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Background: COPD patients have a higher risk of pneumonia when treated with fluticasone propionate (FP) than with placebo, and a lower risk with budesonide (BUD). We hypothesized that BUD and FP differentially affect the mucosal barrier in response to viral infection and/or cigarette smoke.Methods: We assessed protective effects of equivalent concentrations of BUD and FP on cytokine production and barrier function (electrical resistance) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) upon exposure to viral mimetic poly-(I:C) and/or cigarette smoke extract (CSE) or epidermal growth factor (EGF).Results: BUD and FP were equally effective in suppressing poly-(I:C)- and/or CSE-induced IL-8 secretion in 16HBE and PBECs. Poly-(I:C) substantially decreased electrical resistance in 16HBE cells and both BUD and FP fully counteracted this effect. However, FP hardly affected 16HBE barrier dysfunction induced by CSE with/without poly-(I:C), whereas BUD (16 nM) provided full protection, an effect likely mediated by affecting EGFR-downstream target GSK-3β. Similarly, BUD, but not FP, significantly improved CSE-induced barrier dysfunction in PBECs. Finally, BUD, but not FP, exerted a modest but significant protective effect against Streptococcus Pneumoniae-induced barrier dysfunction, and BUD, but not FP, prevented cellular adhesion and/or internalization of these bacteria induced by poly-(I:C) in 16HBE.Conclusions: Collectively, both BUD and FP efficiently control epithelial pro-inflammatory responses and barrier function upon mimicry of viral infection. Of potential clinical relevance, BUD more effectively counteracted CSE-induced barrier dysfunction, reinforcing the epithelial barrier and potentially limiting access of pathogens upon smoking in vivo. [ABSTRACT FROM AUTHOR]

Objective:The aim of this study was to investigate the association between maternal overweight before pregnancy and offspring asthma in an ongoing birth cohort study. Maternal overweight may affect the pulmonary and immunological development of the fetus in utero because of the increased levels of inflammatory factors associated with being overweight and thereby increase the asthma risk in childhood.Design:Birth cohort study with follow-up until 8 years of age.Subjects:The study population included 3963 children and their mothers who participated in the Prevention and Incidence of Asthma and Mite Allergy study.Measurements:Maternal overweight before pregnancy was defined as a body mass index (BMI) above 25 kg m−2. Data on wheeze, dyspnea and prescription of inhaled corticosteroids of the child were reported yearly by the parents in a questionnaire. Sensitization to inhalant allergens and bronchial hyperresponsiveness (BHR) were determined at 8 years. Effect modification by predisposition for asthma in the child was tested. Data were analyzed by logistic regression and generalized estimating equations analyses.Results:At 8 years, 14.4% (n=571) of the children had asthma. In total, 20.9% (n=830) of the mothers were overweight before pregnancy. In children predisposed for asthma (n=1058), maternal overweight before pregnancy was associated with an increased risk of asthma in the child at 8 years (OR=1.52, 95% CI: 1.05–2.18) after adjustment for confounding factors, birth weight and the child's BMI. No association was observed in children without a predisposition (OR=0.86, 95% CI: 0.60–1.23). There was no association with sensitization or BHR.Conclusion:Children with a predisposition for asthma may have a higher risk to develop asthma during childhood when their mothers are overweight before pregnancy, irrespective of the child's BMI. [ABSTRACT FROM AUTHOR]

Allergic asthma is usually diagnosed by the presence of variable airway obstruction, bronchial hyperresponsiveness, and allergy. However, a significant proportion of adult asthma patients (up to 40%) are non-allergic. Patients with non-allergic asthma often have a later disease onset and greater disease severity, as reflected by more severe airway obstruction and bronchial hyperresponsiveness. Furthermore, females have a higher risk of developing non-allergic asthma. The latter suggests that hormone-related events play an important role in the development and severity of adult-onset non-allergic asthma. This paper describes the associations between asthma and hormonal changes throughout the female life-span, such as those associated with the monthly cycle of menstruation and menopausal hormonal changes. [ABSTRACT FROM AUTHOR]

Background: Recall bias may provide discrepant relationships of pet exposure with sensitization and asthma development. We studied prospectively effects of pets at home on development of sensitization, asthma and respiratory symptoms from birth up to age 8 years. Methods: Event history analysis was performed on annually registered data of 2951 children, participating in the PIAMA birth cohort study. Results: Children with a cat or dog at home at 3 months of age had a significantly lower prevalence of sensitization to inhalant allergens at age 8, but not of asthma. A cat decreased the risk of house dust mite sensitization at age 8 [odds ratio (OR) = 0.68, 95% confidence interval (CI) 0.49–0.95], a dog of pollen sensitization (OR = 0.49, 95% CI: 0.29–0.83). A cat or dog at home did not significantly affect asthma incidence in each subsequent year. From 2 years of age onwards, the incidence of wheeze (OR = 1.52, 95% CI: 1.12–2.05) and a dry cough at night (OR = 1.28, 95% CI: 1.05–1.57) was higher in children with a dog, whereas removal of a dog increased the risk of developing asthma symptoms. Comparing analyses using prospectively and retrospectively collected data on diagnosed asthma showed important recall bias. Conclusions: Our prospective study shows a protective effect of early presence of pets at home on sensitization to inhalant allergens, but no prevention of asthma development. Furthermore, children with pets had more frequent transient or intermittent asthma symptoms. Parental report of asthma by recall may provide spurious results of these associations. [ABSTRACT FROM AUTHOR]

Introduction: ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV1) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33. Aim: To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene–environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort. Methods: Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV1 and BHR at age 8 years; asthma was based on questionnaire data at age 8. Results: In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV1% predicted. Conclusions: We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation. [ABSTRACT FROM AUTHOR]

