 (0·056), and a negative predictive value of 0·755 (0·097), which is a greater performance than the best quantitative CT measure, the percentage of lung volumes of less than or equal to -950 Hounsfield units (AUC 0·742). INTERPRETATION: Our proposed approach could identify patients with COPD among ex-smokers and current smokers without a previous diagnosis of COPD, with clinically acceptable performance. The use of deep residual networks on chest CT scans could be an effective case-finding tool for COPD detection and diagnosis, particularly in ex-smokers and current smokers who are being screened for lung cancer. FUNDING: Data Science Institute, University of British Columbia; Canadian Institutes of Health Research.


Assuntos
Inteligência Artificial , Processamento de Imagem Assistida por Computador/métodos , Pulmão/patologia , Programas de Rastreamento/métodos , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fumar/efeitos adversos , Idoso , Área Sob a Curva , Canadá , Estudos de Coortes , Análise de Dados , Progressão da Doença , Ex-Fumantes , Feminino , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Curva ROC , Medição de Risco , Fumantes , Tomografia Computadorizada por Raios X/métodos
13.
Sci Rep ; 10(1): 21863, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318519

RESUMO

Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.


Assuntos
/metabolismo , Pulmão/metabolismo , Transcriptoma , Adulto , Idoso , Estudos de Coortes , Bases de Dados de Compostos Químicos , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Serina Endopeptidases/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-33135094

RESUMO

OBJECTIVES: The value of early detection and treatment of chronic obstructive pulmonary disease (COPD) is currently unknown. We assessed the cost effectiveness of primary care-based case detection strategies for COPD. METHODS: A previously validated discrete event simulation model of the general population of COPD patients in Canada was used to assess the cost effectiveness of 16 case detection strategies. In these strategies, eligible patients (based on age, smoking history, or symptoms) received the COPD Diagnostic Questionnaire (CDQ) or screening spirometry, at 3- or 5-year intervals, during routine visits to a primary care physician. Newly diagnosed patients received treatment for smoking cessation and guideline-based inhaler pharmacotherapy. Analyses were conducted over a 20-year time horizon from the healthcare payer perspective. Costs are in 2019 Canadian dollars ($). Key treatment parameters were varied in one-way sensitivity analysis. RESULTS: Compared to no case detection, all 16 case detection scenarios had an incremental cost-effectiveness ratio (ICER) below $50,000/QALY gained. In the most efficient scenario, all patients aged ≥ 40 years received the CDQ at 3-year intervals. This scenario was associated with an incremental cost of $287 and incremental effectiveness of 0.015 QALYs per eligible patient over the 20-year time horizon, resulting in an ICER of $19,632/QALY compared to no case detection. Results were most sensitive to the impact of treatment on the symptoms of newly diagnosed patients. CONCLUSIONS: Primary care-based case detection programs for COPD are likely to be cost effective if there is adherence to best-practice recommendations for treatment, which can alleviate symptoms in newly diagnosed patients.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33076634

RESUMO

Background: Lung inflammation plays a vital role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the characteristics of the inflammatory process remains unclear. There is growing interest in the role of granzyme B (GzmB) because CD8+ T cells can induce apoptosis of target cells by releasing GzmB, which in turn may cause tissue injury and remodeling. However, GzmB is also expressed by regulatory cells, which are able to suppress CD8+ T cell. The role of GzmB+ cells needs to be defined in COPD. Methods: GzmB+ and CD8+ cells on alveolar wall of surgically resected lungs of microscopically classified 12 non-smoking control, 12 panlobular (PLE) and 30 centrilobular emphysema (CLE) subjects were localized by immunohistochemical method. Positively stained cells on alveolar wall were counted and length of corresponding alveolar wall was measured. The results were expressed as mean number of positively stained cells per mm of alveolar wall in each subject. Results: The number of GzmB+ and CD8+ cells on alveolar wall of CLE was greater than that of control or PLE subjects (p<0.05, p<0.001, respectively). There was a positive relationship between the number of alveolar GzmB+ cells and FEV1 (r=0.610, p=0.003) in CLE subjects. The number of alveolar GzmB+ cells progressively decreased with decline of FEV1. Conclusion: Our finding that number of alveolar GzmB+ cells was associated with FEV1 suggests that GzmB+ cells might have protective role in the progression of lung destruction and airflow limitation in CLE, which is the predominant emphysema subtype of COPD.

