Identification of related-genes of T cells in lung tissue of chronic obstructive pulmonary disease based on bioinformatics and experimental validation.

T cells are one of the main cell types shaping the immune microenvironment in chronic obstructive pulmonary disease (COPD). They persist andplay cytotoxic roles. The purpose of this study aimed to explore the potential related-genes of T cells in lung tissue of COPD. Chip data GSE38974 and single_celldata GSE196638 were downloaded from the GEO database. Difference analyses and WGCNA of GSE38974 were performed to identify DEGs and the modules most associated with the COPD phenotype. Various cell subsets were obtained by GSE196638, and DEGs of T cells were further identified. GO, GSEA and KEGG enrichment analyses were conducted to explore the biological functions and regulatory signaling pathways of the DEGs and DEGs of T cells. The intersection of the DEGs, module genes and DEGs of T cells was assessed to acquire related-genes of T cells. The mRNA and protein expression levels of related-genes ofT cells were verified in lung tissue of mouse with emphysema model. Based on GSE38974 difference analysis, 3811 DEGs were obtained. The results of WGCNA showed that the red module had the highest correlation coefficient with the COPD phenotype. GSE196638 analysis identified 124 DEGs of T cells. The GO, GSEAand KEGG enrichment analyses mainly identified genes involved in I-kappaB kinase/NF-kappaB signaling, receptor signaling pathway via STAT, regulationof CD4-positive cells, regulation of T-helper cell differentiation, chemokine signaling pathway, Toll-likereceptor signaling pathway, CD8-positive cells, alpha-beta T cell differentiation, MAPK signaling pathway and Th17 cell differentiation. The DEGs, genes of the red module and DEGs of T cells were overlapped to acquire FOXO1 and DDX17. The results of RT-qPCR and Western Blot indicate that the mRNA and protein expression levels of FOXO1 and DDX17 in lung tissue of emphysema mice were significantly higher compared with those in air-exposed mice. FOXO1 as well as DDX17 may be related-genesof T cells in lung tissue of patient with COPD, and their participation in the biological processes of different signaling pathways may inspire further COPD research.

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this. OBJECTIVES: We studied the tolerogenic role of PD-L1+ dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD. METHODS: We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively. MEASUREMENT AND MAIN RESULTS: A total of 83 participants were enrolled (normal, n = 29; COPD, n = 54). A reduced PD-L1+ conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, p = 0.03). The decrease in the PD-L1+ cDC1 ratio was associated with a rapid decline in COPD (p = 0.02) and correlated with the CD4+ T cells (r = -0.33, p = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of PD-L1 and CD4, but not CD8 were negatively correlated from PBMC in COPD patients (r = -0.43, p = 0.002). Functionally, the PD-L1 blockade enhanced CD4+ T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, p = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, p = 0.03) and CD3/elastin (148 ± 64.9, p = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of RORC, a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = -0.33, p = 0.02). CONCLUSIONS: Circulating PD-L1+ cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation.

PD-1+ T lymphocyte proportions and hospitalized exacerbation of COPD: a prospective cohort study.

OBJECTIVE: To evaluate the predictive value of PD-1 expression in T lymphocytes for rehospitalization due to acute exacerbations of COPD (AECOPD) in discharged patients. METHODS: 115 participants hospitalized with COPD (average age 71.8 ± 6.0 years) were recruited at Fujian Provincial Hospital. PD1+T lymphocytes proportions (PD1+T%), baseline demographics and clinical data were recorded at hospital discharge. AECOPD re-admission were collected at 1-year follow-up. Kaplan-Meier analysis compared the time to AECOPD readmissions among groups stratified by PD1+T%. Multivariable Cox proportional hazards regression and stratified analysis determined the correlation between PD1+T%, potential confounders, and AECOPD re-admission. ROC and DCA evaluated PD1+T% in enhancing the clinical predictive values of Cox models, BODE and CODEX. RESULTS: 68 participants (59.1%) were AECOPD readmitted, those with AECOPD readmission exhibited significantly elevated baseline PD-1+CD4+T/CD4+T% and PD-1+CD8 + T/CD8 + T% compared to non-readmitted counterparts. PD1+ T lymphocyte levels statistically correlated with BODE and CODEX indices. Kaplan-Meier analysis demonstrated that those in Higher PD1+ T lymphocyte proportions had reduced time to AECOPD readmission (logRank p < 0.05). Cox analysis identified high PD1+CD4+T and PD1+CD8+T ratios as risk factors of AECOPD readmission, with hazard ratios of 1.384(95%CI [1.043-1.725]) and 1.401(95%CI [1.013-1.789]), respectively. Notably, in patients aged < 70 years and with fewer than twice AECOPD episodes in the previous year, high PD1+T lymphocyte counts significantly increased risk for AECOPD readmission(p < 0.05). The AECOPD readmission predictive model, incorporating PD1+T% exhibited superior discrimination to the Cox model, BODE index and CODEX index, AUC of ROC were 0.763(95%CI [0.633-0.893]) and 0.734(95%CI [0.570-0.899]) (DeLong's test p < 0.05).The DCA illustrates that integrating PD1+T% into models significantly enhances the utility in aiding clinical decision-making. CONCLUSION: Evaluation of PD1+ lymphocyte proportions offer a novel perspective for identifying high-risk COPD patients, potentially providing insights for COPD management. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR, URL: www.chictr.org.cn/ ), Registration number: ChiCTR2200055611 Date of Registration: 2022-01-14.

