Progression Of Chronic Obstructive Pulmonary Disease Research Articles

Discovering the role of microRNAs and exosomal microRNAs in chest and pulmonary diseases: a spotlight on chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition and ranks as the fourth leading cause of mortality worldwide. Despite extensive research efforts, a reliable diagnostic or prognostic tool for COPD remains elusive. The identification of novel biomarkers may facilitate improved therapeutic strategies for patients suffering from this debilitating disease. MicroRNAs (miRNAs), which are small non-coding RNA molecules, have emerged as promising candidates for the prediction and diagnosis of COPD. Studies have demonstrated that dysregulation of miRNAs influences critical cellular and molecular pathways, including Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad, which may contribute to the pathogenesis of COPD. Extracellular vesicles, particularly exosomes, merit further investigation due to their capacity to transport various biomolecules such as mRNAs, miRNAs, and proteins between cells. This intercellular communication can significantly impact the progression and severity of COPD by modulating signaling pathways in recipient cells. A deeper exploration of circulating miRNAs and the content of extracellular vesicles may lead to the discovery of novel diagnostic and prognostic biomarkers, ultimately enhancing the management of COPD. The current review focus on the pathogenic role of miRNAs and their exosomal counterparts in chest and respiratory diseases, centering COPD.

Beta-elemene alleviates cigarette smoke-triggered inflammation, apoptosis, and oxidative stress in human bronchial epithelial cells, and refrains the PI3K/AKT/mTOR signaling pathway.

Chronic obstructive pulmonary disease (COPD) is a grievous disease that adversely affects human health and life. β-elemene is a type of sesquiterpenoid extracted from Curcuma wenyujin (Zingiberaceae) and displays effects on suppressing tumor growth. However, the regulatory impact of β-elemene in COPD development is not reported. This study explored the functioning of β-elemene in the progression of COPD. The cell survival rate was confirmed through Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis was evaluated through flow cytometry. The protein expressions were examined through western blot. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) were examined through the corresponding commercial kits. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β were inspected through Enzyme-Linked Immunosorbent Assay (ELISA). The study demonstrated that β-elemene exaggerated cell viability and reduced cell apoptosis in BEAS-2B human bronchial epithelial cell line stimulated by cigarette smoke extract (CSE). Oxidative stress was heightened after 5% CSE induction, but this impact was counteracted by β-elemene treatment. In addition, enhancive inflammation induced by cigarette smoke was attenuated by β-elemene treatment. Finally, our results indicated that the triggered the phosphatidylinositol 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway mediated by cigarette smoke was refrained by β-elemene treatment. It was concluded that β-elemene reduced cigarette smoke-triggered inflammation, apoptosis, and oxidative stress in human bronchial epithelial cell line, and refrained PI3K/AKT/mTOR signaling pathway. This study proposed that β-elemene could act as a hopeful drug for the treatment of COPD.

The Role of Viral Infections in the Development and Progression of COPD.

Chronic obstructive pulmonary disease (COPD) is a common chronic disease seen in smokers associated with poor functional status, quality of life, and morbidity and mortality from acute worsening of chronic symptoms, also called exacerbations. As a disease, the risk factors for COPD are well defined; however, there is room for innovation in identifying underlying biological processes, or "endotypes," that lead to the emergence and/or progression of COPD. Identifying endotypes allows for more thorough understanding of the disease, may reveal the means of disease prevention, and may be leveraged in novel therapeutic approaches. In this review, we discuss the interface of viral infections with both cellular and epithelial immunity as a potential endotype of interest in COPD.

An Agent-Based "Virtual Clinical Trial" for the Analysis and Evaluation of COPD Patients Cohorts Behavior

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory condition characterized by inflammation and narrowing of the airways, leading to symptoms such as shortness of breath, coughing, and chest tightness. Treatment typically involves lifestyle adjustments, medication, and pulmonary rehabilitation to improve lung function and quality of life. This study presents a model examining COPD patient behavior within cohort-based strategies, focusing on how environmental factors impact vital signs across the entire cohort. We developed a comprehensive virtual clinical trial model that encompasses study protocol design, participant recruitment, virtual data collection, outcome analysis, and conclusions. This includes remote symptom monitoring, virtual healthcare consultations, treatment adherence assessments, and research data collection. Additionally, we explore the influence of external variables such as environmental conditions, comorbidities, and lifestyle factors on chronic disease symptoms and disease stability. We used an Agent-Based Model(ABM) to incorporate these factors to assess COPD progression and treatment efficacy. Individual agents represent COPD patients, each characterized by attributes such as age, smoking history, lung function, comorbidities, and treatment plans.

