Chronic Obstructive Pulmonary Disease Ex-smokers Research Articles

Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study

BackgroundAlthough asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC).MethodsEBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9.ResultsThe tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups.ConclusionThese results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Pulmonary EV miRNA profiles identify disease and distinct inflammatory endotypes in COPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition without effective disease modifying therapies. Identification of novel inflammatory endotype markers such as extracellular vesicles (EVs), which are important intercellular messengers carrying microRNA (miRNA), may enable earlier diagnosis and disease stratification for a targeted treatment approach. Our aim was to identify differentially expressed EV miRNA in the lungs of COPD patients compared with healthy ex-smokers and determine whether they can help define inflammatory COPD endotypes. EV miRNA were isolated and sequenced from ex-smoking COPD patients and healthy ex-smoker bronchoalveolar lavage fluid. Results were validated with RT-qPCR and compared to differential inflammatory cell counts. Expression analysis identified five upregulated miRNA in COPD (miR-223-3p, miR-2110, miR-182-5p, miR-200b-5p and miR-625-3p) and three downregulated miRNA (miR-138-5p, miR-338-3p and miR-204-5p), all with a log2 fold change of >1/-1, FDR < 0.05. These miRNAs correlated with disease defining characteristics such as FEF 25-75% (a small airways disease measure) and DLCO% (a surrogate measure of emphysema). Receiver operator curve analysis demonstrated miR-2110, miR-223-3p, and miR-182-5p showed excellent combinatory predictive ability (AUC 0.91, p < 0.0001) in differentiating between health and mild COPD. Furthermore, miR-223-3p and miR-338-3p correlated with airway eosinophilia and were able to distinguish "pure eosinophilic" COPD from other airway inflammatory subtypes (AUC 0.94 and 0.85, respectively). This is the first study to identify differentially expressed miRNA in COPD bronchoalveolar lavage fluid EVs. These findings suggest specific lung derived EV miRNA are a strong predictor of disease presence even in mild COPD. Furthermore, specific miRNA correlated with inflammatory cell numbers in COPD, and may have a role in defining inflammatory endotypes for future treatment stratification.

High miR203a-3p and miR-375 expression in the airways of smokers with and without COPD

Smoking is a leading cause of chronic obstructive pulmonary disease (COPD). It is known to have a significant impact on gene expression and (inflammatory) cell populations in the airways involved in COPD pathogenesis. In this study, we investigated the impact of smoking on the expression of miRNAs in healthy and COPD individuals. We aimed to elucidate the overall smoking-induced miRNA changes and those specific to COPD. In addition, we investigated the downstream effects on regulatory gene expression and the correlation to cellular composition. We performed a genome-wide miRNA expression analysis on a dataset of 40 current- and 22 ex-smoking COPD patients and a dataset of 35 current- and 38 non-smoking respiratory healthy controls and validated the results in an independent dataset. miRNA expression was then correlated with mRNA expression in the same patients to assess potential regulatory effects of the miRNAs. Finally, cellular deconvolution analysis was used to relate miRNAs changes to specific cell populations. Current smoking was associated with increased expression of three miRNAs in the COPD patients and 18 miRNAs in the asymptomatic smokers compared to respiratory healthy controls. In comparison, four miRNAs were lower expressed with current smoking in asymptomatic controls. Two of the three smoking-related miRNAs in COPD, miR-203a-3p and miR-375, were also higher expressed with current smoking in COPD patients and the asymptomatic controls. The other smoking-related miRNA in COPD patients, i.e. miR-31-3p, was not present in the respiratory healthy control dataset. miRNA-mRNA correlations demonstrated that miR-203a-3p, miR-375 and also miR-31-3p expression were negatively associated with genes involved in pro-inflammatory pathways and positively associated with genes involved in the xenobiotic pathway. Cellular deconvolution showed that higher levels of miR-203a-3p were associated with higher proportions of proliferating-basal cells and secretory (club and goblet) cells and lower levels of fibroblasts, luminal macrophages, endothelial cells, B-cells, amongst other cell types. MiR-375 expression was associated with lower levels of secretory cells, ionocytes and submucosal cells, but higher levels of endothelial cells, smooth muscle cells, and mast cells, amongst other cell types. In conclusion, we identified two smoking-induced miRNAs (miR-375 and miR-203a-3p) that play a role in regulating inflammation and detoxification pathways, regardless of the presence or absence of COPD. Additionally, in patients with COPD, we identified miR-31-3p as a miRNA induced by smoking. Our identified miRNAs should be studied further to unravel which smoking-induced inflammatory mechanisms are reactive and which are involved in COPD pathogenesis.