Exportin XPO6 upregulation activates the TLR2/MyD88/NF-κB signaling by facilitating TLR2 mRNA nuclear export in COPD pulmonary monocytes.

Chronic obstructive pulmonary disease (COPD) poses a significant health threat characterized by lung inflammation primarily triggered by pulmonary monocytes. Despite the centrality of inflammation in COPD, the regulatory mechanisms governing this response remain elusive, presenting a challenge for anti-inflammatory interventions. In this study, we assessed the expression of exportins in COPD mouse models, revealing a notable upregulation of XPO6 in the mouse lung (P = 0.0011). Intriguingly, we observed a consistent upregulation of XPO6 in pulmonary monocytes from both human and mouse COPD subjects (P < 0.0001). Furthermore, in human lung tissue, XPO6 expression exhibited a positive correlation with TLR2 expression (P = 0). In vitro investigations demonstrated that XPO6 enhances TLR2 expression, activating the MyD88/NF-κB inflammatory signaling pathway. This activation, in turn, promotes the secretion of pro-inflammatory cytokines such as TNFα, IL-6, and IL-1ß in monocytes. Mechanistically, XPO6 facilitates the nuclear export of TLR2 mRNA, ensuring its stability and subsequent protein expression in monocytes. In conclusion, our findings unveil that the upregulation of XPO6 in COPD pulmonary monocytes activates the MyD88/NF-κB inflammatory signaling pathway by facilitating the nuclear export of TLR2 mRNA, thereby identifying XPO6 as a promising therapeutic target for anti-inflammatory interventions in COPD.

Elastin-derived peptides favor type 2 innate lymphoid cells in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a condition characterized by chronic airway inflammation and obstruction, primarily caused by tobacco smoking. Although the involvement of immune cells in COPD pathogenesis is well established, the contribution of innate lymphoid cells (ILCs) remains poorly understood. ILCs are a type of innate immune cells that participate in tissue remodeling processes, but their specific role in COPD has not been fully elucidated. During COPD, the breakdown of pulmonary elastin generates elastin peptides that elicit biological activities on immune cells. This study aimed to investigate the presence of ILC in patients with COPD and examine the impact of elastin peptides on their functionality. Our findings revealed an elevated proportion of ILC2 in the peripheral blood of patients with COPD, and a general activation of ILC as indicated by an increase in their cytokine secretion capacity. Notably, our study demonstrated that serum from patients with COPD promotes ILC2 phenotype, likely due to the elevated concentration of IL-5, a cytokine known to favor ILC2 activation. Furthermore, we uncovered that this increase in IL-5 secretion is partially attributed to its secretion by macrophages upon stimulation by elastin peptides, suggesting an indirect role of elastin peptides on ILC in COPD. These findings shed light on the involvement of ILC in COPD and provide insights into the potential interplay between elastin breakdown, immune cells, and disease progression. Further understanding of the mechanisms underlying ILC activation and their interaction with elastin peptides could contribute to the development of novel therapeutic strategies for COPD management.NEW & NOTEWORTHY Elastin-derived peptides, generated following alveolar degradation during emphysema in patients with COPD, are able to influence the response of type 2 innate lymphoid cells. We show that the orientation of innate lymphoid cells in patients with COPD is shifted toward a type 2 profile and that elastin peptides are indirectly participating in that shift through their influence of macrophages, which in turn impact innate lymphoid cells.

[Research progress of PD-L1 in inflammatory lung diseases].

Programmed death-ligand 1 (PD-L1) is important in maintaining central and peripheral immune tolerance in normal tissues, mediating tumor immune escape and keeping the balance between anti- and pro-inflammatory responses. Inflammation plays an important role in inflammatory lung diseases. This article reviews the research progress and potential clinical value of PD-L1 in inflammatory lung diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma and idiopathic pulmonary fibrosis.

18-ß-glycyrrhetinic acid-loaded polymeric nanoparticles attenuate cigarette smoke-induced markers of impaired antiviral response in vitro.