MiR-1307-5p enhances fibroblast transdifferentiation to exacerbate chronic obstructive pulmonary disease through regulating FBXL16/HIF1α axis

Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive chronic inflammatory lung disease which affects millions of people worldwide. Activated fibroblasts are observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition. In this study, we identified that miR-1307-5p expression was significantly increased in lung fibroblasts derived from COPD patients. Mechanistically, we found that upregulation of miR-1307-5p promoted TGF-β induced lung fibroblast activation and transdifferentiation. We also identified FBXL16 as a direct target for miR-1307-5p mediated myofibroblast activation in COPD. Knockdown of FBXL16 by siRNA prominently increased the expression of myofibroblast markers in MRC-5 fibroblasts after TGF-β administration. Ectopic expression of FBXL16 in MRC-5 counteracted miR-1307-5p agomir-induced fibroblast transdifferentiation. Furthermore, We found that miR-1307-5p promoted pulmonary fibroblast transdifferentiation through FBXL16 regulated HIF1α degradation. In general, our findings indicate that miR-1307-5p is important for COPD pathogenesis, and may serve as a potential target for COPD treatment.

Progress in impulse oscillometry on chronic obstructive pulmonary disease

Impulse oscillometry (IOS) is a force-free, easy-to-use tool for the detection of airway resistance. Compared with spirometry, IOS is more sensitive in detecting early abnormalities in chronic obstructive pulmonary disease (COPD), and IOS parameters have potential research value in identifying the progression of COPD and monitoring the effect of treatment. This review aimed to highlight the significant research findings of IOS in chronic obstructive pulmonary disease and to address the urgent issue that need to be resolved.

HMGB1 promotes M1 polarization of macrophages and induces COPD inflammation.

Chronic obstructive pulmonary disease (COPD) is a pervasive and incapacitating respiratory condition, distinguished by airway inflammation and the remodeling of the lower respiratory tract. Central to its pathogenesis is an intricate inflammatory process, wherein macrophages exert significant regulatory functions, and High mobility group box 1 (HMGB1) emerges as a pivotal inflammatory mediator potentially driving COPD progression. This study explores the hypothesis that HMGB1, within macrophages, modulates COPD through inflammatory mechanisms, focusing on its influence on macrophage polarization. Our investigation uncovered that HMGB1 is upregulated in the context of COPD, associated with an enhanced proinflammatory M1 macrophage polarization induced by cigarette smoke. This polarization is linked to suppressed cell proliferation and induced apoptosis, indicative of HMGB1's role in the disease's inflammatory trajectory. The study further implicates HMGB1 in the activation of the Nuclear factor kappa-B (NF-κB) signaling pathway and chemokine signaling within macrophages, which are likely to amplify the inflammatory response characteristic of COPD. The findings underscore HMGB1's critical involvement in COPD pathogenesis, presenting it as a significant target for therapeutic intervention aimed at modulating macrophage polarization and inflammation.

Differential miRNA Profiling Reveals miR-4433a-5p as a Key Regulator of Chronic Obstructive Pulmonary Disease Progression via PIK3R2- mediated Phenotypic Modulation.

In this study, a high-throughput sequencing technology was used to screen the differentially expressed miRNA in the patients with "fast" and "slow" progression of chronic obstructive pulmonary disease (COPD). Moreover, the possible mechanism affecting the progression of COPD was preliminarily analyzed based on the target genes of candidate miRNAs. The "fast" progressive COPD group included 6 cases, "slow" and Normal progressive COPD groups included 5 cases each, and COPD group included 3 cases. The peripheral blood samples were taken from the participants, followed by total RNA extraction and high throughput miRNA sequencing. The differentially expressed miRNAs among the progressive COPD groups were identified using bioinformatics analysis. Then, the candidate miRNAs were externally verified. In addition, the target gene of this miRNA was identified, and its effects on cell activity, cell cycle, apoptosis, and other biological phenotypes of COPD were analyzed. Compared to the Normal group, a total of 35, 16, and 7 differentially expressed miRNAs were identified in the "fast" progressive COPD, "slow" progressive COPD group, and COPD group, respectively. The results were further confirmed using dual-luciferase reporter assay and transfection tests with phosphoinositide- 3-kinase, regulatory subunit 2 (PIK3R2) as a target gene of miR-4433a-5p; the result showed a negative regulatory correlation between the miRNA and its target gene. The phenotype detection showed that the activation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway might participate in the progression of COPD by promoting the proliferation of inflammatory A549 cells and inhibiting cellular apoptosis. MiR-4433a-5p can be used as a marker and potential therapeutic target for the progression of COPD. As a target gene of miR-4433a-5p, PIK3R2 can affect the progression of COPD by regulating phenotypes, such as cellular proliferation and apoptosis.

