Pathophysiology Of Chronic Obstructive Pulmonary Disease Research Articles

Correlation between Volatile Organic Compounds (VOC) with Leukotriene B4 and Eosinophil Counts in Chronic Obstructive Pulmonary Disease Patients

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by increasing Leukotriene B4 (LTB4) and eosinophil counts. Volatile organic compounds (VOCs) have shown promise as non-invasive biomarkers, reflecting COPD pathophysiology. Identifying specific VOCs associated with increased LTB4 and eosinophil counts could lead to the discovery of potential biomarkers for COPD severity or progression. AIMS: This study aims to investigate the correlation between VOCs and leukotriene B4 (LTB4) levels, as well as eosinophil counts counts in COPD patients. METHOD: Using an observational-analytic method with a case-control approach, 20 COPD patients and 20 controls were enrolled from the respiratory outpatient department of Dr. Saiful Anwar General Hospital, Malang. VOC levels were measured using a breath analyzer, while LTB4 levels were determined through enzyme-linked immunosorbent assays. Spearman’s correlation tests examined associations between VOCs, LTB4, eosinophil counts, and comorbidity, with Mann-Whitney tests comparing results against the control group. Data significance was set at p < 0.05. RESULT: There were 40 COPD patients and 40 controls in this study. There were significant differences between VOCs in the COPD group and the control group (p < 0.05). LTB4 level significantly increased in the COPD group than in the control group (p < 0.001), and there was no difference in the eosinophil level. There was a correlation between LTB4 and VOC level of C2H5OH in COPD patients (p = 0.009; r = 0.410). There was no correlation between eosinophil counts and VOCs (p = 0.939). The level of VOCs was significantly different between patients with only COPD and patients with COPD and comorbid lung cancer (p < 0.05). CONCLUSION: There is a correlation between VOC and LTB4 in COPD patients.

Respiratory Oscillometry and Functional Performance in Different COPD Phenotypes.

Chronic obstructive pulmonary disease (COPD) phenotypes may introduce different characteristics that need to be known to improve treatment. Respiratory oscillometry provides a detailed analysis and may offer insight into the pathophysiology of COPD. In this paper, we used this method to evaluate the differences in respiratory mechanics of COPD phenotypes. This study investigated a sample of 83 volunteers, being divided into control group (CG = 20), emphysema (n = 23), CB (n = 20) and asthma-COPD overlap syndrome (ACOS, n = 20). These analyses were performed before and after bronchodilator (BD) use. Functional capacity was evaluated using the Glittre‑ADL test, handgrip strength and respiratory pressures. Initially it was observed that oscillometry provided a detailed description of the COPD phenotypes, which was consistent with the involved pathophysiology. A correlation between oscillometry and functional capacity was observed (r=-0.541; p = 0.0001), particularly in the emphysema phenotype (r = -0.496, p = 0.031). BD response was different among the studied phenotypes. This resulted in an accurate discrimination of ACOS from CB [area under the receiver operating curve (AUC) = 0.84] and emphysema (AUC = 0.82). These results offer evidence that oscillatory indices may enhance the comprehension and identification of COPD phenotypes, thereby potentially improving the support provided to these patients.

Capturing COPD heterogeneity: anomaly detection and parametric response mapping comparison for phenotyping on chest computed tomography.