Effect of Smoking and Its Cessation on the Transcript Profile of Peripheral Monocytes in COPD Patients.

RationaleSmoking is the primary cause of chronic obstructive pulmonary disease (COPD); however, only 10–20% of smokers develop the disease suggesting possible genomic association in the causation of the disease. In the present study, we aimed to explore the whole genome transcriptomics of blood monocytes from COPD smokers (COPD-S), COPD Ex-smokers (COPD-ExS), Control smokers (CS), and Control Never-smokers (CNS) to understand the differential effects of smoking, COPD and that of smoking cessation.MethodsExploratory analyses in form of principal component analysis (PCA) and hierarchical component analysis (uHCA) were performed to evaluate the similarity in gene expression patterns, while differential expression analyses of different supervised groups of smokers and never smokers were performed to study the differential effect of smoking, COPD and smoking cessation. Differentially expressed genes among groups were subjected to post-hoc enrichment analysis. Candidate genes were subjected to external validation by quantitative RT-PCR experiments.ResultsCNS made a cluster completely segregated from the other three subgroups (CS, COPDS and COPD-ExS). About 550, 8 and 5 genes showed differential expression, respectively, between CNS and CS, between CS and COPD-S, and between COPD-S and COPD-ExS. Apoptosis, immune response, cell adhesion, and inflammation were the top process networks identified in enrichment analysis. Two candidate genes (CASP9 and TNFRSF1A) found to be integral to several pathways in enrichment analysis were validated in an external validation experiment.ConclusionControl never smokers had formed a cluster distinctively separated from all smokers (COPDS, COPD-ExS, and CS), while amongst all smokers, control smokers had aggregated in a separate cluster. Smoking cessation appeared beneficial if started at an early stage as many genes altered due to smoking started reverting towards the baseline, whereas only a few COPD-related genes showed reversal after smoking cessation.

Dysregulation of the CD163-Haptoglobin Axis in the Airways of COPD Patients.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls (p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron.

Chronic obstructive pulmonary disease in non-smokers: role of oxidative stress

BackgroundA striking feature of chronic obstructive pulmonary disease (COPD) is its inability to resolve after cigarette smoke exposure has ended, which has contributed to the possibility that the disease could also be driven by other endogenous causes, such as autoimmunity or chronic infection. The objective of this research was to examine oxidative stress in non-smoker and ex-smoker COPD subjects and its relationship to pulmonary functions and sputum cytology.ResultsThis case control-study enrolled 40 patients with COPD who are non-smokers or ex-smokers and 30 healthy controls of non-smokers or ex-smokers; oxidative stress markers, superoxide dismutase (SOD), and malondialdehyde (MDA) were compared in the two groups. All oxidative stress markers are elevated in the COPD group versus the control group. MDA has a negative correlation with FEV1and dyspnea grade.ConclusionBlood concentrations of SOD and MDA are consistently higher in patients with non-smokers or ex-smoker COPD when compared to non-smokers or ex-smoker healthy controls.

Long-term tobacco exposure and immunosenescence: Paradoxical effects on T-cells telomere length and telomerase activity