PTGES is involved in myofibroblast differentiation via HIF-1α-dependent glycolysis pathway.

Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with lung cancer usually exhibit poor prognoses and low 5-year survival rates. Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both chronic lung dysfunctions resulting in lung fibrosis and increased risk of lung cancer. Myofibroblasts contribute to the progression of asthma, COPD and IPF, leading to fibrosis in the airway and lungs. A growing body of evidence demonstrates that metabolic reprogramming is a major hallmark of fibrosis, being important in the progression of fibrosis. Using gene expression microarray, we identified and validated that the lipid metabolic pathway was upregulated in lung fibroblasts upon interleukin (IL)-4, IL-13 and tumour necrosis factor (TNF)-α treatment. In this study, we described that prostaglandin E synthase (PTGES) was upregulated in lung fibroblasts after IL-4, IL-13 and TNF-α treatments. PTGES increased α-SMA levels and promoted lung fibroblast cell migration and invasion abilities. Furthermore, PTGES was upregulated in a lung fibrosis rat model invivo. PTGES increased AKT phosphorylation, leading to activation of the HIF-1α-glycolysis pathway in lung fibroblast cells. HIF-1α inhibitor or 2-DG treatments reduced α-SMA expression in recombinant PTGES (rPTGES)-treated lung fibroblast cells. Targeting PGE2 signalling in PTGES-overexpressing cells by a PTGES inhibitor reduced α-SMA expression. In conclusion, the results of this study demonstrate that PTGES increases the expression of myofibroblast marker via HIF-1α-dependent glycolysis and contributes to myofibroblast differentiation.

Effectiveness of TheraPEP Versus Conventional Breathing Techniques in Managing Acute COPD Exacerbations

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, often complicated by acute exacerbations that impair lung function and quality of life. Effective airway clearance techniques are essential in managing exacerbations, but the comparative effectiveness of different methods remains unclear. This study aimed to evaluate the short-term effectiveness of TheraPEP, a positive expiratory pressure (PEP) device, versus the Active Cycle of Breathing Technique (ACBT) in managing acute COPD exacerbations. Methods: A randomized controlled trial (RCT) was conducted with 60 patients (≥40 years) admitted with acute exacerbations of COPD. Participants were randomly assigned to either the TheraPEP group (n=30) or the ACBT group (n=30). Each group received three daily sessions of their assigned therapy throughout their hospital stay. Primary outcomes included dyspnea, measured by the modified Borg Dyspnea Scale, and secondary outcomes included sputum clearance, lung function (FEV1, FVC, and FEV1/FVC ratio), oxygen saturation (SpO₂), and quality of life, measured by the Breathlessness, Cough, and Sputum Scale (BCSS). Data were collected at baseline, discharge, and 14-day follow-up. A two-way repeated-measures ANOVA was used to examine changes in dyspnea, lung function, sputum clearance, SpO₂, and BCSS scores over time (baseline, discharge, and 14-day follow-up) within and between groups. The main effects of time (within-subject factor) and group (between-subject factor) were assessed, along with the interaction effects (time × group). Results: Both groups demonstrated significant improvements in dyspnea, lung function, and quality of life from baseline to discharge and follow-up. However, the TheraPEP group showed significantly greater improvements in sputum clearance (p=0.01), oxygen saturation (p=0.03), and BCSS scores (p=0.03) compared to the ACBT group. No significant between-group differences were found for FEV1, FVC, or FEV1/FVC ratio (p > 0.05). Conclusions: Both TheraPEP and ACBT are effective in managing acute COPD exacerbations, but TheraPEP offers additional benefits in terms of sputum clearance and oxygenation. These findings suggest that TheraPEP may be more suitable for patients with severe mucus hypersecretion. Further research is warranted to assess the long-term effects of these therapies on COPD progression and patient outcomes.