Chronic obstructive pulmonary disease (COPD) poses a substantial global health burden, demanding advanced diagnostic tools for early detection and accurate phenotyping. In this line, this study seeks to enhance COPD characterization on chest computed tomography (CT) by comparing the spatial and quantitative relationships between traditional parametric response mapping (PRM) and a novel self-supervised anomaly detection approach, and to unveil potential additional insights into the dynamic transitional stages of COPD. Non-contrast inspiratory and expiratory CT of 1,310 never-smoker and GOLD 0 individuals and COPD patients (GOLD 1-4) from the COPDGene dataset were retrospectively evaluated. A novel self-supervised anomaly detection approach was applied to quantify lung abnormalities associated with COPD, as regional deviations. These regional anomaly scores were qualitatively and quantitatively compared, per GOLD class, to PRM volumes (emphysema: PRMEmph, functional small-airway disease: PRMfSAD) and to a Principal Component Analysis (PCA) and Clustering, applied on the self-supervised latent space. Its relationships to pulmonary function tests (PFTs) were also evaluated. Initial t-Distributed Stochastic Neighbor Embedding (t-SNE) visualization of the self-supervised latent space highlighted distinct spatial patterns, revealing clear separations between regions with and without emphysema and air trapping. Four stable clusters were identified among this latent space by the PCA and Cluster Analysis. As the GOLD stage increased, PRMEmph, PRMfSAD, anomaly score, and Cluster 3 volumes exhibited escalating trends, contrasting with a decline in Cluster 2. The patient-wise anomaly scores significantly differed across GOLD stages (p < 0.01), except for never-smokers and GOLD 0 patients. In contrast, PRMEmph, PRMfSAD, and cluster classes showed fewer significant differences. Pearson correlation coefficients revealed moderate anomaly score correlations to PFTs (0.41-0.68), except for the functional residual capacity and smoking duration. The anomaly score was correlated with PRMEmph (r = 0.66, p < 0.01) and PRMfSAD (r = 0.61, p < 0.01). Anomaly scores significantly improved fitting of PRM-adjusted multivariate models for predicting clinical parameters (p < 0.001). Bland-Altman plots revealed that volume agreement between PRM-derived volumes and clusters was not constant across the range of measurements. Our study highlights the synergistic utility of the anomaly detection approach and traditional PRM in capturing the nuanced heterogeneity of COPD. The observed disparities in spatial patterns, cluster dynamics, and correlations with PFTs underscore the distinct - yet complementary - strengths of these methods. Integrating anomaly detection and PRM offers a promising avenue for understanding of COPD pathophysiology, potentially informing more tailored diagnostic and intervention approaches to improve patient outcomes.

Correlation between Serum Levels of Progranulin and Spirometric Readings in Patients with Chronic Obstructive Pulmonary Disease

Back ground Chronic Obstructive Pulmonary Disease (COPD) is a chronic Inflammatory disease of the airways and/ or parenchyma usually characterized by progressive irreversible airflow with accompanying respiratory symptoms like dyspnea, cough, production of sputum, and/or exacerbations. The pathophysiology Of COPD involves bronchitis and /or emphysema, the effect of inflammation occurs in the lung and also have systemic effect, most common causes is tobacco smoking, occupational pollution, indoor pollution. Progranulin ( PGRN ) is defined as precursor of pleiotropic glycosylated protein ,it have significant role in process of inflammation ,angiogenesis, neoplasia ,cell development ,cell cycle , embryogenesis, wound healing ,modification of autoimmune process, highly found in several type of cells like respiratory epithelial cells. Objective: The aim is to study relationship between serum level of PGRN and spirometric readings in COPD patients. Patients and method: A case control study composed of 40 patients with COPD and 45 controls, demographic characteristic, pulmonary function test and plasma PGRN were measured and made comparison of data in cases with controls, data collected were statically analysis by SPSS. Result: This study found that serum PGRN was elevated in cases of COPD more than controls (230.52±189.01 VS 114.19±68.41 ng/ml) there is significant association between PGRN and COPD ( P value 0.006 ) ,and found that PGRN negatively associated with FEV1 % ( P value 0.04 ) Conclusions: It was concluded that PGRN may be used as blood marker that indicate severity of airflow obstruction in COPD.

Assessing Chronic Obstructive Pulmonary Disease (COPD) Mortality and Morbidity: A Review

From PubMed, referencing articles over the previous 4 years, 146 articles addressing morbidity and mortality of chronic obstructive pulmonary disease (COPD) were reviewed. The major topics covered in this article include the epidemiology of COPD, spirometry with ATS/ERS and GOLD staging, scoring Indices (BODE, ADO, FODEP), trajectories in the development of COPD, pathophysiology of COPD, classification of COPD phenotypes, pharmacotherapy of COPD, causes of Acute Exacerbation of COPD (AECOPD), CT Lung imaging in COPD, and COPD comorbidities. All studies are referenced allowing for greater exploration into given areas of interest (76 ref.).

