Pathogenesis Of Chronic Obstructive Pulmonary Disease Research Articles

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

Bronchoalveolar Lavage Fluid from Chronic Obstructive Pulmonary Disease Patients Increases Neutrophil Chemotaxis Measured by a Microfluidic Platform.

Chronic obstructive pulmonary disease (COPD) is a persistent and progressive respiratory disorder characterized by expiratory airflow limitation caused by chronic inflammation. Evidence has shown that COPD is correlated with neutrophil chemotaxis towards the airways, resulting in neutrophilic airway inflammation. This study aimed to evaluate neutrophil chemotaxis in bronchoalveolar lavage fluid (BALF) from COPD patients using a high-throughput nine-unit microfluidic platform and explore the possible correlations between neutrophil migratory dynamics and COPD development. The results showed that BALF from COPD patients induced stronger neutrophil chemotaxis than the Control BALF. Our results also showed that the chemotactic migration of neutrophils isolated from the blood of COPD patients was not significantly different from neutrophils from healthy controls, and neutrophil migration in three known chemoattractants (fMLP, IL-8, and LTB4) was not affected by glucocorticoid treatment. Moreover, comparison with clinical data showed a trend of a negative relationship between neutrophil migration chemotactic index (C. I.) in COPD BALF and patient's spirometry data, suggesting a potential correlation between neutrophil migration and the severity of COPD. The present study demonstrated the feasibility of using the microfluidic platform to assess neutrophil chemotaxis in COPD pathogenesis, and it may serve as a potential marker for COPD evaluation in the future.

Endoplasmic reticulum stress: a vital process and potential therapeutic target in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), a chronic and progressive disease characterized by persistent respiratory symptoms and progressive airflow obstruction, has attracted extensive attention due to its high morbidity and mortality. Although the understanding of the pathogenesis of COPD has gradually increased because of increasing evidence, many questions regarding the mechanisms involved in COPD progression and its deleterious effects remain unanswered. Recent advances have shown the potential functions of endoplasmic reticulum (ER) stress in causing airway inflammation, emphasizing the vital role of unfolded protein response (UPR) pathways in the development of COPD. A comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original research articles and reviews related to ER stress, UPR, and COPD. The common causes of COPD, namely cigarette smoke(CS)and air pollutants, induce ERstress through the generation of reactive oxygen species (ROS). UPR promotes mucus secretion and further plays a dual role in the cell apoptosis-autophagy axis in the development of COPD. Existing drug research has indicated the potential of UPR as a therapeutic target for COPD. ER stress and UPR activation play significant roles in the etiology, pathogenesis, and treatment of COPD and discuss whether related genes can be used as biomarkers and therapeutic targets.

Harnessing the Therapeutic Potential of Stem Cells in the Management of Chronic Obstructive Pulmonary Disease: A Comprehensive Review.

Chronic obstructive pulmonary disease (COPD) is a prevalent and debilitating respiratory condition with limited treatment options. Stem cell therapy has emerged as a promising approach for COPD management due to its regenerative and immunomodulatory properties. This review article aims to comprehensively explore the therapeutic potential of stem cells in COPD management. The introduction provides background on COPD, highlighting its impact on health and the need for novel therapies. The different types of stem cells relevant to COPD, including embryonic stem cells, adult stem cells, and induced pluripotent stem cells, are described along with their properties and characteristics. The pathogenesis of COPD is discussed, emphasizing the key mechanisms involved in disease development and progression. Subsequently, the role of stem cells in tissue repair, regeneration, and immunomodulation is examined, highlighting their ability to address specific pathological processes in COPD. Mechanisms of action, such as paracrine signaling, immunomodulation, anti-inflammatory effects, and tissue regeneration, are explored. The interaction between stem cells and the host environment, which promotes lung repair, is also discussed. Challenges in stem cell therapy for COPD, including optimal cell sources, delivery methods, safety, and efficacy, are identified. Regulatory considerations and the importance of standardization are emphasized. Potential strategies for optimizing the therapeutic potential of stem cells in COPD management, such as combination therapies and preconditioning techniques, are outlined. Emerging trends and future directions are highlighted, including advanced cell engineering and patient-specific induced pluripotent stem cells. In conclusion, stem cell therapy holds significant promise for COPD management, addressing the limitations of current treatments. Continued research and development are necessary to overcome challenges, optimize therapies, and realize stem cells' full potential in improving the lives of patients with COPD.

