Onset Of COPD Research Articles

Sex-biased Regulation of Extracellular Matrix Genes in COPD.

Compared to men, women often develop COPD at an earlier age with worse respiratory symptoms despite lower smoking exposure. However, most preventive, and therapeutic strategies ignore biological sex differences in COPD. Our goal was to better understand sex-specific gene regulatory processes in lung tissue and the molecular basis for sex differences in COPD onset and severity. We analyzed lung tissue gene expression and DNA methylation data from 747 individuals in the Lung Tissue Research Consortium (LTRC), and 85 individuals in an independent dataset. We identified sex differences in COPD-associated gene regulation using gene regulatory networks. We used linear regression to test for sex-biased associations of methylation with lung function, emphysema, smoking, and age. Analyzing gene regulatory networks in the control group, we identified that genes involved in the extracellular matrix (ECM) have higher transcriptional factor targeting in females than in males. However, this pattern is reversed in COPD, with males showing stronger regulatory targeting of ECM-related genes than females. Smoking exposure, age, lung function, and emphysema were all associated with sex-specific differential methylation of ECM-related genes. We identified sex-based gene regulatory patterns of ECM-related genes associated with lung function and emphysema. Multiple factors including epigenetics, smoking, aging, and cell heterogeneity influence sex-specific gene regulation in COPD. Our findings underscore the importance of considering sex as a key factor in disease susceptibility and severity.

Novel insights into the pathological features of COPD: Focus on oxidative stress and mitophagy

AbstractChronic airway obstructive pulmonary disease (COPD) is a preventable and curable disease characterised by persistent airflow limitation. It is characterised by chronic bronchitis and/or emphysema, and its aetiology is related to various factors such as smoking and infectious factors, and so forth. The pathogenesis is complex and prone to frequent exacerbations, and the prognosis of acute exacerbations of COPD is often poor. As a crucial component of the innate immune system, lung macrophages significantly influence the onset and progression of COPD. When macrophage mitochondria become dysfunctional, many macrophage functions (e.g., phagocytosis, cytokine secretion, chemotaxis, etc.) change. The aim of this paper is to describe the three major pathological features of COPD (oxidative stress imbalance, macrophage polarisation and mitochondrial membrane potential [MMP] production and mitochondrial autophagy), to describe in detail the mechanism of mitochondrial autophagy pathway and its association with oxidative stress and macrophage polarisation and to emphasise the role of macrophage mitochondrial reactive oxygen species (mROS) in COPD, with the aim of providing ideas and directions for subsequent studies.

Breathing new life into the study of COPD with genes identified from genome-wide association studies.

COPD is a major cause of morbidity and mortality globally. While the significance of environmental exposures in disease pathogenesis is well established, the functional contribution of genetic factors has only in recent years drawn attention. Notably, many genes associated with COPD risk are also linked with lung function. Because reduced lung function precedes COPD onset, this association is consistent with the possibility that derangements leading to COPD could arise during lung development. In this review, we summarise the role of leading genes (HHIP, FAM13A, DSP, AGER and TGFB2) identified by genome-wide association studies in lung development and COPD. Because many COPD genome-wide association study genes are enriched in lung epithelial cells, we focus on the role of these genes in the lung epithelium in development, homeostasis and injury.

Extracellular vesicle dynamics in COPD: understanding the role of miR-422a, SPP1 and IL-17 A in smoking-related pathology