Immunosenescence are alterations on immune system that occurs throughout an individual life. The main characteristic of this process is replicative senescence, evaluated by telomere shortening. Several factors implicate on telomere shortening, such as smoking. In this study, we evaluated the influence of smoking and Chronic Obstructive Pulmonary Disease (COPD) on cytokines, telomere length and telomerase activity.Blood samples were collected from subjects aged over 60 years old: Healthy (never smokers), Smokers (smoking for over 30 years) and COPDs (ex-smokers for ≥15 years). A young group was included as control. PBMCs were cultured for assessment of telomerase activity using RT-PCR, and cytokines secretion flow cytometry. CD4+ and CD8+ purified lymphocytes were used to assess telomere length using FlowFISH.We observed that COPD patients have accelerated telomere shortening. Paradoxically, smokers without lung damage showed preserved telomere length, suggesting that tobacco smoking may affect regulatory mechanisms, such as telomerase. Telomerase activity showed diminished activity in COPDs, while Smokers showed increased activity compared to COPDs and Healthy groups.Extracellular environment reflected this unbalance, indicated by an anti-inflammatory profile in Smokers, while COPDs showed an inflammatory prone profile. Further studies focusing on telomeric maintenance may unveil mechanisms that are associated with cancer under long-term smoking.

The role of oxidised self-lipids and alveolar macrophage CD1b expression in COPD

In chronic obstructive pulmonary disease (COPD) apoptotic bronchial epithelial cells are increased, and their phagocytosis by alveolar macrophages (AM) is decreased alongside bacterial phagocytosis. Epithelial cellular lipids, including those exposed on uncleared apoptotic bodies, can become oxidized, and may be recognized and presented as non-self by antigen presenting cells. CD1b is a lipid-presenting protein, previously only described in dendritic cells. We investigated whether CD1b is upregulated in COPD AM, and whether lipid oxidation products are found in the airways of cigarette smoke (CS) exposed mice. We also characterise CD1b for the first time in a range of macrophages and assess CD1b expression and phagocytic function in response to oxidised lipid. Bronchoalveolar lavage and exhaled breath condensate were collected from never-smoker, current-smoker, and COPD patients and AM CD1b expression and airway 8-isoprostane levels assessed. Malondialdehyde was measured in CS-exposed mouse airways by confocal/immunofluorescence. Oxidation of lipids produced from CS-exposed 16HBE14o- (HBE) bronchial epithelial cells was assessed by spectrophotometry and changes in lipid classes assessed by mass spectrometry. 16HBE cell toxicity was measured by flow cytometry as was phagocytosis, CD1b expression, HLA class I/II, and mannose receptor (MR) in monocyte derived macrophages (MDM). AM CD1b was significantly increased in COPD smokers (4.5 fold), COPD ex-smokers (4.3 fold), and smokers (3.9 fold), and AM CD1b significantly correlated with disease severity (FEV1) and smoking pack years. Airway 8-isoprostane also increased in smokers and COPD smokers and ex-smokers. Malondialdehyde was significantly increased in the bronchial epithelium of CS-exposed mice (MFI of 18.18 vs 23.50 for control). Oxidised lipid was produced from CS-exposed bronchial epithelial cells (9.8-fold of control) and showed a different overall lipid makeup to that of control total cellular lipid. This oxidised epithelial lipid significantly upregulated MDM CD1b, caused bronchial epithelial cell toxicity, and reduced MDM phagocytic capacity and MR in a dose dependent manner. Increased levels of oxidised lipids in the airways of COPD patients may be responsible for reduced phagocytosis and may become a self-antigen to be presented by CD1b on macrophages to perpetuate disease progression despite smoking cessation.

Array-based Comparative Genomic Hybridization (aCGH) Reveals Chromosomal Aberrations in Chronic Obstructive Pulmonary Disease (COPD): A Preliminary Study

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease with varying susceptibility. COPD development may be associated with copy number variation (CNV) in susceptible genomic regions. CNV also contributes to COPD heritability as these can cause changes in DNA fragment. CNVs in COPD smokers and COPD ex-smokers have not been examined so far. Thus, genome-wide array based comparative genomic hybridization (aCGH) was performed in COPD (n = 15) and control subjects (n = 13) to identify the vulnerable candidate genes for genetic susceptibility and CNVs in smoker (n = 6) and ex-smoker (n = 9) COPD and compare it with control subjects to identify the candidate genes potentially involved in the pathogenesis of COPD. Copy number gains and losses were detected in several chromosomal regions.&#x0D; Chromosomal regions found to be consistently associated with both subgroups of COPD, as well as, of control group were: 2p11.2, 4q13.2, 8p23.1, 8p11.22, 12p13.31 and 14q32.33. Chromosomal regions associated with COPD were 11p15.5, 15q11.1-q11.2 and Xq28, which had several genes, (viz., CHECK2P2, HERC2P3, GOLGA6L6 and GOLGA8CP) which were associated with COPD smokers, while several other genes (viz., LICAM, LCA10, AVPR2, GDI1, HOTS and H19) were found to be associated with COPD ex-smokers. These loci and genes may be explored further for their potential use as predictive markers and better understanding of pathophysiology of COPD.