Caveolin-1-derived peptide attenuates cigarette smoke-induced airway and alveolar epithelial injury.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD.

Contribution of signaling pathways associated with cellular senescence and regulatory non-coding RNAs to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease of the respiratory system that affects the lung parenchyma and airways; it is one of the leading causes of death in the world, which explains the constant search for new approaches to diagnosis, treatment and prevention of the disease. COPD develops as a result of a complex interaction of molecular genetic factors, a network of epigenetic regulators, and environmental factors that are closely related to lifestyle. The molecular pathogenesis of COPD may include the mechanisms of alteration of the regulation of stressful reactions that prevent cellular senescence.
 Non-coding RNAs play an important role in the regulation of various intracellular signaling pathways and is the most relevant subject of genetic studies of various pathological phenotypes. The expression profile of long non-coding RNA is often disregulated in various diseases. Information on the role of long non-coding RNA in the development of COPD is limited. Long non-coding RNA and the target-genes of signaling pathways involved in cellular senescence form a complex interactive network and may be targets for disease therapy.
 The review presents the data concerning some aspects of the molecular pathogenesis of COPD, as well as role of long non-coding RNAs in the development of the COPD.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD

BackgroundAlveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear.MethodsWe investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD.ResultsEmphysema formation, inflammation, and cell death in the lungs were attenuated in AIM−/− mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM−/− mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM−/− mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality.ConclusionsAIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD.Trial RegistrationThis clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012–0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Does Chronic Obstructive Pulmonary Disease Originate from Different Cell Types?

The onset of chronic obstructive pulmonary disease (COPD) is heterogeneous, and current approaches to define distinct disease phenotypes are lacking. In addition to clinical methodologies, subtyping COPD has also been challenged by the reliance on human lung samples from late-stage diseases. Different COPD phenotypes may be initiated from the susceptibility of different cell types to cigarette smoke, environmental pollution, and infections at early stages that ultimately converge at later stages in airway remodeling and destruction of the alveoli when the disease is diagnosed. This perspective provides discussion points on how studies to date define different cell types of the lung that can initiate COPD pathogenesis, focusing on the susceptibility of macrophages, T and B cells, mast cells, dendritic cells, endothelial cells, and airway epithelial cells. Additional cell types, including fibroblasts, smooth muscle cells, neuronal cells, and other rare cell types not covered here, may also play a role in orchestrating COPD. Here, we discuss current knowledge gaps, such as which cell types drive distinct disease phenotypes and/or stages of the disease and which cells are primarily affected by the genetic variants identified by whole genome-wide association studies. Applying new technologies that interrogate the functional role of a specific cell type or a combination of cell types as well as single-cell transcriptomics and proteomic approaches are creating new opportunities to understand and clarify the pathophysiology and thereby the clinical heterogeneity of COPD.

Scavenger receptor B1 involvement in chronic obstructive pulmonary disease pathogenesis