BackgroundChronic obstructive pulmonary disease (COPD) induced by smoking poses a significant global health challenge. Recent findings highlight the crucial role of extracellular vesicles (EVs) in mediating miRNA regulatory networks across various diseases. This study utilizes the GEO database to uncover distinct expression patterns of miRNAs and mRNAs, offering a comprehensive understanding of the pathogenesis of smoking-induced COPD. This study aims to investigate the mechanisms by which extracellular vesicles (EVs) mediate the molecular network of miR-422a-SPP1 to delay the onset of COPD caused by smoking.MethodsThe smoking-related miRNA chip GSE38974-GPL7723 was obtained from the GEO database, and candidate miRs were retrieved from the Vesiclepedia database. Downstream target genes of the candidate miRs were predicted using mRNA chip GSE38974-GPL4133, TargetScan, miRWalk, and RNA22 databases. This prediction was integrated with COPD-related genes from the GeneCards database, downstream target genes predicted by online databases, and key genes identified in the core module of WGCNA analysis to obtain candidate genes. The candidate genes were subjected to KEGG functional enrichment analysis using the “clusterProfiler” package in R language, and a protein interaction network was constructed. In vitro experiments involved overexpressing miRNA or extracting extracellular vesicles from bronchial epithelial cell-derived exosomes, co-culturing them with myofibroblasts to observe changes in the expression levels of the miR-422a-SPP1-IL-17 A regulatory network, and assessing protein levels of fibroblast differentiation-related factors α-SMA and collagen I using Western blot analysis.ResultsThe differential gene analysis of chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Subsequently, an intersection was taken among the prediction results from TargetScan, miRWalk, and RNA22 databases, the COPD-related gene retrieval results from GeneCards database, the WGCNA analysis results of chip GSE38974-GPL4133, and the differential gene analysis results. This intersection, combined with KEGG functional enrichment analysis, and protein-protein interaction analysis, led to the final screening of the target gene SPP1 and its upstream regulatory gene miR-422a. KEGG functional enrichment analysis of mRNAs correlated with SPP1 revealed the IL-17 signaling pathway involved. In vitro experiments demonstrated that miR-422a inhibition targets suppressed the expression of SPP1 in myofibroblasts, inhibiting differentiation phenotype. Bronchial epithelial cells, under cigarette smoke extract (CSE) stress, could compensate for myofibroblast differentiation phenotype by altering the content of miR-422a in their Extracellular Vesicles (EVs).ConclusionThe differential gene analysis of Chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Further analysis involved the intersection of predictions from TargetScan, miRWalk, and RNA22 databases, gene search on COPD-related genes from the GeneCards database, WGCNA analysis from Chip GSE38974-GPL4133, and differential gene analysis, combined with KEGG functional enrichment analysis and protein interaction analysis. Ultimately, the target gene SPP1 and its upstream regulatory gene miR-422a were selected. KEGG functional enrichment analysis on mRNAs correlated with SPP1 revealed the involvement of the IL-17 signaling pathway. In vitro experiments showed that miR-422a targeted inhibition suppressed the expression of SPP1 in myofibroblast cells, inhibiting differentiation phenotype. Furthermore, bronchial epithelial cells could compensate for myofibroblast differentiation phenotype under cigarette smoke extract (CSE) stress by altering the miR-422a content in their extracellular vesicles (EVs).

The Genetics behind Sulfation: Impact on Airway Remodeling.

In COPD, chronic inflammation and exposure to irritants, such as cigarette smoke, lead to the thickening of bronchial walls. This results from increased deposition of collagen and other extracellular matrix components, contributing to the narrowing of airways. Nevertheless, it is widely recognized that COPD is an inflammatory disorder marked by partially reversible airflow limitation wherein genetic factors interact with the environment. In recent years, numerous investigations have substantiated the correlation between gene polymorphisms and COPD. SUMF1 has been implicated in diverse cellular processes, including lysosomal function and extracellular matrix maintenance, both of which play pivotal roles in respiratory health. The genetic variations in SUMF1 could lead to an imbalanced sulfation in the extracellular matrix of lung tissue, potentially playing a role in the onset of COPD. Recent studies have uncovered a potential link between dysregulation of SUMF1 and COPD progression, shedding light on its involvement in the abnormal sulfatase activity observed in COPD patients. Through a comprehensive review of current literature and experimental findings, this article aims to contribute to the growing body of knowledge surrounding the genetic intricacies concerning sulfation of airway remodeling and possible pharmacological applications in COPD and asthma management.