Influence of disease severity, smoking status and therapy regimes on leukocyte subsets and their ratios in stable chronic obstructive pulmonary disease.

IntroductionBlood cells are involved in systemic inflammation in chronic obstructive pulmonary disease (COPD). We aimed to assess differences in leukocyte subsets and their ratios between COPD patients and healthy individuals as well as their association with disease severity, smoking status and therapy in COPD.Material and methodsOne hundred and nine patients in the stable phase of COPD and 95 controls participated in the study. After blood sampling, white blood cells (WBC), neutrophils (NEUTRO), monocytes (MO), lymphocytes (LY) and basophils (BA) were determined on a Sysmex XN-1000 analyser, and ratios were calculated afterwards.ResultsWhite blood cells, NEUTRO, MO and BA were higher in COPD patients than in controls. Also, COPD patients had increased neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), monocyte to lymphocyte ratio (MLR), basophil to lymphocyte ratio (BLR), basophil to monocyte ratio (BMR) and monocyte/granulocyte to lymphocyte ratio (M/GLR). Smoking has an impact on leukocyte counts, with BA, BLR and BMR being higher in COPD smokers vs. ex-smokers. Patients with very severe COPD were distinguished from moderate COPD by NLR, dNLR and M/GLR. In addition, those parameters were associated with lung function and dyspnoea, and NLR and dNLR also with multicomponent COPD indices BODCAT and DOSE. Great potential of dNLR, NLR and M/GLR in identifying COPD patients was observed regarding their odds ratios (OR) of 5.07, 2.86, 2.60, respectively (p < 0.001). Common COPD therapy did not affect any of the parameters investigated.ConclusionsLeukocyte subsets and their ratios could be implemented in COPD assessment, especially in evaluating disease severity and prediction.

Mitochondrial dysfunction in airways and quadriceps muscle of patients with chronic obstructive pulmonary disease

BackgroundMitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD.MethodsBronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function.ResultsDecreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV1 (% predicted), transfer factor of the lung for carbon monoxide (TLCOC % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression.ConclusionsMitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.

Predictive Value of Exhaled Nitric Oxide and Blood Eosinophil Count in the Assessment of Airway Eosinophilia in COPD.

PurposeFractional exhaled nitric oxide (FENO50) level and peripheral blood eosinophil count may serve as indicators of airway eosinophilia. The aim of this study was to estimate the diagnostic value of these markers for detecting airway eosinophilia in patients with stable chronic obstructive pulmonary disease (COPD) and those experiencing an acute exacerbation (AECOPD).Patients and MethodsFENO50 levels, sputum and blood eosinophil counts were assessed in 53 clinically stable ex-smoker COPD patients and 67 ex-smoker COPD patients experiencing a severe exacerbation. In AECOPD, clinical variables were measured at the time of hospital admission and discharge following treatment.ResultsIn stable COPD, blood eosinophil count but not FENO50 level was found to be a good predictor of airway eosinophilia (area under the receiver operating characteristic curve [ROC AUC]: ≥0.82). The sensitivity and the specificity of the test ranged between 75% and 98%, the negative predictive value (NPV) was high (>90%). In AECOPD, FENO50 was predictive for airway eosinophilia (ROC AUC: >0.8) with high NPV (>88%), but with lower sensitivity and specificity (64–70%). In contrast, the predictive accuracy of blood eosinophil count for airway eosinophilia in AECOPD was modest (ROC AUC: 0.54–0.63). The combined use of the two markers provided only limited additional benefit. Correlation analyses supported ROC curve findings.ConclusionIn stable COPD the peripheral blood eosinophil count, while in AECOPD the FENO50 level is a good surrogate marker of airway eosinophilia.