Objective Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress due to cigarette smoking seems to be one of the major driving mechanisms in COPD pathogenesis. Since the scavenger receptor B1 (SR-B1) appears to play a key role in mediating the uptake for ɑ-tocopherol and other antioxidants in lung tissue, we aimed to investigate its role in COPD pathogenesis. Methods Lung tissue biopsies were obtained from 12 subjects; 6 of these had a diagnosis of COPD in a stable clinical state, the others 6 were current (n = 1) or ex-smokers (n = 5) with normal lung function (controls). 4-Hydroxynonenal (4-HNE)–SR-B1 adducts were detected by immunoprecipitation. ɑ-tocopherol concentration was determined by HPLC. Results SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue found in COPD patients. This effect can be the consequence of oxidative posttranslational modifications, confirmed by the binding of the peroxidation product 4-HNE to SR-B1 possibly leading to its degradation. Conclusions The loss of SR-B1 may be involved in lung ɑ-tocopherol content decrease with the consequence of making lung tissue more susceptible to oxidative damage as suggested by the SR-B1–4-HNE adduct formation, and more prone to COPD development. Thus, our findings suggest a novel role of SR-B1 in pathomechanisms underlying COPD. Significance statement Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress has been suggested to be the major driving mechanism in COPD pathogenesis. Loss of scavenger receptor BI (SR-B1) significantly decreases tocopherol lung content making lung tissue more susceptible to oxidative damage. The results of our study show that SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue. Our findings suggest a novel role of SR- B1 in pathomechanisms underlying COPD.

Integrative genetic and genomic networks identify microRNA associated with COPD and ILD

Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) are clinically and molecularly heterogeneous diseases. We utilized clustering and integrative network analyses to elucidate roles for microRNAs (miRNAs) and miRNA isoforms (isomiRs) in COPD and ILD pathogenesis. Short RNA sequencing was performed on 351 lung tissue samples of COPD (n = 145), ILD (n = 144) and controls (n = 64). Five distinct subclusters of samples were identified including 1 COPD-predominant cluster and 2 ILD-predominant clusters which associated with different clinical measurements of disease severity. Utilizing 262 samples with gene expression and SNP microarrays, we built disease-specific genetic and expression networks to predict key miRNA regulators of gene expression. Members of miR-449/34 family, known to promote airway differentiation by repressing the Notch pathway, were among the top connected miRNAs in both COPD and ILD networks. Genes associated with miR-449/34 members in the disease networks were enriched among genes that increase in expression with airway differentiation at an air–liquid interface. A highly expressed isomiR containing a novel seed sequence was identified at the miR-34c-5p locus. 47% of the anticorrelated predicted targets for this isomiR were distinct from the canonical seed sequence for miR-34c-5p. Overexpression of the canonical miR-34c-5p and the miR-34c-5p isomiR with an alternative seed sequence down-regulated NOTCH1 and NOTCH4. However, only overexpression of the isomiR down-regulated genes involved in Ras signaling such as CRKL and GRB2. Overall, these findings elucidate molecular heterogeneity inherent across COPD and ILD patients and further suggest roles for miR-34c in regulating disease-associated gene-expression.

Plasma Proteomics Study Between the Frequent Exacerbation and Infrequent Exacerbation Phenotypes of Chronic Obstructive Pulmonary Disease.

Frequent exacerbation (FE) and infrequent exacerbation (IE) are two phenotypes of chronic obstructive pulmonary disease (COPD), of which FE is associated with a higher incidence of exacerbation and a serious threat to human health. Because the pathogenesis mechanisms of FE are unclear, this study aims to identify FE-related proteins in the plasma via proteomics for use as predictive, diagnostic, and therapeutic biomarkers of COPD. A cross-sectional study was conducted in which plasma protein profiles were analyzed in COPD patients at stable stage, and differentially expressed proteins (DEPs) were screened out between the FE and IE patients. FE-related DEPs were identified using data-independent acquisition-based proteomics and bioinformatics analyses. In addition, FE-related candidates were verified by enzyme-linked immunosorbent assay. In this study, 47 DEPs were screened out between the FE and IE groups, including 20 upregulated and 27 downregulated proteins. Key biological functions (eg, neutrophil degranulation, extracellular exosome, protein homodimerization activity) and signaling pathways (eg, arginine and proline metabolism) were enriched in association with the FE phenotype. Receiver operating characteristic (ROC) analysis of the 11 combined DEPs revealed an area under the curve of 0.985 (p <0.05) for discriminating FE from IE. Moreover, correlation and ROC curve analyses indicated that creatine kinase, M-type (CKM) and fat storage-inducing transmembrane protein 1 (FITM1) might be clinically significant in patients with the FE phenotype. In addition, plasma expression levels of CKM and FITM1 were validated to be significantly decreased in the FE group compared with the IE group (CKM: p <0.01; FITM1: p <0.05). In this study, novel insights into COPD pathogenesis were provided by investigating and comparing plasma protein profiles between the FE and IE patients. CKM, FITM1, and a combinative biomarker panel may serve as useful tools for assisting in the precision diagnosis and effective treatment of the FE phenotype of COPD.

Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis.

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD.

Implementation of pro- and anti-inflammatory mechanisms of sirtuin-1 in patients with chronic obstructive pulmonary disease and chronic coronary syndrome and their combination

One of the key pathogenetic aspects of chronic obstructive pulmonary disease (COPD) and chronic coronary syndrome (CCS) is endothelial dysfunction. Further study on this pathological process is relevant for a better understanding of the course and increasing the treatment effectiveness of these diseases. In this context, in recent years, there has been a growing body of evidence about sirtuins which, according to the latest research results, were capable of rebalancing vasoconstrictory and vasodilatory mediators, regulating the balance in the protease-antiprotease system, protecting endothelial cells from oxidative stress and may be useful in relation to the pathogenesis of COPD and CCS. Aim. To study changes in the levels of serum endothelial nitric oxide synthase (NOS3/eNOS) and sirtuin 1 (SIRT1) in patients with a combined course of COPD and CCS and with COPD or CCS alone. Materials and methods. In order to study endothelial dysfunction and the role of SIRT1 in the processes of its development, we examined 60 patients with combined course of COPD and with CCS or COPD alone. The control group included 10 apparently healthy individuals. Levels of SIRT1 and NOS3/eNOS were studied by enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (hsCRP) – by immunoturbidimetric method; clinical data and medical records were analyzed. Commonplace statistical analyses were used. Results. The results have shown that the serum level of SIRT1 in patients with COPD and CCS was lower than that in the control group. The level of hsCRP was significantly higher in patients with the studied pathology than that in apparently healthy individuals and was the highest in patients with combined COPD and CCS. The study on serum NOS3/eNOS has showed the highest concentration in COPD patients, and it was significantly higher in all groups of patients with the studied pathology than that in healthy individuals. A direct correlation has been found between the serum level of SIRT1 and hsCRP and an inverse correlation – with the level of NOS3/eNOS. Conclusions. Thus, the pleiotropic effects and multifaceted molecular interactions of SIRT1 are a promising direction in the search for effective new therapeutic strategies in COPD and CCS.

Unleashing the Power of IL-17: A Promising Frontier in Chronic Obstructive Pulmonary Disease (COPD) Treatment.

Chronic obstructive pulmonary disease (COPD) is a pulmonary ailment that is both degenerative and incapacitating, with a global prevalence affecting millions. Despite notable progress in treatment methodologies, there is still a critical requirement for innovative therapeutic interventions. The pathogenesis of COPD has recently seen a significant focus on the role of interleukin 17 (IL-17), a pro-inflammatory cytokine. This review investigates the potential of IL-17 targeting as a viable therapeutic approach for treating COPD. The literature indicates a complex correlation between IL-17 and COPD. Research has indicated that IL-17 plays a role in the manifestation of airway inflammation, remodeling, and mucus hypersecretion, considered characteristic attributes of COPD. Elevated levels of IL-17 have been observed in the lungs of individuals with COPD, indicating its potential as a therapeutic target for intervention. Furthermore, preclinical studies utilizing animal models of COPD have demonstrated the efficacy of anti-IL-17 antibodies in reducing airway inflammation and remodeling. Comprehending the mechanical principles that underlie IL-17 signaling in COPD is imperative for advancing focused, therapeutic interventions. Activating diverse signaling pathways, such as the β-catenin and Act 1 adaptor protein (ACT 1) mediated pathways, is a crucial aspect of COPD pathogenesis triggered by IL-17. As a result, the suppression of IL-17 signaling has exhibited encouraging outcomes in mitigating pulmonary hypertension induced by hypoxia and interrupting the signaling mediated by ACT 1. Notwithstanding these promising discoveries, additional investigation is required to comprehensively explain the function of IL-17 in COPD and its viability as a target for therapy. The efficacy and safety of biological treatments that target IL-17 in COPD patients necessitate thorough investigation despite their initial positive outcomes. Furthermore, identifying appropriate patient subpopulations that would benefit most from IL-17-targeted therapies and optimizing treatment protocols are binding domains for future investigation. The current review presents a persuasive case for the imperative requirement of an additional investigation into the targeting of IL-17 for COPD management. Through a comprehensive analysis of the complex relationship between IL-17 and COPD pathogenesis, novel therapeutic avenues can be explored, potentially transforming the approach to managing this incapacitating condition. As we explore this novel domain, the possibility of pioneering therapies aimed at IL-17 presents a ray of optimism for the multitudes of individuals afflicted with the onerous consequences of COPD.