The role of pulmonary vascular endothelium in chronic obstructive pulmonary disease (COPD): Does endothelium play a role in the onset and progression of COPD?

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung pathology characterized by persistent airflow limitation and is the third leading cause of death globally. COPD pathophysiology includes both environmental and host risk factors and the presence of comorbidities contributes to its harmful outcome. Cardiovascular disease (CVD) is closely related to COPD and their coexistence is associated with worse outcomes than either condition alone. COPD impairs the cardiovascular system favoring mostly endothelial dysfunction that is a significant COPD prognostic factor at different stages of the disease. The mechanisms promoting endothelial dysfunction in the systemic and/or pulmonary circulation of COPD patients are different and include systemic inflammation, alteration of adhesion and pro-inflammatory molecules, oxidative stress, cellular senescence, and apoptosis. Nevertheless, the role of endothelium in the onset and progression of COPD and CVD is not yet fully understood. Hence, the purpose of this narrative review is to analyze the literature and provide evidence supporting the importance of endothelial dysfunction in COPD.

An investigation of the risk factors of chronic obstructive pulmonary disease in natural population-based cohorts in China - a nested case-control study.

Chronic obstructive pulmonary disease (COPD) has become one of the most significant chronic diseases in China. According to conventional wisdom, smoking is the pathogenic factor. However, current research indicates that the pathophysiology of COPD may be associated with prior respiratory system events (e.g., childhood hospitalization for pneumonia, chronic bronchitis) and environmental exposure (e.g., dust from workplace, indoor combustion particles). Dyspnea, persistent wheezing, and other respiratory symptoms further point to the need for pulmonary function tests in this population. Reducing the burden of chronic diseases in China requires a thorough understanding of the various factors that influence the occurrence of COPD. Using a cohort from the natural population, this study used nested case-control analysis. We carried out a number of researches, including questionnaire surveys and pulmonary function testing, in the Northwest and Southeast cohorts of China between 2014 and 2021. After removing any variations in the baseline data between patients and control subjects using propensity score matching analysis, the risk factors were examined using univariate or multivariate regression. It was discovered that prior history of chronic bronchitis, long-term wheezing symptoms, and environmental exposure-including smoking and biofuel combustion-were risk factors for COPD. Dyspnea, symptoms of mobility limitation, organic matter, and a history of hospitalization for pneumonia at an early age were not significant in the clinical model but their incidence in COPD group is higher than that in healthy population. COPD screening effectiveness can be increased by looking for individuals with chronic respiratory symptoms. Smokers should give up as soon as they can, and families that have been exposed to biofuels for a long time should convert to clean energy or upgrade their ventilation. Individuals who have previously been diagnosed with emphysema and chronic bronchitis ought to be extra mindful of the prevention or advancement of COPD.

Association of ADAM33 gene with COPD pathophysiology: a case–control study

BackgroundWorldwide, Chronic Obstructive pulmonary disease (COPD) is a main cause of morbidity and mortality. Considering the global increase in the prevalence of COPD, research on the genetic factors that predispose to COPD is reviving. Recently, ADAM 33 has been found to be related to severe lung function decline and COPD.Aim and objectiveThe present study is carried out with the main aim of determining the association of SNP, i.e., S2 (rs528557), with COPD.MethodA case–control methodology is used to recruit participants. 50 COPD patients over 40 years of age and with a history of more than 20 pack years of cigarette smoking were enlisted. The same number of age and gender-matched controls with no COPD history were involved. PCR sequencing was used to analyze the genetic polymorphism of the ADAM 33 gene (SNP, i.e., S2 (rs528557). Statistical analysis was carried out using SPSS version 21. The Chi-square test was used to determine the difference in SNP rs528557 genotypes and alleles between controls and COPD.ResultsThe findings of this study revealed that the G allele was present in all COPD cases (100%) and 72% of control (p = < 0.001). The minor C allele was 14% and 32% in COPD patients and control, respectively. The G/G genotype is overrepresented in cases (25.5%) than in the control (9.2%). The C/C genotype is overrepresented in controls (3.8%) than in COPD patients (0.9%).ConclusionThe findings of this study demonstrate a significant association of the ADAM 33 gene (SNP, i.e., S2 (rs528557) with COPD pathophysiology in the studied group.