Therapeutic potential of 18-β-glycyrrhetinic acid-loaded poly (lactic-co-glycolic acid) nanoparticles on cigarette smoke-induced in-vitro model of COPD

Chronic obstructive pulmonary disease (COPD) is strongly linked to cigarette smoke, which contains toxins that induce oxidative stress and airway inflammation, ultimately leading to premature airway epithelial cell senescence and exacerbating COPD progression. Current treatments for COPD are symptomatic and hampered by limited efficacy and severe side effects. This highlights the need to search for an optimal therapeutic candidate to address the root causes of these conditions. This study investigates the possible potential of poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles encapsulating the plant-based bioactive compound 18-β-glycyrrhetinic acid (18βGA) as a strategy to intervene in cigarette smoke extract (CSE)-induced oxidative stress, inflammation, and senescence, in vitro. We prepared 18βGA-PLGA nanoparticles, and assessed their effects on cell viability, reactive oxygen species (ROS) production, anti-senescence properties (expression of senescence-associated β galactosidase and p21 mRNA), and expression of pro-inflammatory genes (CXCL-1, IL-6, TNF-α) and inflammation-related proteins (IL-8, IL-15, RANTES, MIF). The highest non-toxic concentration of 18βGA-PLGA nanoparticles to healthy human broncho epithelial cell line BCiNS1.1 was identified as 5 µM. These nanoparticles effectively mitigated cigarette smoke-induced inflammation, reduced ROS production, protected against cellular aging, and counteracted the effects of CSE on the expression of the inflammation-related genes and proteins. This study underscores the potential of 18βGA encapsulated in PLGA nanoparticles as a promising therapeutic approach to alleviate cigarette smoke-induced oxidative stress, inflammation, and senescence. Further research is needed to explore the translational potential of these findings in clinical and in vivo settings.

Smoking cessation program preferences of individuals with chronic obstructive pulmonary disease: a qualitative study.

To explore the views of tobacco-smoking chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) patients on telehealth-based cessation programs and the role of e-cigarettes as an aid to quit smoking. Tobacco smoking accelerates the progression of COPD. Traditional smoking cessation programs often do not entirely address the unique needs of COPD patients, leading to suboptimal effectiveness for this population. This research is aimed at describing the attitudes and preferences of COPD and ACO patients toward innovative, telehealth-based smoking cessation strategies and the potential application of e-cigarettes as a quitting aid. A qualitative exploratory approach was adopted in this study, employing both focus groups and individual interviews with English-speaking adults with diagnosed COPD or ACO. Participants included both current smokers (≥ 5 cigarettes/day) and recent ex-smokers (who quit < 12 months ago). Data were systematically coded with iterative reliability checks and subjected to thematic analysis to extract key themes. A total of 24 individuals participated in this study. The emergent themes were the perceived structure and elements of a successful smoking cessation program, the possible integration of telehealth with digital technologies, and the strategic use of e-cigarettes for smoking reduction or cessation. The participants stressed the importance of both social and professional support in facilitating smoking cessation, expressing a high value for insights provided by ex-smokers serving as mentors. A preference was observed for group settings; however, the need for individualized plans was also highlighted, considering the diverse motivations individuals had to quit smoking. The participants perceived online program delivery as potentially beneficial as it could provide immediate access to support during cravings or withdrawals and was accessible to remote users. Opinions on e-cigarettes were mixed; some participants saw them as a less harmful alternative to conventional smoking, while others were skeptical of their efficacy and safety and called for further research.

Active Components of Wen Fei Fu Yang Qu Tan Fang and its Molecular Targets for Chronic Obstructive Pulmonary Disease Based on Network Pharmacology and Molecular Docking.

