Pathobiology Of Chronic Obstructive Pulmonary Disease Research Articles

TSLP is localized in and released from human lung macrophages activated by T2-high and T2-low stimuli: relevance in asthma and COPD

BackgroundMacrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs. MethodsWe employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli. ResultsTSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages. ConclusionsOur results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.

COPD in People with HIV: Epidemiology, Pathogenesis, Management, and Prevention Strategies.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation and persistent respiratory symptoms. People with HIV (PWH) are particularly vulnerable to COPD development; PWH have demonstrated both higher rates of COPD and an earlier and more rapid decline in lung function than their seronegative counterparts, even after accounting for differences in cigarette smoking. Factors contributing to this HIV-associated difference include chronic immune activation and inflammation, accelerated aging, a predilection for pulmonary infections, alterations in the lung microbiome, and the interplay between HIV and inhalational toxins. In this review, we discuss what is known about the epidemiology and pathobiology of COPD among PWH and outline screening, diagnostic, prevention, and treatment strategies.

Characterization of the COPD alveolar niche using single-cell RNA sequencing

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.

Determinants of Pulmonary Emphysema Severity in Taiwanese Patients with Chronic Obstructive Pulmonary Disease: An Integrated Epigenomic and Air Pollutant Analysis.

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. Objectives: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. Methods: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. Results: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below − 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). Conclusion: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan.

Chromatin Landscapes of Human Lung Cells Predict Potentially Functional Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Variants

Genome-wide association studies (GWASs) have identified dozens of loci associated with risk of chronic obstructive pulmonary disease (COPD). However, identifying the causal variants and their functional role in the appropriate cell type remains a major challenge. We aimed to identify putative causal variants in 82 GWAS loci associated with COPD susceptibility and predict the regulatory impact of these variants in lung-cell types. We used an integrated approach featuring statistical fine mapping, open chromatin profiling, and machine learning to identify functional variants. We generated chromatin accessibility data using the Assay for Transposase-Accessible Chromatin with High-Throughput Sequencing (ATAC-seq) for human primary lung-cell types implicated in COPD pathobiology. We then evaluated the enrichment of COPD risk variants in lung-specific open chromatin regions and generated cell type-specific regulatory predictions for >6,500 variants corresponding to 82 COPD GWAS loci. Integration of the fine-mapped variants with lung open chromatin regions helped prioritize 22 variants in putative regulatory elements with potential functional effects. Comparison with functional predictions from 222 Encyclopedia of DNA Elements (ENCODE) cell samples revealed cell type-specific regulatory effects of COPD variants in the lung epithelium, endothelium, and immune cells. We identified potential causal variants for COPD risk by integrating fine mapping in GWAS loci with cell-specific regulatory profiling, highlighting the importance of leveraging the chromatin status in relevant cell types to predict the molecular effects of risk variants in lung disease.

Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.

Periostin and Thymic Stromal Lymphopoietin-Potential Crosstalk in Obstructive Airway Diseases.

Periostin and thymic stromal lymphopoietin (TSLP) are newly described markers of obstructive airway diseases and the mechanism by which both markers participate in immune response remains poorly understood. The aim of our study was to determine periostin and TSLP concentration in serum and induced sputum (IS) in patients with atopic asthma, chronic obstructive pulmonary disease (COPD), and controls, as well as to evaluate the potential link between periostin, TSLP, and Th2 immune response. Serum and IS levels of periostin, TSLP, IL-4, and IL-13 were determined in 12 atopic asthmatics, 16 COPD sufferers, and 10 controls. We noticed a significantly higher IS periostin and TSLP concentration at protein and mRNA level in asthmatics compared to the two other groups; additionally, periostin and TSLP were correlated positively with IS eosinophil count. A strong positive correlation between IS periostin and TSLP protein levels (r = 0.96) as well as mRNA expression level (r = 0.95) was found in patients with asthma. The results of our study show that periostin and TSLP are associated with eosinophilic airway inflammation and seem to be important drivers of atopic asthma but not COPD pathobiology. Very strong correlations between local periostin, TSLP, eosinophils, and IL-4 in asthma point to the link between periostin–TSLP and Th2 response.