Exploring Type 2 Inflammation in Chronic Obstructive Pulmonary Disease

This symposium took place during the 2023 meeting of the European Respiratory Society (ERS), with a focus on targeting chronic obstructive pulmonary disease (COPD) with Type 2 inflammation, and the emerging biologic landscape. The speakers discussed the clinical consequences of COPD through an understanding of pathological changes, the spectrum of inflammatory pathways, the role of Type 2 inflammation in the pathophysiology of COPD, and the evolving clinical landscape in COPD. Klaus Rabe, Full Member (Chair), LungenClinic, Grosshansdorf, Germany, utilised hypothetical clinical scenarios to contextualise the clinical presentation of COPD as a consequence of disease pathology, specifically chronic inflammation leading to structural changes of airways and parenchymal destruction resulting in airflow limitation, leading to worsening symptoms, and increasing further exacerbation risk. Stephanie Christenson, Assistant Professor of pulmonology at the University of California, San Francisco, USA, followed with a discussion of the heterogeneity of inflammatory pathways, exploration of distinct inflammatory cells and cytokines, and the evolving state of the knowledge of the diverse inflammatory pathways associated with COPD. COPD inflammation can be differentiated by distinct inflammatory cells and cytokines into Type 1/Type 3 inflammation (i.e., neutrophilic inflammation) and Type 2 inflammation. However, there is potential overlap in the various inflammatory mechanisms driving COPD via the alarmins IL-33 and thymic stromal lymphopoietin. In addition, the key cytokines IL-4, IL-13, and IL-5 mediate the pathophysiology of COPD with Type 2 inflammation. Altogether, the heterogeneous inflammatory pathways contribute to characteristic features of COPD, fibrosis (small airways), wall thickening, airway remodelling, and clinical features, such as shortness of breath at rest. Dave Singh, Professor of respiratory pharmacology at The University of Manchester, UK, then discussed active areas of investigation in the development of additional treatments for patients with COPD.

Lung and Gut Microbiome in COPD.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. The association between lung and gut microbiomes in the pathogenesis of COPD has been recently uncovered. The goal of this study was to discuss the role of the lung and gut microbiomes in COPD pathophysiology. A systematic search of the PubMed database for relevant articles submitted up to June 2022 was performed. We examined the association between the lung and gut microbiome dysbiosis, reflected in bronchoalveolar lavage (BAL), lung tissue, sputum, and feces samples, and the pathogenesis and progression of COPD. It is evident that the lung and gut microbiomes affect each other and both play a vital role in the pathogenesis of COPD. However, more research needs to be carried out to find the exact associations between microbiome diversity and COPD pathophysiology and exacerbation genesis. Another field that research should focus on is the impact of treatment interventions targeting the human microbiome in preventing COPD genesis and progression.

COPD AND THE AIRWAY MICROBIOME: WHAT RESPIROLOGISTS NEED TO KNOW.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. The lower airways contain a rich and diverse microbiome, which may play a significant regulatory role in both health and disease. In COPD, the microbiome becomes perturbed, causing dysbiosis. Increased representation of members in the Proteobacteria phylum and certain members in the Firmicutes phylum has been associated with increased risk of exacerbations and mortality. Therapies such as inhaled corticosteroids and azithromycin may modulate the airway microbiome or its metabolites in patients with COPD. This paper provides an up-to-date overview of the airway microbiome and its importance in the pathophysiology of COPD and as potential therapeutic target in the future.

