Pathogenesis Of Chronic Obstructive Pulmonary Disease Research Articles

Comprehensive Analysis of a Competing Endogenous RNA Co-Expression Network in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is the main cause of mortality world widely. Non-coding RNAs (lncRNAs) and associated competitive endogenous RNAs (ceRNAs) networks were recently proved to lead to mRNA gene expression downregulation but were still unclear in COPD. This study aims to investigate and elucidate the mechanisms underlying the involvement of ceRNA co-expression networks in COPD pathogenesis. Obtained expression signature of data from the Gene Expression Omnibus database and compared the differentially expression of mRNAs and miRNAs between COPD patients and healthy smokers. Predicted the miRNA-lncRNA and miRNA-mRNA interaction using online library and employed CIBERSORT to measure the proportions of the 22 immune cells in the COPD and control groups. Established a ceRNA-network comprising 11 lncRNAs, 5 miRNAs, and 16 mRNAs. Using the weighted correlation network analysis method, we identified hub genes and hub miRNAs and obtained one core sub-network, XIST, FGD5-AS1, KCNQ1OT1, HOXA11-AS, LINC00667, H19, PRKCQ-AS1, NUTM2A-AS1/has-mir-454-3p/ZNF678, PRRG4. COPD patients had different proportions of immune cells than controls, and these variations were associated with the magnitude of pulmonary function parameters. The ceRNA-network, particularly the core sub-network, may be a putative goal for COPD, in which specific immune cells were involved.

Soluble epoxide hydrolase deficiency attenuates airway inflammation in COPD via IRE1α/JNK/AP-1 signaling pathway.

Soluble Epoxide Hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids and critically affects airway inflammation in chronic obstructive pulmonary disease (COPD). Considering the excessive endoplasmic reticulum stress is associated with the earlier onset of COPD. The role of sEH and endoplasmic reticulum stress in the pathogenesis of COPD remains unknown. 16 weeks of cigarette-exposed mice were used to detect the relationship between sEH and endoplasmic reticulum stress in COPD. Human epithelial cells were used in vitro to determine the regulation mechanism of sEH in endoplasmic reticulum stress induced by cigarette smoke. sEH deficiency helps reduce emphysema formation after smoke exposure by alleviating endoplasmic reticulum stress response. sEH deficiency effectively reverses the upregulation of phosphorylation IRE1α and JNK and the nuclear expression of AP-1, alleviating the secretion of inflammatory factors induced by cigarette smoke extract. Furthermore, the treatment with endoplasmic reticulum stress and IRE1α inhibitor downregulated cigarette smoke extract-induced sEH expression and the secretion of inflammatory factors. sEH probably alleviates airway inflammatory response and endoplasmic reticulum stress via the IRE1α/JNK/AP-1 pathway, which might attenuate lung injury caused by long-term smoking and provide a new pharmacological target for preventing and treating COPD.

Identification of circRNA-associated ceRNA networks in peripheral blood mononuclear cells as potential biomarkers for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), which is a common respiratory disorder with high morbidity and mortality globally, has a complex pathogenesis that is not fully understood. Some circular RNAs (circRNAs) have been recognized to serve as miRNA sponges for regulating target RNA transcripts during the processes of human diseases. In this study, we aimed to investigate novel circRNA-associated biomarkers for COPD,245 differentially expressed circRNAs were identified, including 111 upregulated and 134 downregulated circRNAs. These candidate circRNAs were enriched in inflammation-associated pathways (such as mTOR, B-cell receptor, and NF-κB signaling pathways) via Gene Ontologyand Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A combination of two circRNAs (upregulated hsa_circ_0067209 and downregulated hsa_circ_0000673) demonstrated good diagnostic value (area under the receiver operating characteristiccurve(AUC)= 0.866) for COPD byreceiver operating characteristic curve(ROC)analysis and qRT-PCR validation. Subsequently, hsa-miR-8082 and hsa-miR-1248 were identified as targets for hsa_circ_0067209 and hsa_circ_0000673, respectively, via bioinformatics analysis and a dual-luciferase reporter assay, and the combination of these two miRNAs displayed better diagnosis potential for COPD (AUC = 0.967)than each other. Evaluation of COPD-related mRNA profiles revealed that the upregulated genes ABRand TRPM6were predicted downstream targetsfor hsa_circ_0067209/hsa-miR-8082, whereas the downregulated gene RORCwas a predicted downstream target for hsa_circ_0000673/hsa-miR-1248. In summary, hsa_circ_0067209 and hsa_circ_0000673 have potential as novel diagnostic biomarkers of COPD. In addition, competing endogenous RNA networks of hsa_circ_0067209/hsa-miR-8082/ABR/TRPM6 and hsa_circ_0000673/hsa-miR- &#160;1248/RORC may play critical regulation roles for COPD pathogenesis.</p>.