The Genetics behind Sulfation: Impact on Airway Remodeling

In COPD, chronic inflammation, and exposure to irritants, such as cigarette smoke, leads to the thickening of bronchial walls. This results from increased deposition of collagen and other extracellular matrix components, contributing to the narrowing of airways. Nevertheless, it is widely recognized that COPD is an inflammatory disorder marked by partially reversible airflow limitation wherein genetic factors interact with the environment. In recent years, numerous investigations have substantiated the correlation between gene polymorphisms and COPD. SUMF1 has been implicated in diverse cellular processes, including lysosomal function and extracellular matrix maintenance, both of which play pivotal roles in respiratory health. The genetic variations in SUMF1 could lead to an imbalanced sulfation in the extracellular matrix of lung tissue, potentially playing a role in the onset of COPD. Recent studies have uncovered a potential link between dysregulation of SUMF1 and COPD progression, shedding light on its involvement in the abnormal sulfatase activity observed in COPD patients. Through a comprehensive review of current literature and experimental findings, this article aims to contribute to the growing body of knowledge surrounding the genetic intricacies concerning sulfation, of airway remodeling and possible pharmacological applications in COPD and asthma management.

α1-Antitrypsin deficiency associated with increased risk of heart failure.

Individuals with α1-antitrypsin deficiency have increased elastase activity resulting in continuous degradation of elastin and early onset of COPD. Increased elastase activity may also affect elastic properties of the heart, which may impact risk of heart failure. We tested the hypothesis that α1-antitrypsin deficiency is associated with increased risk of heart failure in two large populations. In a nationwide nested study of 2209 patients with α1-antitrypsin deficiency and 21 869 controls without α1-antitrypsin deficiency matched on age, sex and municipality, we recorded admissions and deaths due to heart failure during a median follow-up of 62 years. We also studied a population-based cohort of another 102 481 individuals from the Copenhagen General Population Study including 187 patients from the Danish α1-Antitrypsin Deficiency Registry, all with genetically confirmed α1-antitrypsin deficiency. Individuals with versus without α1-antitrypsin deficiency had increased risk of heart failure hospitalisation in the nationwide cohort (adjusted hazard ratio 2.64, 95% CI 2.25-3.10) and in the population-based cohort (1.77, 95% CI 1.14-2.74). Nationwide, these hazard ratios were highest in those without myocardial infarction (3.24, 95% CI 2.70-3.90), without aortic valve stenosis (2.80, 95% CI 2.38-3.29), without hypertension (3.44, 95% CI 2.81-4.22), without atrial fibrillation (3.33, 95% CI 2.75-4.04) and without any of these four diseases (6.00, 95% CI 4.60-7.82). Hazard ratios for heart failure-specific mortality in individuals with versus without α1-antitrypsin deficiency were 2.28 (95% CI 1.57-3.32) in the nationwide cohort and 3.35 (95% CI 1.04-10.74) in the population-based cohort. Individuals with α1-antitrypsin deficiency have increased risk of heart failure hospitalisation and heart failure-specific mortality in the Danish population.

MCP-4 and Eotaxin-3 Are Novel Biomarkers for Chronic Obstructive Pulmonary Disease.