Sputum microbiome profiling in COPD: beyond singular pathogen detection

Culture-independent microbial sequencing techniques have revealed that the respiratory tract harbours a complex microbiome not detectable by conventional culturing methods. The contribution of the microbiome to chronic obstructive pulmonary disease...

Fibroblast Growth Factor 23 is Associated with a Frequent Exacerbator Phenotype in COPD: A Cross-Sectional Pilot Study.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease punctuated by exacerbations (AECOPD). Subjects with frequent AECOPD, defined by having at least two exacerbations per year, experience accelerated loss of lung function, deterioration in quality of life and increase in mortality. Fibroblast growth factor (FGF)23, a hormone associated with systemic inflammation and altered metabolism is elevated in COPD. However, associations between FGF23 and AECOPD are unknown. In this cross-sectional study, individuals with COPD were enrolled between June 2016 and December 2016. Plasma samples were analyzed for intact FGF23 levels. Logistic regression analyses were used to measure associations between clinical variables, FGF23, and the frequent exacerbator phenotype. Our results showed that FGF23 levels were higher in frequent exacerbators as compared to patients without frequent exacerbations. FGF23 was also independently associated with frequent exacerbations (OR 1.02; 95%CI 1.004–1.04; p = 0.017), after adjusting for age, lung function, smoking, and oxygen use. In summary, FGF23 was associated with the frequent exacerbator phenotype and correlated with number of exacerbations recorded retrospectively and prospectively. Further studies are needed to explore the role of FGF 23 as a possible biomarker for AECOPD to better understand the pathobiology of COPD and to help develop therapeutic targets.

Network Analysis of Lung Transcriptomics Reveals a Distinct B-Cell Signature in Emphysema.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by a combination of airways disease (bronchiolitis) and parenchymal destruction (emphysema), whose relative proportion varies from patient to patient. To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD. We used network analysis of lung transcriptomics (Affymetrix arrays) in 70 former smokers with COPD to compare differential expression and gene coexpression in bronchiolitis and emphysema. We observed that in emphysema (but not in bronchiolitis) (1) up-regulated genes were enriched in ontologies related to B-cell homing and activation; (2) the immune coexpression network had a central core of B cell-related genes; (3) B-cell recruitment and immunoglobulin transcription genes (CXCL13, CCL19, and POU2AF1) correlated with emphysema severity; (4) there were lymphoid follicles (CD20(+)IgM(+)) with active B cells (phosphorylated nuclear factor-κB p65(+)), proliferation markers (Ki-67(+)), and class-switched B cells (IgG(+)); and (5) both TNFRSF17 mRNA and B cell-activating factor protein were up-regulated. These findings were by and large reproduced in a group of patients with incipient emphysema and when patients with emphysema were matched for the severity of airflow limitation of those with bronchiolitis. Our study identifies enrichment in B cell-related genes in patients with COPD with emphysema that is absent in bronchiolitis. These observations contribute to a better understanding of COPD pathobiology and may open new therapeutic opportunities for patients with COPD.

The Role of Mitochondria and Oxidative/Antioxidative Imbalance in Pathobiology of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. The major risk factor of COPD, which has been proven in many studies, is the exposure to cigarette smoke. However, it is 15–20% of all smokers who develop COPD. This is why we should recognize the pathobiology of COPD as involving a complex interaction between several factors, including genetic vulnerability. Oxidant-antioxidant imbalance is recognized as one of the significant factors in COPD pathogenesis. Numerous exogenous and endogenous sources of ROS are present in pathobiology of COPD. One of endogenous sources of ROS is mitochondria. Although leakage of electrons from electron transport chain and forming of ROS are the effect of physiological functioning of mitochondria, there are various intra- and extracellular factors which may increase this amount and significantly contribute to oxidative-antioxidative imbalance. With the coexistence with impaired antioxidant defence, all these issues lead to oxidative and carbonyl stress. Both of these states play a significant role in pathobiology of COPD and may account for development of major comorbidities of this disease.

JTD special edition 'Hot Topics in COPD'-The microbiome in COPD.