Although small airway remodeling (SAR) leading to airflow obstruction is a common consequence of human cigarette smoking, the airways have been largely ignored in animal models of chronic obstructive pulmonary disease (COPD). We examined lung structure in a guinea pig model of chronic cigarette smoke exposure to ascertain whether smoke induced SAR, and to evaluate how these anatomic lesions correlate with physiologic changes. We used tissue from guinea pigs exposed to cigarette smoke or air for 6 mo. Pulmonary function tests were performed, and histologic sections were prepared. Airspace size (Lm) and changes in the structure of the small airways were evaluated by morphometric analysis. Chronic smoke exposure was associated with increased airway wall thickness and increased amounts of thick collagen fibers in the walls of the small airways, as well as with increased Lm. The increase in thick collagen fibers related negatively to peak expiratory volume (PEF) and the ratio of forced expiratory volume in 1 s to forced ventilatory capacity (FEV0.1/FVC), and positively to airway resistance. Physiologic lung volumes were predicted by airspace size, but residual volume (RV) and total lung capacity (TLC) also were related to airway wall thickness. Amounts of smooth muscle were not changed and did not predict any physiologic abnormalities. We conclude that cigarette smoke exposure results in SAR in the guinea pig, alterations that are reflected in increased airways resistance with diminished airflow and air trapping, mimicking human disease. This model should prove useful in further investigations into the mechanisms of airway remodeling. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation. Although smoking cessation improves symptoms and the decline in lung Function in COPD, it is unknown whether bronchial inflammation in patients with established COPD varies with the duration of smoking cessation. Methods: 114 patients (99 men) with COPD of mean (SD) age 62 (8) years, a median (IQR) smoking history of 42 (31-55) pack years, no inhaled or oral corticosteroids, all current or ex-smokers (n = 42, quit >1 month, median cessation duration 3.5 years), post-bronchodilator FEV1 63 (9)% predicted, and FEV1/IVC 48 (9)% were studied cross sectionally. The numbers of subepithelial T lymphocytes (CD3, CD4, CD8), neutrophils, macrophages, eosinophils, mast cells, and plasma cells were measured in bronchial biopsy specimens (median (IQR)/0.1 mm²) using Fully automated image analysis. Results: Ex-smokers with COPD had higher CD3+, CD4+, and plasma cell numbers than current smokers with COPD (149 (88-225) v 108 (61-1 64), p=0.036 58 (32-90) v 40 (25-66), p=0.023; and 9.0 (5.5-20) v 7.5 (3.1-14), p=0.044, respectively), but no difference in other inflammatory cells. Short term ex-smokers (⩾3.5 years) had higher CD4+ and CD8+ cell numbers than current smokers (p = 0.017, p=0.023 respectively). Conversely, long term ex-smokers (quit 13.5 years) had lower CD8+ cell numbers than short term ex-smokers (p = 0.009), lower CD8/CD3 ratios than both current smokers and short-term ex-smokers (p=0.012, p=0.003 respectively), and higher plasma cell numbers than current smokers (p=0.003). Conclusions: With longer duration of smoking cessation, CD8 cell numbers decrease and plasma cell numbers increase. This indicates that bronchial T lymphocyte and plasma cell counts, but not other inflammatory cells, are related to duration of smoking cessation in patients with COPD. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICS) provide short term benefits in asthma but the long term effects are still unknown. Methods: 281 patients diagnosed with moderate to severe asthma in 1963-75 were re-examined in 1991-9. Information was collected on forced expiratory volume in 1 second (FEV1), bronchial hyperresponsiveness, atopy, smoking, use and dosage of oral and ICS. Patients were included in the analyses if they had at least three FEV1 measurements during two consecutive years after the age of 30 and used ICS during follow up. Results: Analyses were performed on 122 patients. During a median follow up period of 23 years, 71 men and 51 women had on average 37 and 40 individual FEV1 measurements, respectively. Linear mixed effect models showed that men had a mean annual decline in FEV1 of 20.6 mI/year less after ICS initiation than before (p=0.011), and in women the decline in FEV1 was 3.2 mI/year less (p=0.73). In individuals with <5 pack years of smoking the decline in FEV1 was 36.8 mI/year less after ICS institution in men (p=0.0097) and 0.8 mI/year less in women (p=0.94), the difference between the sexes being significant (p=O.O45). These effects were not observed in those with ⩾5 pack years smoking. A higher daily dose of ICS was associated with a smaller decline in FEV1 in men (p=0.006), an effect not observed in women. Conclusion: Treatment with ICS in adult patients with moderate to severe asthma was associated with a reduction in the decline in FEV1 over a 23 year follow up period in men who had smoked <5 pack years. This effect was dose dependent and was not present in women or in men with ⩾5 pack years of smoking at follow up. The lack of effect of ICS on the decline in FEV1 in women needs further study. [ABSTRACT FROM AUTHOR]

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting 132 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of CS will result in disease deterioration. Methods: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 μg FP +50 μg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study. Results: The drop out rate after randomisation was similar in the two groups. Withdrawal of FR resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (5) v 0.0 (0.8)% (SFC) (p=0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p =0.15). The mean annual incidence rate of mild exacerbations was 1.3 (5) v 0.6 (SFC), p =0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone. Conclusions: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA. [ABSTRACT FROM AUTHOR]

Airway inflammation in asthma is orchestrated by recruitment of T helper (Th)2 lymphocytes to the lung and subsequent production of Th2-like cytokines upon allergen challenge. To examine whether allergen-induced dysfunction of the β2-adrenergic receptor (β2-AR) contributes to the enhanced T(h2) cell activity in asthma. β2-adrenergic regulation of cytokine mRNA expression was studied in α-CD3/α-CD28-activated peripheral blood lymphocytes from seven asthma patients before and 6 h after allergen challenge, in conjunction with the effects of β2-agonist fenoterol on T cell chemotaxis and signalling pathways. A complete loss of β2-AR control over expression of the Th2 cytokines IL-4, IL-5 and IL-13, but not of the Th1 cytokine IFN-γ, was observed after allergen challenge. Furthermore, we found impaired β2-AR regulation of T cell migration as well as signal transduction pathways, i.e. the phosphorylation of cyclic adenosine monophosphate-responsive element binding protein and the inhibition of the mitogen-activated protein kinase pathway. The loss of β2-AR control was associated with increased β-adrenergic receptor kinase expression, which might be involved in β2-AR desensitization. In addition, we demonstrate for the first time that T cells exposed to the chemokine thymus and activation-regulated chemokine show hyporesponsiveness to fenoterol. Our results suggest that allergen-induced loss of β2-AR control, possibly mediated by chemokine release, plays an important role in enhanced Th2-like activity in asthma. [ABSTRACT FROM AUTHOR]

Asthma is a genetically complex disease characterized by respiratory symptoms, intermittent airway obstruction and airway hyper-responsiveness due to airway inflammation and remodelling. The ADAM33 gene is associated with asthma and airway hyper-responsiveness and is postulated as a gene for airway remodelling. To investigate whether polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in patients with asthma. In a cohort of 200 asthma patients followed over 20 years, eight single nucleotide polymorphisms of the ADAM33 gene were analysed to estimate their effect on annual FEV1 decline. The rare allele of the S_2 polymorphism was significantly associated with excess decline in FEV1 ( P<0.05). These findings suggest that a variant in ADAM33 is not only important in the development of asthma but also in disease progression, possibly related to enhanced airway remodelling. [ABSTRACT FROM AUTHOR]

Background: It has been shown that treatment with a long acting beta2 agonist in addition to a glucocorticoid is beneficial in the treatment of asthma. In asthma inflammatory cells, particularly eosinophils, migrate into the pulmonary tissue and airway lumen by means of adhesion molecules expressed on resident tissue cells--that is, fibroblasts--and become activated by cytokines and adhesive interactions. A study was undertaken to determine whether an interaction exists between the long acting beta2 agonist formoterol and the glucocorticoid budesonide on inhibition of adhesion molecule expression, as well as chemo/cytokine production by human lung fibroblasts.Methods: Lung fibroblasts were preincubated with therapeutically relevant drug concentrations of 10(-8) M to 10(-10) M. Cells were stimulated with interleukin (IL)-1beta (1 or 10 U/ml) for 8 hours and supernatants were collected for measurement of GM-CSF and IL-8 concentrations. The cells were fixed and subjected to a cell surface ELISA technique to measure the expression of ICAM-1 and VCAM-1.Results: Formoterol exerted an additive effect on the inhibition of IL-1beta stimulated ICAM-1 and VCAM-1 upregulation and GM-CSF production by budesonide in concentrations of 10(-9) M and above (p<0.05). IL-8 production was not influenced by formoterol.Conclusion: Formoterol exerts an additive effect on the anti-inflammatory properties of budesonide. In vitro data support the finding that the combination of budesonide and formoterol in asthma treatment strengthens the beneficial effect of either drug alone. [ABSTRACT FROM AUTHOR]

Background: The β2 adrenoceptor and its 5' untranslated region contain a number of genetic variants. The aim of this study was to investigate the potential for genetic variation at this locus to influence the expression of β2 adrenoceptors on circulating peripheral blood mononuclear cells (PBMCs). Methods: Genotype was determined in 96 individuals with asthma for four polymorphisms at the β2 adrenoceptor locus. β2 adrenoceptor binding and cyclic AMP responses to isoprenaline in PBMCs were determined and the relationship between genotype/haplotype and β2 adrenoceptor expression and response to isoprenaline examined. Results: β2 adrenoceptor promoter polymorphisms were found to be common in white subjects. Strong linkage disequilibrium exists across this locus, resulting in the occurrence of several common hoplotypes. No single polymorphism or haplotype was correlated with the level of β2 adrenoceptor expression or cyclic AMP responses to isoprenaline in vitro. Conclusion: β2 adrenoceptor polymorphisms, when considered in isolation or by extended haplosypes, do not determine the basal level of expression or coupling of β2 adrenoceptors in PBMCs from asthmatic subjects. [ABSTRACT FROM AUTHOR]

Focuses on development of airflow limitation in chronic obstructive pulmonary disease. Close relationship between the presence of inflammatory cells and their mediators and airway remodelling; Presence of increased amounts of sputum; Bronchoalveolar lavage fluid; Airway wall inflammation; Exaggerated response of the airways to pharmacological, chemical, physical or physiological stimuli.