The aim of our study was to examine the production of monocyte chemoattractant protein (MCP-4) and eotaxin-3 during the onset and progression of COPD. The expression levels of MCP-4 and eotaxin-3 were evaluated in COPD samples and healthy controls using immunostaining and ELISA. The relationship between the clinic pathological features in the participants and the expression of MCP-4 and eotaxin-3 were evaluated. The association of MCP-4/eotaxin-3 production in COPD patients was also determined. The results revealed enhanced production of MCP-4 and eotaxin-3 in COPD patients especially the cases with AECOPD in both bronchial biopsies and bronchial washing fluid samples. Furthermore, the expression signatures of MCP-4/eotaxin-3 show high AUC values in distinguishing COPD patients and healthy volunteers and AECOPD and stable COPD cases, respectively. Additionally, the number of MCP-4/eotaxin-3 positive cases was notably increased in AECOPD patients compared to those with stable COPD. Moreover, the expression of MCP-4 and eotaxin-3 was positively correlated in COPD and AECOPD cases. In addition, the levels of MCP-4 and eotaxin-3 could be increased in HBEs stimulated with LPS, which is a risk factor of COPD. Moreover, MCP-4 and eotaxin-3 may exert their regulatory functions in COPD by regulating CCR2, 3, and 5. These data indicated that MCP-4 and eotaxin-3 were potential markers for the clinical course of COPD, which could provide guidance for accurate diagnosis and treatment for this disease in future clinical practice.

Investigation of time profile of FEV1 across the onset of potential COPD: a retrospective cohort study using medical checkup data in Japan

This study compared the time profile of FEV1 after COPD diagnosis among rapid decliners, slow decliners, and sustainers in the year of COPD diagnosis. COPD subjects were identified from the annual medical checkup records of Hitachi, Ltd., employees in Japan (April 1998-March 2019). Subjects were categorized into 3 groups (rapid decliner [decrease of FEV1 ≥ 63 mL/year], slow decliner [< 63 and ≥ 31 mL/year], and sustainer [< 31 mL/year]) for 5 years. The time profile of FEV1 was compared using mixed-effects model for 5 years after diagnosis; risk factors of rapid decliner were detected using logistic model/gradient boosting decision tree. Of 1294 eligible subjects, 18.6%, 25.7%, and 55.7% were classified as rapid decliners, slow decliners, and sustainers, respectively. The annual rates of FEV1 decline were similar 3 years before and until COPD diagnosis. The mean FEV1 in rapid decliners was 2.82 ± 0.04 L in year 0 and 2.41 ± 0.05 L in year 5, and in sustainers, it was 2.67 ± 0.02 L and 2.72 ± 0.02 L (year 0, p = 0.0004). In conclusion, FEV1 declined yearly before diagnosis and the time profiles of FEV1 were different in the 3 groups after COPD diagnosis. Therefore, appropriate treatment of the 3 groups with regular lung function tests is necessary to follow FEV1 decline after COPD onset.

Gender-specific disease trajectories prior to the onset of COPD allow individualized screening and early intervention.

Nation-wide hospitalization databases include diagnostic information at the level of an entire population over an extended period of time. Comorbidity network and early disease development can be unveiled. Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition for which it is crucial to identify early disease indicators. The identification of gender-specific conditions preceding the onset of COPD may reveal disease progression patterns allowing for early diagnosis and intervention. The objective of the study was to investigate the antecedent hospitalization history of patients newly diagnosed with COPD and to retrace a gender-specific trajectory of coded entities prior to the onset of COPD. A population-wide hospitalization database including information about all hospitalizations in Switzerland between 2002 and 2018 was used. COPD cases were extracted from the database and comorbidities occurring prior to the onset of COPD identified. Comorbidities significantly over-represented in COPD compared with a 1:1, age- and sex-matched control population were identified and their longitudinal evolution was analyzed. Between 2002 and 2018, 697,714 hospitalizations with coded COPD were recorded in Switzerland. Sixty-two diagnoses were significantly over-represented before onset of COPD. These preceding comorbidities included both well-established conditions and novel links to COPD. Early pre-conditions included nicotine and alcohol abuse, obesity and cardiovascular diseases. Later comorbidities included atrial fibrillation, diseases of the genitourinary system and pneumonia. Atherosclerotic heart diseases were more prevalent in males, whereas hypothyroidism, varicose and intestinal disorders were more frequent in females. Disease trajectories were validated using an independent data set. Gender-specific disease trajectories highlight early indicators and pathogenetic links between COPD and antecedent diseases and could allow for early detection and intervention.