The pathogenesis of chronic obstructive pulmonary disease (COPD) and its exacerbations, are intricately linked to colonisation and infection with bacteria and other microbes. Despite their undeniable importance, we have a poor understanding of the complex relationships between COPD phenotypes, physiology, cellular and molecular biology and the roles of colonising microbe or infecting pathogens. The management algorithms for the care of patients with COPD that include microbial influences, have almost exclusively been developed using microbial methods that were entirely dependent on the ability to grow bacteria on suitable media. The shortcomings of this approach are becoming clear now that it is possible to completely and accurately define the microbial ecology of ecosystems using genomic methods, which do not rely on the ability to cultivate the organisms present. Whilst our appreciation of the relationships between some bacterial ecosystems and the organ in which they reside in humans is now relatively advanced, this is not true for lung. This perspective serves to highlight the growing importance of including an accurate description of bacterial ecology in any attempt to decipher the pathobiology of COPD. While this field is in its infancy, there is significant potential to gain new insights which will translate into more rational and effective treatment algorithms for patients with COPD.

Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD.

Sex and Gender Differences in Chronic Obstructive Pulmonary Disease

Abstract:Gender differences are evident in chronic obstructive pulmonary disease (COPD) pathogenesis, manifestations, and response to therapy. Consequently, a better understanding of the gender-influenced factors in COPD pathobiology can help clinicians to make appropriate decisions surrounding the

New Paradigms in the Pathogenesis of Chronic Obstructive Pulmonary Disease I

This paper reviews the potential participation of novel pathogenic mechanisms in chronic obstructive pulmonary disease (COPD) relating to aging, including oxidative stress and enhanced expression of markers of senescence in emphysematous lungs and the potential enhanced tissue destruction involving alveolar apoptosis. These insights provide new beginnings for future investigations in the pathobiology of COPD which may lead to future therapies for this condition.

Inflammation and thoracic surgery: a complex interaction

We appreciated the reading of the work of Amar et al. [1]. The authors reported data suggesting that markers of inflammation such as C-reactive protein (CRP) and IL-6 can help to classify patients who are at high risk for major postoperative complications (PC) following thoracic surgery. Systemic inflammation is thus considered to be important in the pathogenesis of important PC. Defining the precise inflammatory response represents a sensitive issue, frequently debated within scientific community. Plasma levels of cytokines or CRP are probably not sufficient to determine whether a patient or experimental animal is hyper-inflammatory or hypo-inflammatory. If only the pro-inflammatory mediators are measured, then the patient will appear hyper-inflammatory. Conversely, if only cytokine antagonists or anti-inflammatory mediators are measured, the subject appears to be hypo-inflammatory. Indeed, both proand antiinflammatorymediatorsmaybecirculating at the same time in the plasma [2]. Better methods for determining the precise immunological status may be achieved via either a multiplex format for cytokinemeasurements or an evaluation of cellular function. Many cellular aspects become dysfunctional in inflammation, for example in chronic obstructive pulmonary disease (COPD), and may be characterized as either excessive activation or depressed function. Excessive activation refers to cells that are primed so that they respond in a very vigorous manner to a second stimulus (for example, neutrophils generating excess toxic products that cause damage to nearby cells [3]). Conversely, an example of depressed functionwould be neutrophils’ failure to phagocytize any clearly invading pathogens. One of the current areas of active investigation concerning cellular function is the induction of cellular apoptosis or necrosis. The signalling mechanisms and molecules that induce apoptosis are currently being described in great detail by several investigators. The pathobiology of COPD (a disease that can be considered a model of pulmonary inflammation) encompasses multiple injurious processes including inflammation (excessive or inappropriate innate and adaptive immunity), cellular apoptosis, altered cellular and molecular alveolar maintenance program, abnormal cell repair, extracellular matrix destruction (protease and antiprotease imbalance), and oxidative stress (oxidant and antioxidant imbalance) [4]. Apoptosis may contribute to the pathogenesis of sepsis by the delayed removal of those cells that shouldbe removed, i.e., neutrophils, andearly removalof those cells that should not be removed, i.e., lymphocytes. Activated protein C has emerged as a novel therapeutic agent for use in selectedpatientswith severe sepsis, even though the mechanism of its benefit is not well established. It has anticoagulant, anti-inflammatory, antiapoptotic, and profibrinolytic properties, but it is not clear through which of thesemechanismsAPCexerts its benefit in severe sepsis. Focus has recently turned to the role of APC in maintaining endothelial barrier function, and in vitro and in vivo studies have examined this relationship [5]. In conclusion, CRP and IL-6 alterations are extremely nonspecific, and an accurate diagnostic test for sepsis would be a welcome addition in the management of specific patients undergoing thoracic surgery, whereas the condition supporting the surgical indication could easily be correlated with a previous pulmonary inflammation, i.e., lung cancer arising in COPD patients.