Study Objectives: The influence of bronchiolitis obliterans syndrome (BOS) on costs after lung transplantation was investigated by comparing the costs of patients with and without this condition.Design: Follow-up costs were prospectively investigated in a medical technology assessment of the Dutch Lung Transplant Program, in relation to the development of the BOS. First, average follow-up costs per week per patient were compared between patients who did or did not develop BOS. Second, in the BOS group, these costs were compared before and after the onset of BOS.Setting: Dutch Lung Transplant Program, University Hospital of Groningen.Results: Data on 53 patients (37 patients without BOS and 16 with BOS) who underwent transplantation between November 1990 and April 1995 were available. The average follow-up time of these 53 patients was 1.5 years. The follow-up costs amounted to an average (in Dutch guilders [Dfl]) of 1,774/wk for non-BOS patients, compared to 3,072/wk for BOS patients (+ 73%; p = 0.002; one Dfl = 50 cents US currency). This difference in costs was largely accounted for by an increase in used health-care resources, in particular hospitalization and medication. For the BOS patients, the average costs per week before and after the onset of BOS were 1,941 Dfl and 2,422 Dfl, respectively.Conclusion: BOS is associated with substantial extra costs. These findings reemphasize the need to focus efforts on prevention of BOS to enhance the cost-effectiveness of lung transplantation. [ABSTRACT FROM AUTHOR]

Background: There is no agreement on how a bronchodilator response should be expressed. Ideally, the index used should be able to distinguish asthma from chronic obstructive lung disease and be independent of initial FEV1.Methods: Two hundred and seventy four adults (aged 18-60 years) outpatients with obstructive airways disease were studied. Patients were divided into syndrome groups on the basis of a standardised history: asthma (n = 99), asthmatic bronchitis (n = 88), and chronic obstructive lung disease (n = 51); 36 subjects could not be attributed to any subgroup. FEV1 was measured before and 20 minutes after inhalation of 1000 micrograms terbutaline. Different expressions of bronchodilator response (delta FEV1) were compared with respect to their dependence on initial FEV1 and their efficacy in separating subjects with asthma from those with chronic obstructive lung disease. delta FEV1 was expressed as a percentage of initial FEV1 (delta FEV1%init), absolute value (delta FEV1[1]), percentage of predicted FEV1 (delta FEV1%pred), standardised residual (delta SR-FEV1), and percentage of maximal possible increase (delta FEV1%[pred-init]).Results: delta FEV1%init was more dependent on initial FEV1 (p = -0.405) than delta FEV1[1] (r = -0.145), delta FEV1%pred (r = -0.166), and delta SR-FEV1 (r = -0.127). delta FEV1%[pred-init] reached infinity when initial FEV1 approached predicted levels. delta FEV1%pred had a higher likelihood ratio (1.71) for separating patients with asthma from those with chronic obstructive lung disease than other expressions of bronchodilator response. Asthmatic patients had larger mean bronchodilator responses than patients in other subgroups; this difference was largest for delta SR-FEV1 (F = 9.19) and delta FEV1%pred (F = 9.03); it was much smaller for delta FEV1%init (F = 5.89). Despite significant differences in mean response, there was a large overlap of individual responses between diagnostic subgroups. The bronchodilator response was continuously and unimodally distributed for all expressions.Conclusions: delta FEV1%pred appears to be the most useful method of expressing bronchodilator response, both for clinical and for research purposes. Reversibility of airways obstruction in response to a bronchodilator is a continuous variable and not a dichotomous triat. Any cut off level of a "positive" bronchodilator response is therefore arbitrary. [ABSTRACT FROM AUTHOR]

The relation between citric acid cough threshold and airway hyperresponsiveness was investigated in 11 non-smoking patients with allergic asthma (mean FEV1 94% predicted) and 25 non-atopic smokers with chronic airflow obstruction (mean FEV1 65% predicted). Cough threshold was determined on two occasions by administering doubling concentrations of citric acid. Seven of the 11 asthmatic subjects and 14 of 25 smokers with chronic airflow obstruction had a positive cough threshold on both test days. Cough threshold measurements were reproducible in both groups (standard deviation of duplicate measurements 1.2 doubling concentrations in asthma, 1.1 doubling concentrations in chronic airflow obstruction). Citric acid provocation did not cause bronchial obstruction in most patients, though four patients had a fall in FEV1 of more than 20% for a short time on one occasion only. No significant difference in cough threshold was found between the two patient groups despite differences in baseline FEV1 values. There was no significant correlation between cough threshold and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) histamine in either group. Thus sensory nerves can be activated with a tussive agent in patients with asthma and chronic airflow obstruction without causing bronchial smooth muscle contraction. [ABSTRACT FROM PUBLISHER]

Focuses on the role played by ADAM33 gene in the pathogenesis of asthma. Determinants of the development of asthma; Explanation for the lack of consistency of associated single-nucleotide polymorphisms; Need to examine the putative function and the expression pattern of the gene product to fully understand the role of ADAM33 gene in the pathogenesis of asthma.

Spirometry is used worldwide to diagnose respiratory disease, and it is a validated measure to assess airway obstruction. Irreversible airway obstruction is the defining feature of chronic obstructive pulmonary disease (COPD). Thus, an FEV1/FVC ratio <70% is used to diagnose COPD, and the severity is thereafter based on the level of FEV1. This definition is widely used in clinical practice and research, yet may lead to confusion with respect to the diagnosis associated with the presence of airway obstruction. The three main reasons are the following: (1) Fixed airflow obstruction may be the result of specific diagnoses such as cystic fibrosis; (2) FEV1/FVC ratio changes with ageing, and it is therefore inappropriate to use the same ratio at 40 and 90 years, leaving aside gender differences; (3) even when specific diagnoses are excluded, fixed airflow obstruction may be the end-stage of many different underlying processes. The authors believe that they have strong arguments that a COPD diagnosis based solely on spirometric values is nonsense. More sophisticated lung function tests, such as plethysmography, forced oscillation and lung clearance index, may help further to delineate the characteristics of low lung function. However, these are not feasible in most clinical contexts and in epidemiologic studies. Therefore, the authors throw down the gauntlet: spirometry is an essential tool in patient evaluation but dangerous for disease diagnosis, and the term COPD should only be used in the appropriate clinical (diagnostic) context. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of resilience with self‐care and quality of life in people with chronic obstructive pulmonary disease. Design: Cross‐sectional study. Methods: Data were collected between February and May 2021. Self‐care was measured with the self‐care of chronic illness inventory, quality of life was measured with the clinical chronic obstructive pulmonary disease questionnaire and resilience was measured with the resilience evaluation scale. Possible confounders were included (sex, age, smoking, time since diagnosis of chronic obstructive pulmonary disease, educational level, social support and pulmonary function). Multiple regression analysis was performed among the determinants, confounders and both outcomes. Results: Participants scored fairly well on resilience (mean 22.5). Self‐care scored reasonably well (mean maintenance 65.9, mean monitoring 70.9, mean management 59.9 and mean confidence 71.5). Quality of life scored mediocre (mean 2.6). The results of the linear multiple regression were resilience, which is associated with self‐care confidence and quality of life when adjusted for possible confounders. This means people with chronic obstructive pulmonary disease with higher resilience have better self‐care confidence and higher quality of life. The outcome contributes to strengthening nursing care and further developing nurses' knowledge. The results can contribute to increasing awareness for healthcare professionals that resilience can potentially increase self‐care and quality of life. [ABSTRACT FROM AUTHOR]