PHARMACOTHERAPY AND LUNG FUNCTION DECLINE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE : A SYSTEMATIC REVIEW

Chronic obstructive pulmonary disease (COPD) is a long-term condition that affects millions of individuals all over the world and is a major contributor to the rise in hospital admission rates. According to projections made by the World Health Organization (WHO), COPD would become the third greatest cause of mortality worldwide by the year 2020. These patients are also very substantial consumers of the resources made available by the health and social care systems. Because there is now no treatment that can reverse the effects of COPD, patients are responsible for their own healthcare and the management of their condition. There is a correlation between the amount of cigarettes smoked and the degree to which COPD is present. The pathophysiology of COPD is intimately tied to the impact that cigarette smoke has on the lungs. Pharmacological trials that were carried out more than three decades ago with the use of short-acting bronchodilators or inhaled glucocorticoids did not succeed in demonstrating a statistically significant slower rate of FEV1 decline in comparison to the placebo group in their intention-to-treat populations. In light of these equivocal data, the belief that smoking cessation is the only treatment that can delay the course of COPD became widespread. Unfortunately, this pessimism has had a negative impact on how the general public views COPD and has decreased interest in alternative therapeutic techniques. Tiotropium had a greater FEV1 than the placebo, and it also reduced the annual reduction in FEV1 after bronchodilator usage in individuals with COPD who were in the GOLD stage 1 or 2 range. FEV1 drop might be stopped by FF or VI. The patients expressed satisfaction with the treatment, which resulted in fewer exacerbations. It seems like fluticasone furoate or vilanterol could slow down the drop in FEV1 levels.

Chronic Obstructive Pulmonary Disease and Its Effect on Red Blood Cell Indices.

Chronic obstructive pulmonary disease (COPD) constitutes a set of heterogeneous symptoms affecting millions of people worldwide. The associated comorbidities developing in COPD involve dysregulation in physiological pathways resulting from systemic inflammation in respiratory airways. In addition to mentioning the pathophysiology, stages, and consequences of COPD, this paper also defines red blood cell (RBC) indices such as hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red blood cell distribution width, and RBC count. It explains the role of RBC indices and RBC structural abnormalities with disease severity and exacerbations in COPD patients. Although many factors have been studied as a marker of morbidity and mortality for COPD patients, RBC indices have emerged as revolutionary evidence. Therefore, the effectiveness of evaluating RBC indices in COPD patients and their importance as a negative predictor of survival, mortality, and clinical outcomeshave been debated through rigorous literature reviews. Furthermore, the prevalence, mechanisms of development, and prognosis of underlying anemia and polycythemia in COPD have also been evaluated, with anemia most significantly associated with COPD. Therefore, more studies should be conducted to address underlying anemia in COPD patients to lessen the severity and disease burden. Correcting the RBC indices in COPD patients remarkably impacts the quality of life and reduces in-patient admissions, healthcare resource utilization, and costs. Hence, it is noteworthy to understand the significance of considering RBC indices while dealing with COPD patients.

The receptor for advanced glycation end products (RAGE) is involved in mitochondrial function and cigarette smoke-induced oxidative stress.

The mechanisms underlying muscle dysfunction with Chronic Obstructive Pulmonary Disease (COPD) are poorly understood. Indirect evidence has recently suggested a role of Advanced Glycation End Products (AGEs) and their receptor (RAGE) in the pathophysiology of COPD. Accordingly, this study aimed to examine the redox balance and mitochondrial alterations in the skeletal muscle of a mouse model deficient in the receptor for AGE (RAGE-KO) and wild-type C57BL/6 exposed to cigarette smoke for 8-months using immunoblotting, spectrophotometry, and high-resolution respirometry. Cigarette smoke exposure increased by two-fold 4-HNE levels (P < 0.001), a marker of oxidative stress, and markedly downregulated contractile proteins, mitochondrial respiratory complexes, and uncoupling proteins levels (P < 0.001). Functional alterations with cigarette smoke exposure included a greater reliance on complex-I supported respiration (P < 0.01) and lower relative respiratory capacity for fatty acid (P < 0.05). RAGE knockout resulted in 47% lower 4-HNE protein levels than the corresponding WT control mice exposed to cigarette smoke (P < 0.05), which was partly attributed to increased Complex III protein levels. Independent of cigarette smoke exposure, RAGE KO decreased mitochondrial specific maximal respiration (P < 0.05), resulting in a compensatory increase in mitochondrial content measured by citrate synthase activity (P < 0.001) such that muscle respiratory capacity remained unaltered. Together, these findings suggest that knockout of RAGE protected the skeletal muscle against oxidative damage induced by 8 months of cigarette smoke exposure. In addition, this study supports a role for RAGE in regulating mitochondrial content and function and can thus serve as a potential therapeutic target.