Post-tuberculosis lung disease and chronic obstructive pulmonary disease.

The burden of chronic airway diseases, including chronic obstructive pulmonary disease (COPD), continues to increase, especially in low- and middle-income countries. Post-tuberculosis lung disease (PTLD) is characterized by chronic lung changes after the "cure" of pulmonary tuberculosis (TB), which may be associated with the pathogenesis of COPD. However, data on its prevalence, clinical manifestations, computed tomography features, patterns of lung function impairment, and influencing factors are limited. The pathogenic mechanisms underlying PTLD remain to be elucidated. This review summarizes the recent advances in PTLD and TB-associated COPD. Research is urgently needed both for the prevention and management of PTLD.

Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is progressive and irreversible chronic lung inflammatory disease. Cigarette smoke, the main cause of COPD, is often associated with double-stranded DNA release which potentially activates DNA-sensing pathways, such as STING. This study, therefore, analyzed the role of STING pathway in inducing pulmonary inflammation, steroid resistance, and remodeling in COPD. Primary cultured lung fibroblasts were isolated from healthy non-smoker, healthy smoker, and smoker COPD individuals. The expression of STING pathway, remodeling, and steroid resistance signatures were investigated in these fibroblasts upon LPS stimulation and treatment with dexamethasone and/or STING inhibitor, at both mRNA and protein levels using qRT-PCR, western blot, and ELISA. At baseline, STING was elevated in healthy smoker fibroblasts and to a higher extent in smoker COPD fibroblasts when compared to healthy non-smoker fibroblasts. Upon using dexamethasone as monotherapy, STING activity was significantly inhibited in healthy non-smoker fibroblasts but showed resistance in COPD fibroblasts. Treating both healthy and COPD fibroblasts with STING inhibitor in combination with dexamethasone additively inhibited STING pathway in both groups. Moreover, STING stimulation triggered a significant increase in remodeling markers and a reduction in HDAC2 expression. Interestingly, treating COPD fibroblasts with the combination of STING inhibitor and dexamethasone alleviated remodeling and reversed steroid hyporesponsiveness through an upregulation of HDAC2. These findings support that STING pathway plays an important role in COPD pathogenesis, via inducing pulmonary inflammation, steroid resistance, and remodeling. This raises the possibility of using STING inhibitor as a potential therapeutic adjuvant in combination with common steroid treatment.

GSPE attenuates CSE-induced lung inflammation and emphysema by regulating autophagy via the reactive oxygen species/TFEB signaling pathway.