Aims: To assess the effectiveness of an unsupervised home‐based pulmonary rehabilitation with self‐management program in patients with chronic obstructive pulmonary disease (COPD). Background: A few recent studies have shown that unsupervised home‐based pulmonary rehabilitation can improve the clinical outcome of patients with COPD. More studies are needed to prove its benefits. Design: This study used a quasi‐experimental design. Methods: Seventy‐two admitted COPD patients were assigned to experimental group or control group through purposeful sampling. Data were collected from March 2016 to November 2017 in the Thoracic Intensive Care Unit of a Medical Center in Taiwan. The Medical Research Council dyspnea scale, the COPD Self‐Efficacy Scale and the Clinical COPD Questionnaire were measured before education and at the first, second and third months after discharge. Results: The Medical Research Council dyspnea scale and COPD Self‐Efficacy Scale results in the experimental group were significantly improved compared with the control group in the third month after discharge. The Clinical COPD Questionnaire score continued to improve in both groups in the third month after discharge, and there was no difference between the two groups. Conclusion: A short‐term unsupervised home‐based pulmonary rehabilitation with self‐ management program had significant benefits for patients with COPD. The long‐term effects need to be confirmed. Summary statement: What is already known about this topic? The literature emphasizes the importance of alternative supervision of home‐based pulmonary rehabilitation rather than center‐based pulmonary rehabilitation for patients who find this inconvenient to access.Few studies have shown that unsupervised home‐based pulmonary rehabilitation can improve the clinical outcome of patients with chronic obstructive pulmonary disease (COPD). What this paper adds? This study demonstrates that a short‐term unsupervised home‐based pulmonary rehabilitation with self‐management program can improve dyspnea during physical activity, self‐care efficacy in certain activities and quality of life after discharge in patients with COPD. The implications of this paper: The findings of this study can be used as the basis for providing a short‐term unsupervised home‐based pulmonary rehabilitation with self‐management program for patients with COPD after discharge.We recommend that patients with COPD undergo unsupervised home‐based pulmonary rehabilitation with self‐management for 3 months after discharge, especially if regular hospital visits for this are not convenient.The effect of longer‐term unsupervised home‐based pulmonary rehabilitation can be further studied in the future. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether there is an association between subgingival microbial diversity and reduced respiratory function. Materials and Methods: A group of dentate 58–72‐year‐old men in Northern Ireland had a comprehensive periodontal examination including subgingival plaque sampling. DNA was extracted from plaque samples and the V1–V3 regions of the 16S rRNA gene were analysed by high‐throughput sequencing and a microbial diversity index (MDI) was derived. Spirometry measurements were made using a wedge bellows spirometer. The primary outcome variable of interest was the percentage of predicted forced expiratory volume in 1 s (% predicted FEV1). Analysis included multiple linear regression with adjustment for various confounders. Results: Five‐hundred and seven men were included in the analysis. The mean age was 63.6 years (SD = 3.1). Of these, 304 (60.0%) men had no or mild periodontitis, 105 (20.7%) had moderate periodontitis and 98 (19.3%) had severe periodontitis. Multiple linear regression analysis showed that a one unit increase in MDI was associated with a 0.71% loss (95% confidence interval: 0.06%–1.35%; p =.03) in % predicted FEV1 after adjustment for all confounders. Conclusions: In this group of dentate men from Northern Ireland, subgingival microbial diversity was associated with reduced respiratory function. [ABSTRACT FROM AUTHOR]

Millions of people worldwide have chronic obstructive pulmonary disease (COPD), and one of the most common and troublesome symptoms that must be managed is fatigue. While there are existing interventions to address COPD-related fatigue, not all patients experience benefit. A better understanding of the factors associated with COPD-fatigue could elucidate new approaches to address COPD-related fatigue, thereby offering relief to a greater number of patients. The purpose of this review was to identify the physiologic, psychologic, and situational factors associated with COPD-related fatigue. A total of four databases, PubMed, CINAHL, Scopus, and Google Scholar, were searched. Those that were peer reviewed, in English, and published between 2000 and 2021, were included in the review. A total of 25 articles were included in this scoping review. The following factors were related to fatigue in COPD: dyspnea, pain, anxiety, depression, and sleep. Fatigue is a debilitating symptom with factors influential to the symptom and outcomes. Research is indicated to explore targeted and personalized interventions addressing the factors related to fatigue to mitigate this widespread symptom. [ABSTRACT FROM AUTHOR]

Objectives. To verify the prevalence of frailty in patients hospitalized with acute exacerbation of COPD; to compare two frailty assessment methods: Edmonton Scale and the Fried Frailty Phenotype, and to associate frailty with functioning in these patients. Methods. Patients hospitalized due to an acute exacerbation of COPD were included. The assessment of pulmonary function, frailty, and functioning was performed. Frailty assessment was performed by the Edmonton Scale and Fried Frailty Phenotype. Individuals were classified into "frail," "pre-frail" and "non-frail." Functioning was evaluated by the one sit-to-stand test. Results. Thirty-five individuals were included (17 male, 69 ± 9 years; FEV1/FVC 47 ± 10%; FEV1 34 (24–52) % predicted). Participants scored 3 (3-4) points on the Edmonton Scale and 7 (5–9) points on the Fried Frailty Phenotype. According to the Fried model, 17% were considered prefrail and 83% frail and in the Edmonton scale, 20% were classified as nonfrail, 29% prefrail, and 51% frail. There was a positive moderate correlation between the two methods (r = 0.42; p = 0.011); however, there was no agreement between them (p = 0.20). This probably occurs because they assess the same construct, i.e., frailty; however, they are different in their components. There was a negative and moderate correlation between the Fried Frailty Phenotype and functioning (r = −0.43; p = 0.009). Conclusion. Most hospitalized individuals with exacerbated COPD with severe and very severe airflow limitation are frail and the assessment methods correlate, but there is no agreement. Additionally, there is association between frailty and functioning in this population. [ABSTRACT FROM AUTHOR]