Expression profile of the free radicals metabolism and antioxidant genes in chronic obstructive lung disease

Chronic obstructive pulmonary disease (COPD) is a multifactorial heterogeneous chronic inflammatory disease of the respiratory system. Oxidative stress plays a central role in the pathophysiology of COPD. The goal of the study is the identification of new molecular markers of COPD based on the analysis of the expression profile of genes involved to oxidative stress response and antioxidant protection in peripheral blood mononuclear cells. Methods. To identify differential gene expression in COPD we performed expression profiling of 84 oxidative stress response and antioxidant protection genes in peripheral blood mononuclear cells samples from COPD (N=10 with frequent exacerbation emphysema and bronchitis phenotype, N=10 rare exacerbation emphysema phenotype and N=10 smoking controls). RNA was isolated from PBMCs, and gene expression was assessed using RT2 Profiler PCR Arrays « Human Oxidative Stress Plus PCR Array» (Qiagen). Results. Significant changes were revealed in the expression profile of several genes in frequent exacerbation emphysema and bronchitis phenotype COPD phenotype: decreased expression of BNIP3, GCLC, PRNP, TTN, HSP90AA1 gene; and increased expression of FTH1, PRDX3, SOD2 genes. In the group of COPD patients with rare exacerbation emphysema phenotype, an increase in the transcriptional activity of most genes that play a key role in the mechanisms of cell protection from free radical damage was found: FTH1, PRDX3, SOD2, PTGR1,GPX4, GSR, PTGS1, HSPA1A, NCF1 и NCF2, PRDX5, SIRT2, SQSTM1, SRXN1, TXNRD2, LHPP. We confirmed the assumption that the blood cell transcriptome reflects the pathogenesis and systemic nature of COPD and can be considered as a source of information for assessing the severity of the disease, monitoring the effectiveness of therapy, and searching for new non-invasive biomarkers of the disease and its various phenotypes.

Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD

IntroductionPatients with chronic obstructive pulmonary disease (COPD) are often hospitalised due to severe acute exacerbation (AE) or community-acquired pneumonia (CAP). Previous studies revealed the association of cough reflex sensitivity with...

New Frontiers in Chronic Obstructive Pulmonary Disease: Where Are We Heading?

This symposium took place during the 2022 meeting of the European Respiratory Society (ERS). Focusing on new frontiers in chronic obstructive pulmonary disease (COPD), the speakers discussed the current understanding of the heterogeneity of COPD, the spectrum of inflammatory pathways in COPD pathophysiology, and the evolving clinical landscape in COPD. Alvar Agustí, Professor of Medicine at the University of Barcelona, Spain, introduced the concept of a gene, environment, and time (GETomic) perspective of COPD, ending with the trajectome, or range of lung function trajectories, through the lifespan. Stephanie Christenson, Assistant Professor of Pulmonology at the University of California, San Francisco, USA, followed by exploring the role of inflammation in COPD, highlighting that it is a heterogeneous disease with broad inflammatory pathways. This includes types 1, 17, and 2 inflammation; a wide range of immune effector cells beyond eosinophils; and key cytokines such as IL-33, IL-4, IL-13, and IL-5, which mediate the pathophysiology of COPD in response to cigarette smoke and other environmental insults. The need for continued investigation of molecular phenotypes was expanded on further by MeiLan Han, Professor of Medicine at the University of Michigan, Ann Arbor, USA, who explored the knowns and unknowns in the standard-of-care management of patients with COPD, highlighting the evolving understanding and identification of disease endotypes and phenotypes; poor understanding of COPD disease progression; the importance of smoking status in response to currently available treatments; and significant unmet need for additional treatment, even among patients on triple therapy. Dave Singh, Professor of Respiratory Pharmacology at the University of Manchester, UK, then discussed active areas of investigation in the development of additional treatments for patients with COPD.