A semi-supervised adaptive Markov Gaussian embedding process (SAMGEP) for prediction of phenotype event times using the electronic health record

While there exist numerous methods to identify binary phenotypes (i.e. COPD) using electronic health record (EHR) data, few exist to ascertain the timings of phenotype events (i.e. COPD onset or exacerbations). Estimating event times could enable more powerful use of EHR data for longitudinal risk modeling, including survival analysis. Here we introduce Semi-supervised Adaptive Markov Gaussian Embedding Process (SAMGEP), a semi-supervised machine learning algorithm to estimate phenotype event times using EHR data with limited observed labels, which require resource-intensive chart review to obtain. SAMGEP models latent phenotype states as a binary Markov process, and it employs an adaptive weighting strategy to map timestamped EHR features to an embedding function that it models as a state-dependent Gaussian process. SAMGEP’s feature weighting achieves meaningful feature selection, and its predictions significantly improve AUCs and F1 scores over existing approaches in diverse simulations and real-world settings. It is particularly adept at predicting cumulative risk and event counting process functions, and is robust to diverse generative model parameters. Moreover, it achieves high accuracy with few (50–100) labels, efficiently leveraging unlabeled EHR data to maximize information gain from costly-to-obtain event time labels. SAMGEP can be used to estimate accurate phenotype state functions for risk modeling research.

Nutrition as a modifiable factor in the onset and progression of pulmonary function impairment in COPD: a systematic review.

ContextChronic obstructive lung disease (COPD) is a progressive lung disease characterized by persistent airflow limitation. An increasing amount of evidence suggests an effect of dietary quality on the risk of COPD in the general population and pulmonary function decline in patients with COPD.ObjectiveThe association of dietary intake and nutrient status with COPD risk and onset, as well as pulmonary function decline (change in forced expiratory volume in 1 second, forced vital capacity, or the ratio of the former to the latter) in patients with COPD was investigated in this systematic review.Data SourcesThe PubMed database was searched by combining terms of pulmonary function or COPD with diet, nutrient status, or nutritional supplementation.Data ExtractionOriginal studies and systematic reviews and meta-analyses were included. Articles obtained were independently screened for relevance on the bases of title and abstract by 2 researchers. Eventually, 89 articles were included in the analysis.ResultsThe unhealthy Western-style diet is associated with an increased risk of COPD and an accelerated decline of pulmonary function. Intake of fruit, vegetables, dietary fibers, vitamins C and E, polyphenols, and β-carotene were individually associated with lower COPD risk, whereas consumption of processed meat was associated with higher COPD risk. Data on the effect of dietary quality on pulmonary function decline in patients with COPD are limited and inconsistent. Strong evidence for beneficial effects on pulmonary function decline was found only for vitamin D supplementation.ConclusionConsidering the increasing burden of COPD, more attention should be given to dietary quality as a modifiable factor in disease development and progression in patients with COPD.Systematic Review RegistrationPROSPERO registration no. CRD42021240183.

Prevalence of a decreased FEV3/FEV6 ratio in symptomatic smokers with preserved lung function