Objective. To explore more efficient treatments for chronic obstructive pulmonary disease (COPD), effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) and electroacupuncture were tested on rats with COPD, and silent information regulator transcript-1 (SIRT1)/nuclear factor-kappaB (NF-κB) signaling was further investigated to interpret the therapy. Methods. In total, 70 rats were randomly divided into control (Control), model (Model), aminophylline (APL), ECC-BYF III, electroacupuncture (EA), ECC-BYF III+EA, and sham electroacupuncture (SA) groups. Cigarette smoke exposure combined with repeated bacterial infections was used to establish COPD models in 1–12 weeks. From 13 to 20 weeks, the ECC-BYF III and APL groups received corresponding drugs; the EA group received electroacupuncture therapy, wherein Dazhui (GV 14), Feishu (BL 13), and Shenshu (BL 23) points were selected; the ECC-BYF III+EA group received ECC-BYF III intragastrically combined with electroacupuncture; and the SA group received simulated electroacupuncture (nonacupoint). Pulmonary function, pulmonary histopathology, the expressions of SIRT1/NF-κB signaling, and inflammation-related mRNA and protein were detected. Results. Significant deterioration was observed in pulmonary function and pulmonary histopathology in rats with COPD (P < 0.01), and inflammatory state was illustrated by increased levels of interleukin- (IL-) 6 and tumor necrosis factor alpha (TNF-α) and decreased levels of IL-10 (P < 0.01). After the intervention of APL, ECC-BYF III, EA, and ECC-BYF III+EA, both pulmonary function and pulmonary histopathology were improved (P < 0.05 and P < 0.01), whereas the levels of IL-6 and TNF-α were decreased and IL-10 was increased (P < 0.05 and P < 0.01). Additionally, the mRNA expressions of IL-6, TNF-α, NF-κB, and acetylated NF-κBp65 (Ac-NF-κB) were noted to decrease, and SIRT1 and IL-10 were increased (P < 0.05 and P < 0.01); the protein expression of SIRT1 was upregulated, and NF-κBp65 and Ac-NF-κB were downregulated (P < 0.05 and P < 0.01). The effect of ECC-BYF III+EA was better in terms of improving pulmonary function and alleviating inflammation than that of the other treatment groups (P < 0.01 and P < 0.05). Conclusions. ECC-BYF III, electroacupuncture, and their combination can suppress inflammation, among which the combination therapy has been proven to be the most effective treatment, and the mechanism may be involved in activating SIRT1/NF-κB signaling. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation and symptoms such as shortness of breath. Although many studies have demonstrated dysregulated microRNA (miRNA) and gene (mRNA) expression in the pathogenesis of COPD, how miRNAs and mRNAs systematically interact and contribute to COPD development is still not clear. To gain a deeper understanding of the gene regulatory network underlying COPD pathogenesis, we used Sparse Multiple Canonical Correlation Network (SmCCNet) to integrate whole blood miRNA and RNA-sequencing data from 404 participants in the COPDGene study to identify novel miRNA–mRNA networks associated with COPD-related phenotypes including lung function and emphysema. We hypothesized that phenotype-directed interpretable miRNA–mRNA networks from SmCCNet would assist in the discovery of novel biomarkers that traditional single biomarker discovery methods (such as differential expression) might fail to discover. Additionally, we investigated whether adjusting -omics and clinical phenotypes data for covariates prior to integration would increase the statistical power for network identification. Our study demonstrated that partial covariate adjustment for age, sex, race, and CT scanner model (in the quantitative emphysema networks) improved network identification when compared with no covariate adjustment. However, further adjustment for current smoking status and relative white blood cell (WBC) proportions sometimes weakened the power for identifying lung function and emphysema networks, a phenomenon which may be due to the correlation of smoking status and WBC counts with the COPD-related phenotypes. With partial covariate adjustment, we found six miRNA–mRNA networks associated with COPD-related phenotypes. One network consists of 2 miRNAs and 28 mRNAs which had a 0.33 correlation (p = 5.40E-12) to forced expiratory volume in 1 s (FEV1) percent predicted. We also found a network of 5 miRNAs and 81 mRNAs that had a 0.45 correlation (p = 8.80E-22) to percent emphysema. The miRNA–mRNA networks associated with COPD traits provide a systems view of COPD pathogenesis and complements biomarker identification with individual miRNA or mRNA expression data. [ABSTRACT FROM AUTHOR]

Selective phosphodiesterase (PDE) inhibitors are a class of nonsteroid anti-inflammatory drugs for treating chronic inflammatory diseases. Modulation of systemic and airway inflammation is their pivotal mechanism of action. Furthermore, PDE inhibitors modulate cough reflex and inhibit airway mucus secretion. Roflumilast, a selective PDE4 inhibitor, has been extensively studied for the efficacy and safety in chronic obstructive pulmonary disease (COPD) patients. According to the mechanisms of action, the potential roles of PDE inhibitors in treating chronic respiratory diseases including severe asthma, asthma-COPD overlap (ACO), noncystic fibrosis bronchiectasis, and chronic cough are discussed. Since roflumilast inhibits airway eosinophilia and neutrophilia in COPD patients, it reduces COPD exacerbations in the presence of chronic bronchitis in addition to baseline therapies. The clinical studies in asthma patients have shown the comparable efficacy of roflumilast to inhaled corticosteroids for improving lung function. However, the clinical trials of roflumilast in severe asthma have been limited. Although ACO is common and is also associated with poor outcomes, there is no clinical trial regarding its efficacy in patients with ACO despite a promising role in reducing COPD exacerbation. Since mucus hypersecretion is a result of neutrophil secretagogue in patients with chronic bronchitis, experimental studies have shown that PDE4s are regulators of the cystic fibrosis transmembrane conductance regulator (CFTR) in human airway epithelial cells. Besides, goblet cell hyperplasia is associated with an increased expression of PDE. Bronchiectasis and chronic bronchitis are considered neutrophilic airway diseases presenting with mucus hypersecretion. They commonly coexist and thus lead to severe disease. The role of roflumilast in noncystic fibrosis bronchiectasis is under investigation in clinical trials. Lastly, PDE inhibitors have been shown modulating cough from bronchodilation, suppressing transient receptors potential (TRP), and anti-inflammatory properties. Hence, there is the potential role of the drug in the management of unexplained cough. However, clinical trials for examining its antitussive efficacy are pivotal. In conclusion, selective PDE4 inhibitors may be potential treatment options for chronic respiratory diseases apart from COPD due to their promising mechanisms of action. [ABSTRACT FROM AUTHOR]

This study was to explore the use of convolutional neural network (CNN) for the classification and recognition of computerized tomography (CT) images of chronic obstructive pulmonary disease (COPD) and the therapeutic effect of clarithromycin combined with salmeterol/fluticasone. First, the clinical data of COPD patients treated in hospital from September 2018 to December 2020 were collected, and CT and X-ray images were also collected. CT-CNN and X ray-CNN single modal models were constructed based on the LeNet-5 model. The randomized fusion algorithm was introduced to construct a fused CNN model for the diagnosis of COPD patients, and the recognition effect of the model was verified. Subsequently, the three-dimensional reconstruction of the patient's bronchus was performed using the classified CT images, and the changes of CT quantitative parameters in COPD patients were compared and analyzed. Finally, COPD patients were treated with salmeterol/fluticasone (COPD-C) and combined with clarithromycin (COPD-T). In addition, the differences between patients' lung function indexes, blood gas indexes, St. George respiratory questionnaire (SGRQ) scores, and the number of acute exacerbations (AECOPD) before and after treatment were evaluated. The results showed that the randomized fusion model under different iteration times and batch sizes always had the highest recognition rate, sensitivity, and specificity compared to the two single modal CNN models, but it also had longer training time. After CT images were used to quantitatively evaluate the changes of the patient's bronchus, it was found that the area of the upper and lower lung lobes of the affected side of COPD patients and the ratio of the area of the tube wall to the bronchus were significantly changed. The lung function, blood gas index, and SGRQ score of COPD-T patients were significantly improved compared with the COPD-C group (P < 0.05), but there was no considerable difference in AECOPD (P > 0.05). In summary, the randomized fusion-based CNN model can improve the recognition rate of COPD, and salmeterol/fluticasone combined with clarithromycin therapy can significantly improve the clinical treatment effect of COPD patients. [ABSTRACT FROM AUTHOR]

Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved. [ABSTRACT FROM AUTHOR]

Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Mucus hypersecretion and chronic airway inflammation are standard characteristics of several airway diseases, such as chronic obstructive pulmonary disease and asthma. Increased mucus secretion from increased mucin gene expression in the airway epithelium is associated with poor prognosis and mortality. We previously showed that the absence of tissue inhibitor of metalloproteinase 1 (TIMP-1) enhances lung inflammation, airway hyperreactivity, and lung remodeling in asthma in an ovalbumin (OVA) asthma model of TIMP-1 knockout (TIMPKO) mice as compared to wild-type (WT) controls and mediated by increased galectin-3 (Gal-3) levels. Additionally, we have shown that in the lung epithelial cell line A549, Gal-3 inhibition increases interleukin-17 (IL-17) levels, leading to increased mucin expression in the airway epithelium. Therefore, in the current study, we further examined the relationship between Gal-3 and the production of IL-17-axis cytokines and critical members of the mucin family in the murine TIMPKO asthma model and the lung epithelium cell line A549. While Gal-3 may regulate a Th1/Th2 response, IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. Gal-3 and IL-17 interactions induce mucus expression in OVA-sensitized mice. We conclude that Gal-3 may play an essential role in the pathogenesis of asthma, and modulation of Gal-3 may prove helpful in the treatment of this disease. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying differences in the susceptibility to chronic obstructive pulmonary disease (COPD) exacerbations between patients are not well understood. Recent studies have shown that the patients with frequent COPD exacerbations is related to specific protein expression in lung tissue. Anterior gradient 3 (AGR3) is expressed in airway epithelial cells in the lung and proteomic analysis revealed that its expression is decreased in patients with frequent COPD exacerbations. Moreover, the loss of epithelial integrity might facilitate trans-epithelial permeability of pathogens in such patients. This study was performed to determine that AGR3 protein play a role in COPD frequency exacerbators. Methods: Human lung tissues were collected from current-smoking patients (Control; n = 15) as well as patients with infrequent COPD exacerbations (IFCOPD; n = 18) and frequent COPD exacerbations (FCOPD; n = 8). While AGR3 protein expression was measured by immunohistochemistry and western blotting, AGR mRNA expression was determined by real time quantitative polymerase chain reaction (RT-qPCR). Furthermore, adherent junctions (AJs) and tight junctions (TJs) protein expression in human lung tissues were measured by immunohistochemistry. The effects of cigarette smoke extract (CSE) on AJ and TJ protein and mRNA expression in BEAS-2B cells were assessed by western blotting and RT-qPCR. In addition, the effect of AGR3 overexpression and knockdown on AJ and TJ protein expression was determined. Results: AGR3 was mainly expressed in the airway epithelium and AGR3-positive products were localized in the cytoplasm. Western blotting and RT-qPCR results showed that AGR3 protein (p = 0.009) and mRNA (p = 0.04) expression in the FCOPD group was significantly lower than that in the IFCOPD group. Moreover, E-cadherin, occludin, and zonula occludens-1 (ZO-1) expression was lower in the FCOPD group than in the IFCOPD group. The protein and mRNA expression of E-cadherin, occludin, and ZO-1 was decreased within 24 h post-CSE exposure. AGR3 overexpression rescued CSE-induced downregulation of E-cadherin, occludin, and ZO-1. Conclusion: Difference in AGR3 expression in the lung tissue might be correlated with increased susceptibility to COPD exacerbation. AGR3 can prevent CSE-induced downregulation of E-cadherin, occludin, and ZO-1 in airway epithelial cells. Loss of AGR3 might promote viral and bacterial infection and induce immune inflammation to increase COPD exacerbation. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by chronic inflammation upon inhalation of noxious particles, e.g., cigarette smoke. FAM13A is one of the genes often found to be associated with COPD, however its function in the pathophysiology of COPD is incompletely understood. We studied its role in airway epithelial barrier integrity and cigarette smoke-induced epithelial responses. Materials and Methods: Protein level and localization of FAM13A was assessed with immunohistochemistry in lung tissue from COPD patients and non-COPD controls. In vitro , FAM13A expression was determined in the absence or presence of cigarette smoke extract (CSE) in primary airway epithelial cells (AECs) from COPD patients and controls by western blotting. FAM13A was overexpressed in cell line 16HBE14o- and its effect on barrier function was monitored real-time by electrical resistance. Expression of junctional protein E-cadherin and β-catenin was assessed by western blotting. The secretion of neutrophil attractant CXCL8 upon CSE exposure was measured by ELISA. Results: FAM13A was strongly expressed in airway epithelium, but significantly weaker in airways of COPD patients compared to non-COPD controls. In COPD-derived AECs, but not those of controls, FAM13A was significantly downregulated by CSE. 16HBE14o- cells overexpressing FAM13A built up epithelial resistance significantly more rapidly, which was accompanied by higher E-cadherin expression and reduced CSE-induced CXCL8 levels. Conclusion: Our data indicate that the expression of FAM13A is lower in airway epithelium of COPD patients compared to non-COPD controls. In addition, cigarette smoking selectively downregulates airway epithelial expression of FAM13A in COPD patients. This may have important consequences for the pathophysiology of COPD, as the more rapid build-up of epithelial resistance upon FAM13A overexpression suggests improved (re)constitution of barrier function. The reduced epithelial secretion of CXCL8 upon CSE-induced damage suggests that lower FAM13A expression upon cigarette smoking may facilitate epithelial-driven neutrophilia. [ABSTRACT FROM AUTHOR]

Background. Esophageal cancer is one of the leading causes of cancer-related death worldwide. Despite the significant progress in the overall treatment of esophageal cancer in recent years, the prognosis for patients who require surgery remains poor. Methods. The present study investigated the clinicopathological features of 503 patients who underwent radical esophagectomy at Huashan Hospital of Fudan University between January 2005 and January 2015. Nomograms that predicted the esophageal squamous cell carcinoma (ESCC) survival rates were established using the Cox proportional hazard regression model. Discrimination and calibration, which were calculated after bootstrapping, were used as a measure of accuracy. Results. Multivariate analyses were used to select five independent prognostic variables and build the nomogram. These variables were pathological T stage, pathological N factor, rate of positive LNs, history of chronic obstructive pulmonary disease (COPD) and postoperative sepsis. The nomogram was built to predict the rates for overall survival (OS) and disease-free survival (DFS). The concordance index for the nomogram prediction for OS and DFS was 0.720 and 0.707, respectively. Compared to the conventional TNM staging system, the nomogram had better predictive accuracy for survival (OS 0.720 vs. 0.672, P < 0.001 ; DFS 0.707 vs. 0.667; P < 0.001). Conclusions. The present study incorporated pathological T stage, pathological N factor, rate of positive LNs, history of COPD, and postoperative sepsis into a nomogram to predict the OS and DFS of ESCC patients. This practical system may help clinicians in both decision-making and clinical study design. The assessment of lung function for patients with COPD preoperative, and the control of disease progression are needed. Furthermore, the postoperative infection of patients should be controlled. Further studies may help to extend the validation of this method and improve the model through parameter optimization. [ABSTRACT FROM AUTHOR]