Cigarette smoke can enhance reactive oxygen species (ROS) production in inflammatory and epithelial cells. Subsequently, ROS enhance autophagy-induced inflammation due to alveolar macrophages (AMs), the primary source of cytokines implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, we hypothesized that grape seed proanthocyanidin extract (GSPE), an effective antioxidant, could inhibit emphysema and airway inflammation by ameliorating cigarette smoke extract (CSE)-induced autophagy via suppressing oxidative stress in macrophages. We observed that GSPE significantly attenuated histological changes observed in CSE-induced emphysema and airway inflammation in the lungs of mice. Moreover, GSPE ameliorated lung inflammation by reducing the number of cells, macrophages, and neutrophils and the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels measured in bronchioloalveolar lavage fluid. ROS levels increased after CSE instillation and significantly decreased with in vitro GSPE treatment. GSPE decreased transcription factor EB (TFEB) oxidation by reducing ROS, inhibiting TFEB nuclear translocation. Furthermore, GSPE inhibited ROS-induced autophagy in RAW 264.7cells, bone marrow-derived macrophages, and AMs. Inhibiting autophagy through GSPE treatment diminishes CSE-induced lung inflammation by inhibiting the NLRP3 inflammasome. This study demonstrates that GSPE can ameliorate CSE-induced inflammation and emphysema via autophagy-induced NLRP3 inflammasome regulation through the ROS/TFEB signaling pathway in a COPD mouse model.

Serum Proteomic Profiling in Patients with Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with high morbidity and mortality rates. This study used proteomic profiling of serum to identify the differentially expressed proteins in COPD patients compared with healthy controls, to expand the knowledge of COPD pathogenesis and to ascertain potential new targets for diagnosis and treatment of COPD. Serum samples were collected from 56 participants (COPD group n = 28; Healthy Control group n = 28). A data-independent acquisition quantitative proteomics approach was used to identify differentially expressed proteins (DEPs) between the two groups. Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment, and protein-protein interaction analyses of DEPs were conducted to identify their relevant biological processes, cellular components, and related pathways. We used a parallel reaction monitoring (PRM)-based targeted quantitative proteomics approach to validate those findings. Of 8484 peptides identified by searching the UniProtKB/Swiss-Prot knowledgebase, 867 proteins were quantifiable, of which 20 were upregulated and 35 were downregulated in the COPD group. GO functional annotation indicated that the subcellular localization of most DEPs was extracellular. The top three molecular functions of the DEPs were signaling receptor binding, antigen binding, and immunoglobulin receptor binding. The most relevant biological process was immune response. The transforming growth factor-β signaling pathway, Staphylococcus aureus infection, and hematopoietic cell lineage were the top three pathways identified in the KEGG pathway functional enrichment. Our PRM analyses confirmed the identification of 11 DEPs identified in our data-independent acquisition analyses, 8 DEPs were upregulated and 3 DEPs were downregulated. This study using data-independent acquisition analyses with PRM confirmation of findings identified 11 DEPs in the serum of patients with COPD. These DEPs are potential diagnostic or prognostic biomarkers or may be future targets for the treatment of COPD.

Scutellarein alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis by chelating iron and interacting with arachidonate 15-lipoxygenase.

Ferroptosis, an iron-dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti-ferroptotic activity of scutellarein was investigated through CCK8, real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA-sequencing (RNA-seq), electrospray ionization mass spectra (ESI-MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras-selective lethal small molecule (RSL)-3-induced ferroptosis and mitochondria injury in BEAS-2B cells, and ameliorated LPS/CS-induced COPD in mice. Furthermore, scutellarein also repressed RSL-3- or LPS/CS-induced lipid peroxidation, GPX4 down-regulation, and overactivation of Nrf2/HO-1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL-3- or LPS/CS-induced Fe2+ elevation through directly chelating Fe2+ . Moreover, scutellarein bound to the lipid peroxidizing enzyme arachidonate 15-lipoxygenase (ALOX15), which resulted in an unstable state of the catalysis-related Fe2+ chelating cluster. Additionally, ALOX15 overexpression partially abolished scutellarein-mediated anti-ferroptotic activity. Our findings revealed that scutellarein alleviated COPD by inhibiting ferroptosis via directly chelating Fe2+ and interacting with ALOX15, and also highlighted scutellarein as a candidate for the treatment of COPD and other ferroptosis-related diseases.

Vitamin D status and chronic obstructive pulmonary disease risk: a prospective UK Biobank study

BackgroundLow vitamin D status has been linked to an increased risk for various inflammatory diseases. Conflicting results have been reported regarding chronic obstructive pulmonary disease (COPD). This study aims to...