To investigate the mechanism of Wen Fei Fu Yang Qu Tan Fang (WFFYQTF) in the treatment of chronic obstructive pulmonary disease (COPD) using network pharmacology and pharmacodynamics. The TCMSP database was utilized to identify the chemical components and molecular targets of WFFYQTF. Cytoscape software was employed to construct a "drug component-target" network. COPD risk genes and intersecting molecular targets of WFFYQTF were identified using GeneCards, OMIM, and DisGeNET databases. The STRING website was the place where protein-protein interaction (PPI) analysis was performed. Cytoscape topological analysis was applied for screening out key targets of WFFYQTF. GO and KEGG enrichment analyses were conducted using the DAVID database to elucidate the treatment targets of COPD with WFFYQTF. A total of 136 active components of WFFYQTF were identified, including key components such as quercetin, kaempferol, and luteolin, which were found to be particularly significant. Additionally, 412 drug targets and 7121 COPD risk genes were screened out, and 323 treatment targets of COPD with WFFYQTF were determined by Wayne analysis. Core targets identified via PPI analysis included SRC, STAT3, AKT1, HSP90AA1, and JUN. Pathways such as the hypoxia responce, inflammatory response, PI3K/AKT pathway, TH17 pathway and MAPK pathway were obtained with GO and KEGG enrichment analyses. Molecular docking results suggested that quercetin could be soundly bound to STAT3 and AKT1, and kaempferol to SRC. WFFYQTF can effectively impede COPD progression through the coordinated action of multiple components, targets, and pathways during treatment.

Identification of diagnostic biomarkers and immune cell profiles associated with COPD integrated bioinformatics and machine learning.

This retrospective transcriptomic study leveraged bioinformatics and machine learning algorithms to identify novel gene biomarkers and explore immune cell infiltration profiles associated with chronic obstructive pulmonary disease (COPD). Utilizing an integrated analysis of metadata encompassing six gene expression omnibus (GEO) microarray datasets, 987 differentially expressed genes were identified. Further gene ontology and pathway enrichment analyses revealed the enrichment of these genes across various biological processes and pathways. Moreover, a systematic integration of two machine learning algorithms along with pathway-gene correlations identified six candidate biomarkers, which were validated in a separate cohort comprising six additional microarray datasets, ultimately identifying ADD3 and GNAS as diagnostic biomarkers for COPD. Subsequently, the diagnostic efficacy of ADD3 and GNAS was assessed, and the impact of their expression levels on overall survival was further evaluated and quantified in the validation cohort. Examination of immune cell subtype infiltration found increased proportions of cytotoxic CD8+ T cells, resting and activated NK cells, along with decreased M0 and M2 macrophages, in COPD versus control samples. Correlation analyses also uncovered significant associations between ADD3 and GNAS expression and infiltration of various immune cell types. In conclusion, this study elucidates crucial COPD diagnostic biomarkers and immune cell profiles which may illuminate the immunopathological drivers of COPD progression, representing personalized therapeutic targets warranting further investigation.

Effect of allyl isothiocyanate on 4-HNE induced glucocorticoid resistance in COPD and the underlying mechanism

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition, and its clinical management primarily targets bronchodilation and anti-inflammatory therapy. However, these treatments often fail to directly address the progression of COPD, particularly its associated glucocorticoid (GC) resistance. This study elucidates the mechanisms underlying GC resistance in COPD and explores the therapeutic potential of allyl isothiocyanate (AITC) in modulating MRP1 transport. We assessed the levels of the oxidative stress product 4-HNE, HDAC2 protein, inflammatory markers, and pulmonary function indices using animal and cell models of GC-resistant COPD. The cascade effects of these factors were investigated through interventions involving AITC, protein inhibitors, and dexamethasone (DEX). Cigarette smoke-induced oxidative stress in COPD leads to the accumulation of the lipid peroxidation product 4-HNE, which impairs HDAC2 protein activity and diminishes GC-mediated anti-inflammatory sensitivity due to disrupted histone deacetylation. AITC regulates MRP1, facilitating the effective efflux of 4-HNE from cells, thereby reducing HDAC2 protein degradation and restoring dexamethasone sensitivity in COPD. These findings elucidate the mechanism of smoking-induced GC resistance in COPD and highlight MRP1 as a potential therapeutic target, as well as the enormous potential of AITC for combined GC therapy in COPD, promoting their clinical applications.

It is high time to discard a cut-off of 0.70 in the diagnosis of COPD.