Smoking-Associated Exposure of Human Primary Bronchial Epithelial Cells to Aldehydes: Impact on Molecular Mechanisms Controlling Mitochondrial Content and Function.

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease primarily caused by exposure to cigarette smoke (CS). During the pyrolysis and combustion of tobacco, reactive aldehydes such as acetaldehyde, acrolein, and formaldehyde are formed, which are known to be involved in respiratory toxicity. Although CS-induced mitochondrial dysfunction has been implicated in the pathophysiology of COPD, the role of aldehydes therein is incompletely understood. To investigate this, we used a physiologically relevant in vitro exposure model of differentiated human primary bronchial epithelial cells (PBEC) exposed to CS (one cigarette) or a mixture of acetaldehyde, acrolein, and formaldehyde (at relevant concentrations of one cigarette) or air, in a continuous flow system using a puff-like exposure protocol. Exposure of PBEC to CS resulted in elevated IL-8 cytokine and mRNA levels, increased abundance of constituents associated with autophagy, decreased protein levels of molecules associated with the mitophagy machinery, and alterations in the abundance of regulators of mitochondrial biogenesis. Furthermore, decreased transcript levels of basal epithelial cell marker KRT5 were reported after CS exposure. Only parts of these changes were replicated in PBEC upon exposure to a combination of acetaldehyde, acrolein, and formaldehyde. More specifically, aldehydes decreased MAP1LC3A mRNA (autophagy) and BNIP3 protein (mitophagy) and increased ESRRA protein (mitochondrial biogenesis). These data suggest that other compounds in addition to aldehydes in CS contribute to CS-induced dysregulation of constituents controlling mitochondrial content and function in airway epithelial cells.

Contribution of adaptive immunity to human COPD and experimental models of emphysema.

The pathophysiology of chronic obstructive pulmonary disease (COPD) and the undisputed role of innate immune cells in this condition have dominated the field in the basic research arena for many years. Recently, however, compelling data suggesting that adaptive immune cells may also contribute to the progressive nature of lung destruction associated with COPD in smokers have gained considerable attention. The histopathological changes in the lungs of smokers can be limited to the large or small airways, but alveolar loss leading to emphysema, which occurs in some individuals, remains its most significant and irreversible outcome. Critically, however, the question of why emphysema progresses in a subset of former smokers remained a mystery for many years. The recognition of activated and organized tertiary T- and B-lymphoid aggregates in emphysematous lungs provided the first clue that adaptive immune cells may play a crucial role in COPD pathophysiology. Based on these findings from human translational studies, experimental animal models of emphysema were used to determine the mechanisms through which smoke exposure initiates and orchestrates adaptive autoreactive inflammation in the lungs. These models have revealed that T helper (Th)1 and Th17 subsets promote a positive feedback loop that activates innate immune cells, confirming their role in emphysema pathogenesis. Results from genetic studies and immune-based discoveries have further provided strong evidence for autoimmunity induction in smokers with emphysema. These new findings offer a novel opportunity to explore the mechanisms underlying the inflammatory landscape in the COPD lung and offer insights for development of precision-based treatment to halt lung destruction.

TLR5 Variants Are Associated with the Risk for COPD and NSCLC Development, Better Overall Survival of the NSCLC Patients and Increased Chemosensitivity in the H1299 Cell Line.

Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case–control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.