Smoking, COPD, Infection, and Lung Cancer: How are They Interconnected?

A case of an elderly ex-smoker chronic obstructive pulmonary disease (COPD) patient with controlled type 2 diabetes mellitus (T2DM) as comorbid was followed-up for 10 years. His stable COPD in the course of time slowly declined to multiple acute exacerbation (AE)-COPD and multiple hospital admissions. High-dose systemic corticosteroids given during AE-COPD with prolonged oral steroids continuation led to depressed immunity that ended with severe immunosuppression, causing sepsis and chronic heart failure (CHF) with non-ST elevated myocardial infarction (NSTEMI) and worsening of COPD in his ninth year follow-up. This immunosuppression also triggered the emergence of lung cancer by allowing malignant cell to evade immune surveillance. Fortunately patient is survived and recovered to stable COPD.

Mucociliary Clearance of Different Respiratory Conditions: A Clinical Study.

Introduction Mucociliary clearance (MCC) is the first line of defense of the pulmonary system. Mucociliary clearance impairment may lead to increased risk of respiratory infections, lung injury, pulmonary repair problems, chronic dysfunctions and progression of respiratory diseases. Objective To characterize the MCC of active and passive smokers and individuals with chronic obstructive pulmonary disease (COPD) and compare the MCC behaviors between men and women of different age groups. Methods Patients with COPD (current smokers and ex-smokers) and apparently healthy individuals (current smokers, passive smokers and nonsmokers) were evaluated. All of the subjects underwent lung function and MCC evaluation (saccharin transport test [STT]). Smokers (with or without COPD) were questioned about the smoking history. Results A total of 418 individuals aged 16 to 82 years old, of both genders, were evaluated. The STT values of active and passive smokers were statistically higher than those of the control group ( p < 0.01). Men of the control group had lower values of STT than active smokers (9.7 ± 7.1 and 15.4 ± 10.1 minute, respectively, p < 0.01). In addition, higher MCC velocity was observed in women that are current smokers (11.7 ± 6.8 minute) compared with men (15.4 ± 10.1 minute) in this group ( p = 0.01). Among the younger age groups (< 50 years old), only passive smokers presented higher STT in relation to the control group. Conclusion Passive and active smoking are factors that influence negatively the MCC, and passive smokers may present losses of this mechanism at a younger age. Additionally, male smokers present worse MCC than male nonsmokers.

Decreased expression of a phagocytic receptor Siglec-1 on alveolar macrophages in chronic obstructive pulmonary disease

BackgroundAlveolar macrophages are professional phagocytes that remove microbial pathogens inhaled into the lung. The phagocytic ability is compromised in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying this defect in phagocytosis are not clearly defined.Materials and methodsCell suspensions were collected from lung tissues of patients undergoing lung resection. Alveolar macrophages were detected as FSChi/ SSChi/CD45+/CD206+ cells in the isolated cell suspension by flow-cytometry. The cell surface expression of plasma membrane-bound phagocytic receptors (Fcγ receptor I (FcγRI), a complement receptor CD11b, macrophage scavenger receptor-1 (MSR-1), CD36 and Siglec-1) was determined on the alveolar macrophages. Correlations between the expression levels of the phagocytic receptors and disease severity were analysed. Phagocytosis of fluorescence-tagged bacteria by human alveolar macrophages was evaluated.ResultsThe flow-cytometry analyses revealed that FcγRI, CD11b, MSR-1 and Siglec-1, but not CD36, were expressed on human alveolar macrophages. Among these receptors, Siglec-1 expression was significantly decreased on alveolar macrophages in COPD ex-smokers (n = 11), compared to control never-smokers (n = 11) or control ex-smokers (n = 9). The Siglec-1 expression on alveolar macrophages was significantly correlated with lung function (forced expiratory volume in 1 s) and with the severity of emphysema. Treatment of human alveolar macrophages with an anti-Siglec1 blocking antibody decreased phagocytosis of non-typeable Haemophilus influenzae (NTHi).ConclusionOur findings demonstrated reduced expression of Siglec-1 on alveolar macrophages in COPD, which is involved in engulfment of NTHi.

Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD.

Increased activity of indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase (TPH) have been reported in individuals with chronic obstructive pulmonary disease (COPD). We therefore investigated the effect of gender stratification upon the observed levels of tryptophan metabolites in COPD. Tryptophan, serotonin, kynurenine, and kynurenic acid were quantified in serum of never-smokers (n = 39), smokers (n = 40), COPD smokers (n = 27), and COPD ex-smokers (n = 11) by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). The individual metabolite associations with lung function, blood, and bronchoalveolar lavage (BAL) immune-cell composition, as well as chemokine and cytokine levels, were investigated. Stratification by gender and smoking status revealed that the observed alterations in kynurenine and kynurenic acid, and to a lesser extent serotonin, were prominent in males, irrespective of COPD status (kynurenine p = 0.005, kynurenic acid p = 0.009, and serotonin p = 0.02). Inferred serum IDO activity and kynurenine levels decreased in smokers relative to never-smokers (p = 0.005 and p = 0.004, respectively). In contrast, inferred tryptophan hydroxylase (TPH) activity and serotonin levels showed an increase with smoking that reached significance with COPD (p = 0.01 and p = 0.01, respectively). Serum IDO activity correlated with blood CXC chemokine ligand 9 (CXCL9, p = 0.0009, r = 0.93) and chemokine (C-C motif) ligand 4 (CCL4.(p = 0.04, r = 0.73) in female COPD smokers. Conversely, serum serotonin levels correlated with BAL CD4+ T-cells (%) (p = 0.001, r = 0.92) and CD8+ T-cells (%) (p = 0.002, r = −0.90) in female COPD smokers, but not in male COPD smokers (p = 0.1, r = 0.46 and p = 0.1, r = −0.50, respectively). IDO- and TPH-mediated tryptophan metabolites showed gender-based associations in COPD, which were primarily driven by smoking status.

Increased IFN-\u03b3-producing Th17/Th1 cells and their association with lung function and current smoking status in patients with chronic obstructive pulmonary disease

BackgroundTh17 cells are believed to be important proinflammatory cells in the pathogenesis of chronic obstructive pulmonary disease (COPD). Recent evidence demonstrates that Th17 cells display substantial developmental plasticity, giving rise to Th17/Th1 cells that secret both IL-17 and IFN-γ and are more pathogenic in inflammatory diseases. The aim of this study was to examine the distribution of circulating Th17/Th1 subpopulation and its association with disease severity in patients with COPD.MethodsBlood samples were obtained from 21 never-smokers, 31 smokers with normal lung function and 83 patients with COPD. The frequencies of Th17 cells and the Th17/Th1 subset were measured using flow cytometry. Plasma concentrations of IL-6, transforming growth factor (TGF)-β1 and IL-12 were determined by ELISA. The associations of Th17/Th1 cells with lung function and smoking were evaluated.ResultsIn peripheral blood, significantly increased proportions of Th17/Th1 cells among CD4 cells and Th17 cells were found in COPD patients compared with never-smokers and smokers with normal lung function. The percentages of Th17/Th1 cells showed correlations with forced expiratory volume in 1 (FEV1) % predicted value (r = − 0.244, p < 0.05), and higher proportions of Th17/Th1 cells in GOLD stage IV patients compared with stage I patients. The percentages of Th17/Th1 cells were significantly higher in current smokers compared with ex-smoker COPD patients, and positively correlated with pack-years of smoking (r = 0.352, p < 0.01). The plasma concentrations of IL-6, TGF-β1 and IL-12 were significantly increased in patients with COPD compared with never-smokers and smokers with normal lung function.ConclusionOur results revealed correlations of proportions of IFN-γ-producing Th17/Th1 cells with lung function and smoking, suggesting that increased Th17/Th1 cells may play a role in COPD progression.