Chronic obstructive pulmonary disease (COPD) has traditionally been diagnosed based on the criterion of an FEV1/FVC <0.70. However, this definition has limitations as it may only detect patients with later-stage disease, when pathologic changes have become irreversible. Consequently, it potentially omits individuals with early-stage disease, in whom the pathologic changes could be delayed or reversed. This narrative review summarizes recent evidence regarding early-stage COPD, which may not fulfill the spirometric criteria but nonetheless exhibits features of COPD or is at risk of future COPD progression. A comprehensive approach, including symptoms assessment, various physiologic tests, and radiologic features, is required to diagnose COPD. This approach is necessary to identify currently underdiagnosed patients and to halt disease progression in at- risk patients.

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

Edwardsiella tarda induces airways inflammation and production of autoantibodies against lung tissues through regulation of the IL-33-ST2 axis.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease characterised by irreversible airways obstruction associated with chronic airways inflammation and remodelling, while the pathogenesis and the mechanistic differences between patients remain to be fully elucidated. We previously reported that alarmin cytokine IL-33 may contribute to the production of autoantibodies against respiratory epithelial cells. Here we expand the hypothesis that pulmonary autoimmune responses induced by airway microbiota also contribute to the progression of COPD. We focused on Edwardsiella tarda which we detected uniquely in the induced sputum of patients with acute exacerbations of COPD. Pernasal challenge of the airways of WT mice with supernatants of cultured E. tarda induced marked, elevated expression of IL-33 in the lung tissues. Immunisation of animals with supernatants of cultured E. tarda resulted in significantly elevated airways inflammation, the formation of tertiary lymphatic structures and significantly elevated proportions of T follicular helper T cells in the lung tissue and mediastinal lymph nodes. Interestingly, such challenge also induced production of IgG autoantibodies directed against lung tissue lysate, alveolar epithelial cell proteins and elastin fragment, while putrescine, one of metabolites generated by the bacterium, might play an important role in the autoantibody production. Furthermore, all of these effects were partly but significantly abrogated in mice with deletion of the IL-33 receptor ST2. Collectively, these data support the hypothesis that COPD is progressed at least partly by airways microbiota such as E. tarda initiating autoimmune attack of the airways epithelium mediated at least partly through the IL-33-ST2 axis.

A Low Expression of NRF2 Enhances Oxidative Stress and Autophagy in Myofibroblasts, Promoting Progression of Chronic Obstructive Pulmonary Disease.

The inflammation phenotypes are often closely related to oxidative stress and autophagy pathway activation, which could be developed as a treatment target. The aim of this study was to explore the underlying mechanism of inflammation in chronic obstructive pulmonary disease (COPD). The lung tissue single-cell RNA-seq (scRNA-seq) dataset of GSE171541 was downloaded from the Gene Expression Omnibus (GEO) database. The marker genes were obtained from the CellMarker database. "Seurat" and "harmony" R packages were used for single-cell profiling analysis. Then, the "AUCell" R package was employed to calculate the reactive oxygen species (ROS) and autophagy pathway scores. Gene regulation network analysis was performed by applying the "SCENIC" package, followed by conducting correlation analysis with Spearman's rank correlation method. The cigarettes were used to develop a traumatic model in mice, and the expression of relevant genes was measured by qRT-PCR. The scRNA-seq analysis classified 12 cell subgroups in which the contractility of myofibroblasts was closely associated with the progression of COPD. Further analysis showed that ROS and autophagy pathways were significantly activated in myofibroblasts and that the nuclear factor erythroid 2-related factor 2 (NRF2) and its mediated oxidative stress pathway were inhibited in myofibroblasts. In addition, the downregulated NRF2 gene was negatively correlated with the expression of autophagy and ROS activation. In the traumatic mice model, NRF2 was downregulated in COPD mice but further elevated in the COPD+NRF2 mice group. Interestingly, the mRNA levels of Kelchlike ECH-associated protein 1 (Keap1), NADPH oxidase (NOX), and Cathepsin B (CTSB) were upregulated in COPD group in comparison to the control group but they were downregulated by NRF2. These results suggested that low-expressed NFR2 promoted autophagy and ROS pathway activation in myofibroblasts for COPD progression. We identified a cell myofibroblast cluster closely associated with COPD progression using the scRNA-seq analysis. The downregulated NFR2, as a key risk factor, mediated myofibroblast death by activating the oxidative stress and autophagy pathway for COPD progression.

Cell death crosstalk in respiratory diseases: unveiling the relationship between pyroptosis and ferroptosis in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.