BackgroundThe ratio of forced expiratory volume in 3 seconds to forced expiratory volume in 6 seconds (FEV3/FEV6) has been proposed as an index of peripheral airway disease, and could be decreased in patients at risk for COPD. However, the prevalence of FEV3/FEV6 decrease has never been assessed in patients attending a pneumology clinic. Here we set out to assess the prevalence of a decreased FEV3/FEV6 in smokers with symptoms of chronic bronchitis, and to test its predictive value for COPD diagnosis. MethodsWe performed a retrospective analysis of databased pulmonary function tests (PFTs) for smokers and ex-smokers aged >40 years old, with symptoms of chronic bronchitis and a normal FEV1/FVC ratio. Clinical data were retrieved from the hospital records. Patients presenting with clinical conditions liable to interfere with PFT results were excluded. For those included, we controlled for onset of an obstructive ventilatory defect 1 year later. ResultsThe dataset included 67 patients (median age: 64 years [interquartile range: 53–72], 61% current smokers). FEV1/FVC was above lower limit of normal but lower than 0.7 in 18 patients (27%). FEV3/FEV6 was decreased below the lower limit of normal in 45 patients (67%). The latter did not differ from others patients in clinical data and PFTs except for a lower lung diffusion capacity (DLCO). We found a weak correlation between FEV3/FEV6 and DLCO (r=0.33, p=0.004). PFTs were repeated in 35 patients at 11 [7–12] months, and 20 (54%) presented with obstructive ventilatory defect defined by FEV1/FVC ratio <0.7. A reduction of FEV3/FEV6 was predictive of COPD onset one year later (p=0.04). These results may be biased by a discrepancy between the normality cut-offs used at inclusion and during follow-up (i.e. lower limit of normal and 0.7). ConclusionsDecreased FEV3/FEV6 suggestive of peripheral airway disease is highly prevalent in smokers with symptoms of chronic bronchitis and preserved pulmonary function. Altered FEV3/FEV6 is predictive of reduced FEV1/FVC ratio in the mid-term. A larger prospective study is needed to determine whether decreased FEV3/FEV6 could be used to detect patients at risk for COPD.

Indoor Radon Exposure and COPD, Synergic Association? A Multicentric, Hospital-Based Case–Control Study in a Radon-Prone Area

BackgroundCOPD is a multifactorial disease which causes considerable mortality and morbidity worldwide. Previous studies assessing the possible relationship between indoor radon exposure and COPD have shown inconclusive results. MethodsA multicentric, hospital-based, case-control study was conducted in a Spanish radon-prone area. COPD cases were confirmed by spirometry and controls were selected due to trivial surgery or procedures not related to tobacco consumption. All participants had to have lived for at least 15 years in the same dwelling. Radon measurements were conducted individually in dwellings using alpha-track detectors. Results were obtained using multivariate logistic regression. Results189 cases and 747 controls took part. There was no significant association between residential radon concentrations and COPD onset with a OR of 1.12 (95%CI 0.41–3.06) for individuals exposed to more than 200Bq/m3 compared to those exposed to less than 50Bq/m3. Heavy smokers seem to increase their COPD risk if exposed to higher radon concentrations vs those exposed to lower concentrations. There was a statistically significant synergy index between radon exposure and tobacco consumption, S-index 11.60 (95%CI 3.71–36.26). Indoor radon concentration was higher in never/light smokers with COPD compared to controls. ConclusionsNo association between indoor radon and COPD has been observed. However, there might be some effect modification on the COPD risk in heavy smokers when high radon exposure is present. This is supported by the additive synergy observed. Also, a possible association between indoor radon and COPD onset in never and light smokers needs to be further studied.

Indoor Radon Exposure and COPD, Synergic Association? A Multicentric, Hospital-Based Case–Control Study in a Radon-Prone Area

BackgroundCOPD is a multifactorial disease which causes considerable mortality and morbidity worldwide. Previous studies assessing the possible relationship between indoor radon exposure and COPD have shown inconclusive results. MethodsA multicentric, hospital-based, case-control study was conducted in a Spanish radon-prone area. COPD cases were confirmed by spirometry and controls were selected due to trivial surgery or procedures not related to tobacco consumption. All participants had to have lived for at least 15 years in the same dwelling. Radon measurements were conducted individually in dwellings using alpha-track detectors. Results were obtained using multivariate logistic regression. Results189 cases and 747 controls took part. There was no significant association between residential radon concentrations and COPD onset with a OR of 1.12 (95%CI 0.41–3.06) for individuals exposed to more than 200Bq/m3 compared to those exposed to less than 50Bq/m3. Heavy smokers seem to increase their COPD risk if exposed to higher radon concentrations vs those exposed to lower concentrations. There was a statistically significant synergy index between radon exposure and tobacco consumption, S-index 11.60 (95%CI 3.71–36.26). Indoor radon concentration was higher in never/light smokers with COPD compared to controls. ConclusionsNo association between indoor radon and COPD has been observed. However, there might be some effect modification on the COPD risk in heavy smokers when high radon exposure is present. This is supported by the additive synergy observed. Also, a possible association between indoor radon and COPD onset in never and light smokers needs to be further studied.