Different Relationships between FENO and COPD Characteristics in Smokers and Ex-Smokers

Exhaled nitric oxide (FENO) is a marker of type-2 inflammation in asthma and is used in its management. However, smokers and ex-smokers have lower FENO values, and the clinical use of FENO values in COPD patients is unclear. Therefore, we investigated if FENO had a relationship to different COPD characteristics in smoking and ex-smoking subjects. Patients with COPD (n = 533, 58% females) were investigated while in stable condition. Measurements of FENO50, blood cell counts, IgE sensitisation and lung function were performed. Medication reconciliation was used to establish medication usage. Smokers (n = 150) had lower FENO50 9 (8, 10) ppb (geometric mean, 95% confidence interval) than ex-smokers did (n = 383) 15 (14, 16) ppb, p < 0.001. FENO50 was not associated with blood eosinophil or neutrophil levels in smokers, but in ex-smokers significant associations were found (r = 0.23, p < 0.001) and (r = –0.18, p = 0.001), respectively. Lower FENO values were associated with lower FEV1% predicted in both smokers (r = 0.17, p = 0.040) and ex-smokers (r = 0.20, p < 0.001). Neither the smokers nor ex-smokers with reported asthma or IgE sensitisation were linked to an increase in FENO50. Ex-smokers treated with inhaled corticosteroids (ICS) had lower FENO50 14 (13, 15) ppb than non-treated ex-smokers 17 (15, 19) ppb, p = 0.024. This was not found in smokers (p = 0.325). FENO is associated with eosinophil inflammation and the use of ICS in ex-smoking COPD subjects, but not in smoking subjects suggesting that the value of FENO as an inflammatory marker is more limited in smoking subjects. The association found between low FENO values and low lung function requires further investigation.

Airway host-microbiome interactions in chronic obstructive pulmonary disease

BackgroundLittle is known about the interactions between the lung microbiome and host response in chronic obstructive pulmonary disease (COPD).MethodsWe performed a longitudinal 16S ribosomal RNA gene-based microbiome survey on 101 sputum samples from 16 healthy subjects and 43 COPD patients, along with characterization of host sputum transcriptome and proteome in COPD patients.ResultsDysbiosis of sputum microbiome was observed with significantly increased relative abundance of Moraxella in COPD versus healthy subjects and during COPD exacerbations, and Haemophilus in COPD ex-smokers versus current smokers. Multivariate modeling on sputum microbiome, host transcriptome and proteome profiles revealed that significant associations between Moraxella and Haemophilus, host interferon and pro-inflammatory signaling pathways and neutrophilic inflammation predominated among airway host-microbiome interactions in COPD. While neutrophilia was positively correlated with Haemophilus, interferon signaling was more strongly linked to Moraxella. Moreover, while Haemophilus was significantly associated with host factors both in stable state and during exacerbations, Moraxella-associated host responses were primarily related to exacerbations.ConclusionsOur study highlights a significant airway host-microbiome interplay associated with COPD inflammation and exacerbations. These findings indicate that Haemophilus and Moraxella influence different components of host immune response in COPD, and that novel therapeutic strategies should consider targeting these bacteria and their associated host pathways in COPD.

Role of microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by inflammatory cell activation and the release of inflammatory mediators. By measuring microRNA expression in the plasma of COPD subjects, we aimed to identify the clinical relevance of plasma miRNA levels in these patients. A total of 40 COPD patients and 40 healthy controls were enrolled in the study. The COPD model of C57BL/6 mice was also developed by exposing them to cigarette smoke (CS). The expression of microRNA-218-5p was detected by qRT-PCR in all the subjects and mice. The serum level of IL-18 and TGF-β1 was also detected via ELISA kit. To investigate the effects of miR-218-5p, 10 mg/kg of miR-218-5p inhibitor (miR-218-5p antagonist), a scrambled control or PBS (solvent) was intranasally administered on the first and the fourth exposure day, before the start of CS exposure. The results showed that miR-218-5p was significantly down-regulated in patients with COPD, compared to normal subjects. There was a negative correlation between the plasma miR-218-5p level and the duration of disease since diagnosis in COPD ex-smokers. CS-induced COPD mice experiments with a miR-218-5p inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. These findings supported that miR-218-5p may, therefore, play an important role in the pathogenesis of COPD.