The effect of multiple outgrowths from bronchial tissue explants on progenitor/stem cell number in primary bronchial epithelial cell cultures from smokers and patients with COPD.

Although studies suggest a deficiency in stem cell numbers in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), the role of bronchial epithelial progenitor/stem (P/S) cells is not clear. The objectives of this study were to investigate expression of progenitor/stem (P/S) cell markers, cytokeratin (CK) 5, CK14 and p63 in bronchial epithelial explants and cell cultures obtained from smokers with and without COPD following multiple outgrowths, and to study this effect on bronchial epithelial cell (BEC) proliferation. Bronchial epithelial explants were dissected from lung explants and cultured on coverslips. Confluent cultures were obtained after 3-4 weeks' (transfer, Tr1), explants were then transferred and cultured for a second (Tr2) and third (Tr3) time, respectively. At each stage, expression of CK5, CK14 and p63 in explants and BEC were determined by immunostaining. In parallel experiments, outgrowing cells from explants were counted after 4wks, and explants subsequently transferred to obtain new cultures for a further 3 times. As the transfer number advanced, CK5, CK14 and p63 expression was decreased in both explants and BEC from both smokers without COPD and patients with COPD, with a more pronounced decrease in BEC numbers in the COPD group. Total cell numbers cultured from explants were decreased with advancing outgrowth number in both groups. Smoking status and lung function parameters were correlated with reduced P/S marker expression and cell numbers. Our findings suggest that the number of P/S cells in airway epithelium may play a role in the pathogenesis of COPD, as well as a role in the proliferation of airway epithelial cells, in vitro.

DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell

Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5′-aza-2′-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.

The Activation of M1 Macrophages is Associated with the JNK-m6A-p38 Axis in Chronic Obstructive Pulmonary Disease.

Excessive activation of M1 macrophages affects the chronic inflammatory response of the airways and leads to the development of chronic obstructive pulmonary disease (COPD). Therefore, it needs to be closely monitored and investigated. MAPK signaling pathway is involved in the activation of M1 macrophages, and N6-methyladenosine (m6A) is involved in the pathogenesis of COPD. However, it is unknown whether activation of the MAPK signaling pathway is mediated by m6A in M1 macrophages in COPD. The GEO data were analyzed using bioinformatics techniques to assess the differences between COPD and healthy individuals in the levels of M1 macrophages, their secreted cytokines, and m6A regulators. The MAPK signaling pathway was significantly enriched in the list of differentially regulated genes between COPD and healthy individuals. We further analyzed the correlation between M1 macrophages, m6A, and the MAPK signaling pathway. Next, blood samples from COPD and healthy individuals were collected and analyzed by using flow cytometry, ELISA, and RT-PCR. Western blotting was performed using CSE-induced THP-1 cells. COPD and healthy mice were used for Me-RIP sequencing and flow cytometry experiments. Validation of the results of the above bioinformatics analysis by molecular biology experiments and sequencing techniques. We found that GEO data and blood specimens from COPD patients showed increased M1 macrophages, higher levels of IL-6 and TNF-α, and higher mRNA expression of key mediators of the MAPK signaling pathway (p38, ERK, and JNK). Western blotting showed increased expression of p38, ERK, and JNK in the CSE group. In contrast, the expression of m6A regulators was low. Also, M1 macrophages in COPD mice were hyperactivated and had reduced m6A modifications of p38, ERK, and JNK compared with control. m6A may be involved in M1 macrophage hyperactivation by regulating the MAPK signaling pathway, thereby influencing the development of COPD.