The ageing lung under stress.

Healthy ageing of the lung involves structural changes but also numerous cell-intrinsic and cell-extrinsic alterations. Among them are the age-related decline in central cellular quality control mechanisms such as redox and protein homeostasis. In this review, we would like to provide a conceptual framework of how impaired stress responses in the ageing lung, as exemplified by dysfunctional redox and protein homeostasis, may contribute to onset and progression of COPD and idiopathic pulmonary fibrosis (IPF). We propose that age-related imbalanced redox and protein homeostasis acts, amongst others (e.g. cellular senescence), as a "first hit" that challenges the adaptive stress-response pathways of the cell, increases the level of oxidative stress and renders the lung susceptible to subsequent injury and disease. In both COPD and IPF, additional environmental insults such as smoking, air pollution and/or infections then serve as "second hits" which contribute to persistently elevated oxidative stress that overwhelms the already weakened adaptive defence and repair pathways in the elderly towards non-adaptive, irremediable stress thereby promoting development and progression of respiratory diseases. COPD and IPF are thus distinct horns of the same devil, "lung ageing".

Blood Eosinophilia Predicts Poor Outcome in Lung Transplant Recipients

Eosinophils are associated with the onset of chronic respiratory diseases like asthma and COPD. In lung transplantation, patients with increased bronchoalveolar lavage eosinophils demonstrated a worse chronic lung allograft dysfunction (CLAD)-free survival and overall survival. We investigated the association between blood eosinophilia, graft survival and CLAD-free survival after lung transplantation. A retrospective analysis was performed including all transplanted patients within our center between 2011 and 2016 (n=376). Blood eosinophils were measured as part of the routine clinical follow-up including all measurements prior to 01/06/2019. A ROC analysis was performed to define cut-offs for blood eosinophilia and patients were subsequently divided in those with high blood eosinophilia vs. those with lower eosinophilia based on the defined cut-off. All patients received oral steroids as part of their standard immunosuppressive drug regimen. ROC analysis revealed that the optimal threshold for blood eosinophilia is >7.85% (p=0.0026) for overall survival and >7.75% (p=0.001) for CLAD-free survival. Using a threshold of >8%, 112 patients had high blood eosinophilia and 264 had low eosinophilia (16 patients developed high eosinophilia after CLAD). Patients with blood eosinophilia >8% demonstrated worse graft survival (p=0.004) and CLAD-free survival (p=0.0076) compared to those with lower blood eosinophilia. Within the high eosinophilia group, 65 (58%) patients were diagnosed with CLAD, of which 42 (37.5%) patients had BOS and 23 (20.5%) had RAS. In the group with lower eosinophilia, 80 (30.3%) patients developed CLAD with 71 (26.9%) BOS and 9 (3.4%) RAS (p<0.0001). Lung transplant recipients with high blood eosinophilia (>8%) demonstrate inferior graft survival and CLAD-free survival, specifically RAS. These findings require further research and may lead to the development of an easy to use, non-invasive marker for poor transplant outcome.