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Glycosylation represents one of the most abundant posttranslational modification of proteins. Glycosylation products are diverse and are regulated by the cooperative action of various glycosyltransferases, glycosidases, substrates thereof: nucleoside sugars and their transporters, and chaperons. In this article, we focus on a glycosyltransferase, α1,6-fucosyltransferase (Fut8) and its product, the core fucose structure on N-glycans, and summarize the potential protective functions of this structure against emphysema and chronic obstructive pulmonary disease (COPD). Studies of FUT8 and its enzymatic product, core fucose, are becoming an emerging area of interest in various fields of research including inflammation, cancer and therapeutics. This article discusses what we can learn from studies of Fut8 and core fucose by using knockout mice or in vitro studies that were conducted by our group as well as other groups. We also include a discussion of the potential protective functions of the keratan sulfate (KS) disaccharide, namely L4, against emphysema and COPD as a glycomimetic. Glycomimetics using glycan analogs is one of the more promising therapeutics that compensate for the usual therapeutic strategy that involves targeting the genome and the proteome. These typical glycans using KS derivatives as glycomimetics, will likely become a clue to the development of novel and effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long‐term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex disease caused by the disturbance of genetic and environmental factors. Single-nucleotide polymorphisms (SNPs) play a vital role in the genetic dissection of complex diseases. In-depth analysis of SNP-related information could recognize disease-associated biomarkers and further uncover the genetic mechanism of complex diseases. Risk-related variants might act on the disease by affecting gene expression and gene function. Through integrating SNP disease association study and expression quantitative trait loci (eQTL) analysis, as well as functional enrichment of containing known causal genes, four risk SNPs and four corresponding susceptibility genes were identified utilizing next-generation sequencing (NGS) data of COPD. Of the four risk SNPs, one could be found in the SNPedia database that stored disease-related SNPs and has been linked to a disease in the literature. Four genes showed significant differences from the perspective of normal/disease or variant/nonvariant samples, as well as the high performance of sample classification. It is speculated that the four susceptibility genes could be used as biomarkers of COPD. Furthermore, three of our susceptibility genes have been confirmed in the literature to be associated with COPD. Among them, two genes had an impact on the significance of expression correlation of known causal genes they interact with, respectively. Overall, this research may present novel insights into the diagnosis and pathogenesis of COPD and susceptibility gene identification of other complex diseases. [ABSTRACT FROM AUTHOR]

Rationale. Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is highly heterogeneous with a plethora of different etiologic factors and inflammatory presentations. COPD with higher blood eosinophil count is associated with increased readmission rates and better corticosteroid responses. However, the clinical features of eosinophilic AECOPD are not well explored. Thus, this study was aimed at exploring the clinical differences between eosinophilic and noneosinophilic AECOPD. Methods. A total of 643 AECOPD patients were enrolled in this multicenter cross-sectional study. Finally, 455 were included, 214 in the normal-eosinophil AECOPD (NEOS-AECOPD) group, 63 in the mild increased-eosinophil AECOPD (MEOS-AECOPD) group, and 138 in the severe increased-eosinophil AECOPD (SEOS-AECOPD) group. Demographic data, underlying diseases, symptoms, and laboratory findings were collected. Multiple logistic regression analysis was performed to identify the independent factors associated with blood eosinophils (EOS). Correlations between blood EOS and its associated independent factors were evaluated. Results. The significant differences in 19 factors, including underlying diseases, clinical symptoms, and laboratory parameters, were identified by univariate analysis. Subsequently, multiple logistic regression analysis revealed that lymphocyte%, neutrophil% (NS%), procalcitonin (PCT), and anion gap (AG) were independently associated with blood EOS in AECOPD. Both blood EOS counts and EOS% were significantly correlated with lymphocyte%, NS%, PCT, and AG. Conclusions. Collectively, blood EOS was independently associated with lymphocyte%, NS%, PCT, and AG in AECOPD patients. Lymphocyte% was lower, and NS%, PCT, and AG were higher in eosinophilic AECOPD. Our results indicate that viral-dominant infections are the probable major etiologies of eosinophilic AECOPD. Noneosinophilic AECOPD is more likely associated with bacterial-dominant infections. The systemic inflammation in noneosinophilic AECOPD was more severe. [ABSTRACT FROM AUTHOR]

Background: Genetic association studies have identified single nucleotide polymorphisms (SNPs) related to chronic obstructive pulmonary disease (COPD) susceptibility. The aim of this study was to identify HHIP genetic variants associated with COPD, pulmonary function, and serum and sputum HHIP protein levels in Mexican mestizo smokers. Materials and Methods: Association analysis was performed by carrying out a case–control study in Mexican mestizo smokers comprised of two groups: tobacco-smoking subjects with COPD (COPD-TS, n = 222) and smokers without COPD (SWOC, n = 333). We evaluated three SNPs (rs13147758, rs1828591, and rs13118928) in the HHIP gene. Allele discrimination was accomplished by qPCR using TaqMan probes, and determination of protein levels in the serum and sputum supernatants (SS) was performed using ELISA. Results: Statistically significant differences were observed in the rs13147758 GG genotype (adjusted p = 0.014, OR = 1.95) and the rs13147758-rs1828591 GA haplotype (p = 6.6E-06, OR = 2.65) in the case–control comparison. HHIP protein levels were elevated in SS samples from the COPD-TS group compared to those from the SWOC group (p = 0.03). Based on genotype analysis, HHIP protein levels were lower in the serum samples of rs13147758 GG genotype carriers in the COPD-TS group than in the serum samples of rs13147758 GG genotype carriers from the SWOC group (p < 0.05), but there were no differences in the sputum samples. Conclusion: The rs13147758 GG genotype and the rs13147758-rs1828591 GA haplotype are associated with susceptibility to COPD. Furthermore, an association in protein levels was observed between the HHIP rs13147758 genotype and COPD in Mexican mestizo smokers. [ABSTRACT FROM AUTHOR]

The impact of a history of competitive sports on later smoking behaviour and occurrence of chronic pulmonary diseases is poorly known. We investigated how a history of elite level sports predicted later pulmonary disease morbidity and mortality. Chronic pulmonary disease incidence was assessed from national hospital and cause-of-death registers from 1970 to 2015 among Finnish male former elite athletes (n = 2078) and matched controls (n = 1453) alive in 1970 (mean age 45.0 years). Hazard ratios (HRs) were calculated by Cox proportional hazards model. In 1985, cohort members reported on their smoking habits, engagement in physical activity/sports and physician-diagnosed chronic diseases. The risk of any chronic pulmonary disease or death was lower among former athletes than controls (age-adjusted HR 0.61; 95% CI 0.46–0.83). The risk was significantly lower among endurance (HR 0.54), mixed (HR 0.61), and power sports athletes (HR 0.66) compared to controls. The age- and smoking pack-year-adjusted HRs of incident diseases from the time of the 1985 questionnaire until the end of follow-up in former athletes was 0.58 (95% CI 0.37–0.93) compared to controls. In 1985 athletes smoked less and their cumulative smoking quantity was lower than that of controls. Former athletes were more physically active and self-reported less physician-diagnosed emphysema. The risk of any chronic pulmonary disease was lower among former athletes than controls even after considering smoking status and cumulative smoking quantity. Ability to compete at the highest level of sports in young adulthood associated with a reduced risk of pulmonary disease in later life. [ABSTRACT FROM AUTHOR]