Endothelin-1 Gene Polymorphism in Chronic Obstructive Pulmonary Disease: A Case-Control Study

Abstract&#x0D; Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a common multifactorial disease which has heterogeneous pathogenesis. The most important risk factor is smoking. In addition to many pathogenic mechanisms taking part in inflammatory process, Our study group does research on the relation of COPD with single nucleotide gene polymorphism at ET-1 gene. In the current studies there being a high ratio of Endotelin-1 (ET-1) in BAL liquid of COPD cases made researchers think ET-1 may have an important role in pathogenesis of COPD. &#x0D; Methods: This prospective case-control study included 89 patients admitted with COPD and 87 control patients. In our study, we search for the density of single nucleotide gene polymorphism (+134 insA/delA) in ET-1 gene in the 87 smoking COPD and 89 healthy cases. Allele ratio and genotype distribution, distribution amongst three genotype in the COPD patient and healthy control group was analyzed. In this study, for endothelin gene -3A/-4A (-138 insertion/deletion) polymorphism analysis, PCR-RFLP method was used. &#x0D; Results: In comparison with the healthy group, the COPD group has higher ratio of ET-1 gene (+134 insA/delA) polymorphism (p&lt; 0,001). &#x0D; Conclusion: Endotelin-1 gene polymorphism (+134 insA/delA) significantly increased in the patients than healthy ones (p

Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by a slow progression and caused by the inhalation of harmful particulate matter. Cigarette smoke and air pollutants are the primary contributing factors. Currently, the pathogenesis of COPD remains incompletely understood. The PI3K/Akt signaling pathway has recently emerged as a critical regulator of inflammation and oxidative stress response in COPD, playing a pivotal role in the disease's progression and treatment. This paper reviews the association between the PI3K/Akt pathway and COPD, examines effective PI3K/Akt inhibitors and novel anti-COPD agents, aiming to identify new therapeutic targets for clinical intervention in this disease.

Periodontitis contributes to COPD progression via affecting ferroptosis

BackgroundPeriodontitis has emerged as a potential risk factor for chronic obstructive pulmonary disease (COPD). However, the precise mechanism through which periodontitis influences the progression of COPD requires further investigation. Ferroptosis is one of the crucial pathogenesis of COPD and recent researches suggested that periodontitis was associated with ferroptosis. Nonetheless, the relationship among periodontitis, COPD and ferroptosis remains unclear. This study aimed to elucidate whether periodontitis contributes to COPD exacerbation and to assess the potential impact of ferroptosis on periodontitis affecting COPD.MethodsThe severity of COPD was assessed using Hematoxylin and eosin (H&E) staining and lung function tests. Iron assays, malondialdehyde (MDA) measurement and RT-qPCR were used to investigate the potential involvement of ferroptosis in the impact of periodontitis on COPD. Co-cultures of periodontitis associated pathogen Phophyromonas gingivalis (P. gingivalis) and lung tissue cells were used to evaluate the effect of P. gingivalis on inducing the ferroptosis of lung tissue via RT-qPCR analysis. Clinical Bronchoalveolar Lavage Fluid (BALF) samples from COPD patients were collected to further validate the role of ferroptosis in periodontal pathogen-associated COPD.ResultsPeriodontitis aggravated the COPD progression and the promotion was prolonged over time. For the first time, we demonstrated that periodontitis promoted the ferroptosis-associated iron accumulation, MDA contents and gene expressions in the COPD lung with a time-dependent manner. Moreover, periodontitis-associated pathogen P. gingivalis could promote the ferroptosis-associated gene expression in single lung tissue cell suspensions. Clinical BALF sample detection further indicated that ferroptosis played essential roles in the periodontal pathogen-associated COPD.ConclusionPeriodontitis could contribute to the exacerbation of COPD through up-regulating the ferroptosis in the lung tissue.

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.&#x0D; 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.&#x0D; 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.