Emerging drugs for the treatment of chronic obstructive pulmonary disease

By 2020 chronic obstructive pulmonary disease (COPD) will be the third leading cause of mortality and fifth leading cause of morbidity. Research over the past two decades has shed important insights on the pathobiology of COPD, leading to the development of novel drugs. In the past, symptomatic treatment with bronchodilators was the predominant focus of COPD management. With increased awareness of the importance of airway inflammation in COPD progression, there has been a shift in emphasis to drugs that attack various targets in the inflammatory cascade. These drugs include phosphodiesterase 4 inhibitors, leukotriene modifiers and TNF antagonists, which are poised to enter the COPD market in the very near future. Tyrosine kinase antagonists, inhibitors of NF-κB, neutrophil elastase inhibitors, chemokine antagonists, mucolytics and novel antibiotics are being evaluated for possible effectiveness in COPD. Many of these drugs may enter the COPD market within the next decade. This paper reviews the molecular rationale for these emerging drugs and their potential efficacy in COPD.

The pathobiology of COPD

Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in the pulmonary tissue. The disease is associated with a switch from a self-limiting inflammatory response, mainly initiated by smoke inhalation, to a chronic persistent inflammatory response after prolonged interaction with cigarette smoke. The development and progression of chronic obstructive pulmonary disease have been associated with increased oxidative stress and reduced antioxidant resources. As a result, the antioxidant capacity decreases in COPD patients. Additionally, there is an imbalance between the release of proteases and of endogenous anti-protease enzymes that prevent elastin digestion. The inflammatory basis of COPD is now well established. In patients with COPD increased numbers of macrophages and neutrophils have been found in induced sputum, the former predominating in mild disease. Biopsy data confirm these observations but also demonstrate increased numbers of CD8-positive T- lymphocytes in the airway wall, which may have a role in the regulation of the inflammatory response to cigarette smoke. The extent of the inflammatory reaction is correlated with the severity of the disease. An imbalance between pro- and anti-inflammatory cytokines may favour this process. Several mediators are involved in COPD including leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF-alpha), and interleukin8 (IL-8). They are selective attractants of neutrophils and regulate the ongoing inflammatory process. The whole process would be predicted to be self-perpetuating leading to a chronic inflammatory state with associated airway remodelling and progressive lung function decline.

Vagotomy for Peptic Ulcer

Culture-independent microbial sequencing techniques have revealed that the respiratory tract harbours a complex microbiome not detectable by conventional culturing methods. The contribution of the microbiome to chronic obstructive pulmonary disease (COPD) pathobiology and the potential for microbiome-based clinical biomarkers in COPD are still in the early phases of investigation. Sputum is an easily obtainable sample and has provided a wealth of information on COPD pathobiology, and thus has been a preferred sample type for microbiome studies. Although the sputum microbiome likely reflects the respiratory microbiome only in part, there is increasing evidence that microbial community structure and diversity are associated with disease severity and clinical outcomes, both in stable COPD and during the exacerbations. Current evidence has been limited to mainly cross-sectional studies using 16S rRNA gene sequencing, attempting to answer the question ‘who is there?’ Longitudinal studies using standardised protocols are needed to answer outstanding questions including differences between sputum sampling techniques. Further, with advancing technologies, microbiome studies are shifting beyond the examination of the 16S rRNA gene, to include whole metagenome and metatranscriptome sequencing, as well as metabolome characterisation. Despite being technically more challenging, whole-genome profiling and metabolomics can address the questions ‘what can they do?’ and ‘what are they doing?’ This review provides an overview of the basic principles of high-throughput microbiome sequencing techniques, current literature on sputum microbiome profiling in COPD, and a discussion of the associated limitations and future perspectives.