4β-Hydroxywithanolide E from Goldenberry (Whole Fruits of Physalis peruviana L.) as a Promising Agent against Chronic Obstructive Pulmonary Disease

Environmental toxicant- and oxidant-induced [e.g., cigarette smoke (CS)] respiratory oxidative stress and inflammatory response play a vital role in the onset and progression of COPD. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents an important mechanism for regulating intracellular oxidative stress and inflammatory response and is a promising target for developing agents against COPD. Herein, a bioactivity-guided purification of goldenberry (whole fruits of Physalis peruviana L.) led to the isolation of a novel and potent Nrf2 activator 4β-hydroxywithanolide E (4β-HWE). Our study indicated that (i) 4β-HWE activated the Nrf2-mediated defensive response through interrupting Nrf2-Keap1 protein-protein interaction (PPI) via modification of Cys151 and Cys288 cysteine residues in Keap1 and accordingly suppressing the ubiquitination of Nrf2. (ii) 4β-HWE enhanced intracellular antioxidant capacity and inhibited oxidative stress in normal human lung epithelial Beas-2B cells and wild-type AB zebrafish. (iii) 4β-HWE blocked LPS-stimulated inflammatory response and inhibited LPS-stimulated NF-κB activation in RAW 264.7 murine macrophages. (iv) 4β-HWE effectively suppressed oxidative stress and inflammatory response in a CS-induced mice model of pulmonary injury. Collectively, these results display the feasibility of using 4β-HWE to prevent or alleviate the pathological progression of COPD and suggest that 4β-HWE is a candidate or a leading molecule against COPD.

Non-infectious rhinitis is more strongly associated with early\u2014rather than late\u2014onset of COPD: data from the European Community Respiratory Health Survey (ECRHS)

PurposeChronic obstructive pulmonary disease (COPD) is associated with several co-morbidities and non-infectious rhinitis (NIR) has emerged as a new possible co-morbidity. The primary aim of this study is to confirm a previously reported association between NIR and COPD in a multicentre population over time. The secondary aim is to investigate the course over time of such an association through a comparison between early- and late-onset COPD.MethodsThis study is part of the European Community Respiratory Health Survey (ECRHS). A random adult population from 25 centres in Europe and one in Australia was examined with spirometry and answered a respiratory questionnaire in 1998–2002 (ECRHS II) and in 2008–2013 (ECRHS III). Symptoms of non-infectious rhinitis, hay fever and asthma, and smoking habits were reported. Subjects reporting asthma were excluded. COPD was defined as a spirometry ratio of FEV1/FVC < 0.7. A total of 5901 subjects were included.ResultsNon-infectious rhinitis was significantly more prevalent in subjects with COPD compared with no COPD (48.9% vs 37.1%, p < 0.001) in ECRHS II (mean age 43) but not in ECHRS III (mean age 54). In the multivariable regression model adjusted for COPD, smoking, age, BMI, and gender, non-infectious rhinitis was associated with COPD in both ECRHS II and III.ConclusionNon-infectious rhinitis was significantly more common in subjects with COPD at a mean age of 43. Ten years later, the association was weaker. The findings indicate that NIR could be associated with the early onset of COPD.

Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes

A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung function testing followed by genotyping with allele-specific arrays for 16 SNPs as well as expression quantitative trait loci at TSLP (rs2289276, rs3806933). Lung function GRS scoring and two-step cluster analyses grouped patients into different COPD phenotypes based on gender, age, smoking index, %FEV1 and lung function GRS. The genetic effect of TSLP on COPD phenotypes was also examined for interactions with the lung function GRS. A total of 270 participants were grouped into 5 clusters. The cluster with the highest levels of lung function GRS was characterized by moderate to severe airflow obstruction and the highest blood eosinophil counts. Regarding TSLP, an increased number of T alleles at both SNPs was found in the cluster characterized by moderate to severe airflow obstruction and heavy smoking (rs2289276, p value = 0.035; rs3806933, p value = 0.047) independent of the lung function GRS. A genetic susceptibility to impaired lung function carries an increased risk of developing COPD characterized by increased eosinophil counts and severe airflow obstruction while individuals with increased TSLP responses to external stimuli have an independent risk of developing severe airflow obstruction in the presence of heavy smoking.