16.
Oncol Lett ; 20(6): 322, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33123238

RESUMO

Surfactant protein D (SP-D) is a member of the collectin family of proteins, which is secreted by airway epithelial cells. SP-D serves an important role in the immune system and in the inflammatory regulation of the lung. SP-D was recently found to suppress lung cancer progression by downregulating epidermal growth factor signaling. However, the relationship between SP-D and pulmonary metastases from colon cancer remains unknown. The present study aimed to determine whether SP-D may suppress the development of the mouse rectal carcinoma cell line, CMT93, in vitro. The present study investigated the effect of SP-D on pulmonary metastases from colon cancer in vivo using SP-D knockout mice. A wound healing assay and cell invasion assay revealed that SP-D suppressed the proliferation, migration and invasion of CMT-93 cells. After injection of CMT-93 cells into the tail vein, SP-D knockout mice were significantly more susceptible to developing pulmonary metastases than C57/BL6 mice (control). Moreover, a novel cell line (CMT-93 pulmonary metastasis; CMT-93 PM) was established from the lesions of pulmonary metastases in C57/BL6 mice following injection of CMT93 into the tail vein. CMT-93 PM exhibited more robust invasion and proliferation compared to CMT93, which was unaffected by exposure to SP-D. A higher incidence of pulmonary metastases was detected following injection of CMT93 PM into the tail vein of C57/BL6 mice compared with CMT-93. Consequently, SP-D may be involved in the pathogenesis of pulmonary metastases from colon cancer.

17.
Biomedicines ; 8(10)2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33050042

RESUMO

Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages' phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I-III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.

18.
EClinicalMedicine ; 26: 100546, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32984790
19.
J Infect Dis ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32959881

RESUMO

BACKGROUND: Whether accelerated aging develops over the course of chronic HIV infection or can be observed prior to significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) prior to the initiation of antiretroviral therapy. METHODS: 378 antiretroviral therapy-naïve PLWH with CD4 T cell counts >500 cells/mm 3 enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared to 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) in PLWH compared to controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS: There were a total of 56,639 DMPs and 6,103 DMRs at a false discovery rate<0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age compared to HIV-negative controls (p=0.001), with black race, low CD4, high CD8 T cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS: PLWH prior to the initiation of antiretroviral therapy and with preserved immune status show evidence of advanced methylation aging.

20.
Biomicrofluidics ; 14(4): 044117, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32849976

RESUMO

The effect of air-borne nanoparticles (NPs) on human health is an active area of research, with clinical relevance evidenced by the current COVID-19 pandemic. As in vitro models for such studies, lung-on-a-chip (LOAC) devices can represent key physical and physiological aspects of alveolar tissues. However, widespread adoption of the LOAC device for NP testing has been hampered by low intra-laboratory and inter-laboratory reproducibility. To complement ongoing experimental work, we carried out finite-element simulations of the deposition of NPs on the epithelial layer of a well-established LOAC design. We solved the Navier-Stokes equations for the fluid flow in a three-dimensional domain and studied the particle transport using Eulerian advection-diffusion for fine NPs and Lagrangian particle tracking for coarse NPs. Using Langmuir and Frumkin kinetics for surface adsorption and desorption, we investigated NP adsorption under different exercise and breath-holding patterns. Conditions mimicking physical exercise, through changes in air-flow volume and breathing frequency, enhance particle deposition. Puff profiles typical of smoking, with breath-holding between inhalation and exhalation, also increase particle deposition per breathing cycle. Lagrangian particle tracking shows Brownian motion and gravitational settling to be two key factors, which may cooperate or compete with each other for different particle sizes. Comparisons are made with experimental data where possible and they show qualitative and semi-quantitative agreement. These results suggest that computer simulations can potentially inform and accelerate the design and application of LOAC devices for analyzing particulate- and microbe-alveolar interactions.

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