Self‐management helps patients understand their illnesses and learn about disease‐related skills so they can better manage their situation. However, published studies on the effectiveness of self‐management for chronic obstructive pulmonary disease (COPD) are heterogeneous. Quasi‐experimental design was used to investigate the effectiveness of a self‐management program in self‐care efficacy and quality of life in patients with COPD. Sixty participants who had experienced COPD were assigned to control group (usual care) or experimental group (self‐care program) (1:1 ratio) according to a purposeful sampling at a Medical Center in Taiwan. The Medical Research Council dyspnea scale, the COPD Self‐Efficacy Scale, the Clinical COPD Questionnaire were used to analyze data. The Medical Research Council dyspnea scale was more significant improvement in the 2 months after discharge in the experimental group than in the control group. The COPD Self‐Efficacy Scale and Clinical COPD Questionnaire scores in the experimental group within 3 months after discharge were significantly improved compared with the control group. These findings demonstrate the application and initial effect of this self‐management program. [ABSTRACT FROM AUTHOR]

Human body surfaces, such as the skin, intestines, and respiratory and urogenital tracts, are colonized by a large number of microorganisms, including bacteria, fungi, and viruses, with the gut being the most densely and extensively colonized organ. The microbiome plays an essential role in immune system development and tissue homeostasis. Gut microbiota dysbiosis not only modulates the immune responses of the gastrointestinal (GI) tract but also impacts the immunity of distal organs, such as the lung, further affecting lung health and respiratory diseases. Here, we review the recent evidence of the correlations and underlying mechanisms of the relationship between the gut microbiota and common respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), lung cancer, and respiratory infection, and probiotic development as a therapeutic intervention for these diseases. [ABSTRACT FROM AUTHOR]

Objective. To improve pulmonary function, exercise capacity and quality of life of two women with Chronic Obstructive Pulmonary Disease (COPD). Material and Methods. Study of two clinical cases, both women. An intervention of 8 weeks was performed, in which the patients performed 3 weekly sessions, of which 1 was performed with supervision of the physiotherapist and 2 sessions were performed at home. The treatment sessions consisted of inspiratory muscle training with an inspiratory threshold and controlled breathing exercises with the pursed lip technique. Results. Quality of life of both women improved at the end of the study. In the woman with severe COPD, Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure (MEP) increased after the intervention. The Peak Expiratory Flow (PEF) improved in both cases, but not the rest of the spirometric values. Dyspnea improved in the woman with moderate COPD but not in the case of the one with severe COPD. Finally, the distance walked in the 6MWT improved in both cases. Conclusions. The training of the inspiratory muscles together with the pursed lip technique positively influences quality of life and exercise capacity of two women with COPD. [ABSTRACT FROM AUTHOR]

Human rhinoviruses (HRVs) are associated with acute exacerbations in patients with chronic obstructive pulmonary disease (COPD) and asthma, which are accompanied by mucus hypersecretion. Whereas, various studies have shown that HRVs increase epithelial mucin production and thus may directly contribute to mucus hypersecretion. The effects of drugs used in the treatment of COPD and asthma on HRV-induced mucin production in epithelial cell cultures have not been studied. In the present study, we assessed effects of HRVs on mucin production and secretion in well-differentiated primary human bronchial epithelial cells (PBEC) and studied the effect of the inhaled corticosteroid fluticasone propionate and the long-acting muscarinic antagonist tiotropium bromide on this process. Differentiated PBEC that were cultured at the air-liquid interface (ALI-PBEC) were infected with HRV-A16 and HRV-1B. Quantitative PCR, immunofluorescence staining, ELISA, periodic acid-Schiff (PAS) staining and immunostaining assays were used to assess the effects of HRV infection. Here we demonstrate that both HRV-A16 and HRV-1B increased mucin (MUC5AC and MUC5B) gene expression and protein release. When exploring this in more detail in HRV-A16-infected epithelial cells, mucin expression was found to be accompanied by increases in expression of SAM-pointed domain-containing Ets-like factor (SPDEF) and SPDEF-regulated genes known to be involved in the regulation of mucin production. We also found that pre-treatment with the purinergic P2R antagonist suramin inhibits HRV-enhanced MUC5AC expression and protein release, implicating involvement of purinergic signaling by extracellular ATP. We furthermore found that both fluticasone and tiotropium decreased HRV-induced mucin production without affecting viral replication, and obtained evidence to suggest that the inhibitory effect of fluticasone involved modulation of SPDEF-regulated genes and extracellular ATP release. These data show that both tiotropium and fluticasone inhibit HRV-induced epithelial mucin production independent of viral clearance, and thus provide insight into the mechanisms underlying beneficial effects of tiotropium and fluticasone in the treatment of COPD, asthma and accompanying exacerbations in these patients. Furthermore, our findings provide additional insight into the mechanisms by which HRV increases epithelial mucin production. [ABSTRACT FROM AUTHOR]

This study aimed to identify symptom clusters of chronic obstructive pulmonary disease (COPD) and to examine the relationship between symptom clusters and health-related quality of life (HRQoL). It included 154 hospitalized patients with COPD. The majority of the participants (88.6%) were aged 60 years and above, and the numbers of men and women were approximately equal (men: 55.2%). The Charlson Comorbidity Index (CCI), the Memorial Symptom Assessment Scale (MSAS), and the Chinese version of the Clinical COPD Questionnaire (CCQ) were used to evaluate comorbidity, participant's symptoms, and HRQoL, respectively. Five symptom clusters were identified using exploratory factor analysis, and symptom clusters, especially the Psychological, Pain and Fatigue, GI, and Dyspnea-Sweat symptom clusters, had negative effects on HRQoL in patients with COPD. Understanding the patterns and occurrences of symptom clusters could be essential for developing effective interventions to manage COPD symptoms and improve the patients' HRQoL. [ABSTRACT FROM AUTHOR]

Keywords: health status; COPD; (MCID) minimal clinically important difference; St. George's Respiratory Questionnaire; patient-reported outcomes EN health status COPD (MCID) minimal clinically important difference St. George's Respiratory Questionnaire patient-reported outcomes 1 4 4 06/05/20 20200602 NES 200602 Introduction Pharmacological clinical trials require obligatory endpoints in evaluating the clinical relevance of their outcomes ([13]; [17]). The most frequently selected health status instrument in scientific research is the St. George's Respiratory Questionnaire (SGRQ) with a proclaimed MCID of four units on a total scale from 0 to 100 ([11]; [17]; [12]). In a published systematic review in the I European Respiratory Journal i , Alma et al. ([3]) reviewed the available content on the MCID of COPD health status tools including the SGRQ ([3]). Assessing health status over time: impact of recall period and anchor question on the minimal clinically important difference of copd health status tools. [Extracted from the article]

More and more clinical observations have implied that microbes have great effects on human diseases. Understanding the relations between microbes and diseases are of profound significance for disease prevention and therapy. In this paper, we propose a predictive model based on the known microbe-disease associations to discover potential microbe-disease associations through integrating Learning Graph Representations and a modified Scoring mechanism on the Heterogeneous network (called LGRSH). Firstly, the similarity networks for microbe and disease are obtained based on the similarity of Gaussian interaction profile kernel. Then, we construct a heterogeneous network including these two similarity networks and microbe-disease associations' network. After that, the embedding algorithm Node2vec is implemented to learn representations of nodes in the heterogeneous network. Finally, according to these low-dimensional vector representations, we calculate the relevance between each microbe and disease by utilizing a modified rule-based inference method. By comparison with three other methods including LRLSHMDA, KATZHMDA and BiRWHMDA, LGRSH performs better than others. Moreover, in case studies of asthma, Chronic Obstructive Pulmonary Disease and Inflammatory Bowel Disease, there are 8, 8, and 10 out of the top-10 discovered disease-related microbes were validated respectively, demonstrating that LGRSH performs well in predicting potential microbe-disease associations. [ABSTRACT FROM AUTHOR]