Tobacco smoking is a leading cause of preventable mortality, and it is the major contributor to diseases such as COPD and lung cancer. Cigarette smoke compromises the pulmonary antiviral immune response, increasing susceptibility to viral infections. There is currently no therapy that specifically addresses the problem of impaired antiviral response in cigarette smokers and COPD patients, highlighting the necessity to develop novel treatment strategies. 18-ß-glycyrrhetinic acid (18-ß-gly) is a phytoceutical derived from licorice with promising anti-inflammatory, antioxidant, and antiviral activities whose clinical application is hampered by poor solubility. This study explores the therapeutic potential of an advanced drug delivery system encapsulating 18-ß-gly in poly lactic-co-glycolic acid (PLGA) nanoparticles in addressing the impaired antiviral immunity observed in smokers and COPD patients. Exposure of BCi-NS1.1 human bronchial epithelial cells to cigarette smoke extract (CSE) resulted in reduced expression of critical antiviral chemokines (IP-10, I-TAC, MIP-1α/1ß), mimicking what happens in smokers and COPD patients. Treatment with 18-ß-gly-PLGA nanoparticles partially restored the expression of these chemokines, demonstrating promising therapeutic impact. The nanoparticles increased IP-10, I-TAC, and MIP-1α/1ß levels, exhibiting potential in attenuating the negative effects of cigarette smoke on the antiviral response. This study provides a novel approach to address the impaired antiviral immune response in vulnerable populations, offering a foundation for further investigations and potential therapeutic interventions. Further studies, including a comprehensive in vitro characterization and in vivo testing, are warranted to validate the therapeutic efficacy of 18-ß-gly-PLGA nanoparticles in respiratory disorders associated with compromised antiviral immunity.

Lung mucosal immunity to NTHi vaccine antigens: Antibodies in sputum of chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory illness in older adults. A major cause of COPD-related morbidity and mortality is acute exacerbation of COPD (AECOPD). Bacteria in the lungs play a role in exacerbation development, and the most common pathogen is non-typeable Haemophilus influenzae (NTHi). A vaccine to prevent AECOPD containing NTHi surface antigens was tested in a clinical trial. This study measured IgG and IgA against NTHi vaccine antigens in sputum. Sputum samples from 40 COPD patients vaccinated with the NTHi vaccine were collected at baseline and 30 days after the second dose. IgG and IgA antibodies against the target antigens and albumin were analyzed in the sputum. We compared antibody signals before and after vaccination, analyzed correlation with disease severity and between sputum and serum samples, and assessed transudation. Antigen-specific IgG were absent before vaccination and present with high titers after vaccination. Antigen-specific IgA before and after vaccination were low but significantly different for two antigens. IgG correlated between sputum and serum, and between sputum and disease severity. Sputum albumin was higher in patients with severe COPD than in those with moderate COPD, suggesting changes in transudation played a role. We demonstrated that immunization with the NTHi vaccine induces antigen-specific antibodies in sputum. The correlation between IgG from sputum and serum and the presence of albumin in the sputum of severe COPD patients suggested transudation of antibodies from the serum to the lungs, although local IgG production could not be excluded.Clinical Trial Registration: NCT02075541.

What is the context? Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory illness in older adults and the third leading cause of death worldwide.One bacterium in the lungs, non-typeable Haemophilus influenzae (NTHi), is responsible for acute exacerbation of the disease, characterized by an increase in airway wall inflammation and symptoms, leading to high morbidity and mortality.A vaccine targeting NTHi was previously developed but did not show efficacy in reducing exacerbations in COPD patients, probably because the vaccine did not elicit an immune response in the lung mucosae, where the bacteria are located.What is the impact? Parenteral immunization with new vaccines targeting NTHi is able to elicit immune defense at the level of lung mucosae.Now that antibodies can be measured in sputum, new vaccines against COPD exacerbations or other lung infections can be tested for efficacy in the actual target tissue.Also, lung immunity against specific pathogens can now be tested.What is new? We determined that antigen-specific antibodies were present in the lungs after vaccination; these were assessed in sputum after vaccination with NTHi surface antigens.NTHi-specific IgG were present in the lungs and appeared to have arrived there primarily by transudation, a type of leakage from the serum to the lung mucosae.Transudation appeared to be stronger in severe than in moderate COPD patients.

The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response.

The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.

Immune Dysregulation in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a disease whose incidence increase with age and is characterised by chronic inflammation and significant immune dysregulation. Inhalation of toxic substances cause oxidative stress in the lung tissue as well as airway inflammation, under the recruitment of chemokines, immune cells gathered and are activated to play a defensive role. However, persistent inflammation damages the immune system and leads to immune dysregulation, which is mainly manifested in the reduction of the body's immune response to antigens, and immune cells function are impaired, further destroy the respiratory defensive system, leading to recurrent lower respiratory infections and progressive exacerbation of the disease, thus immune dysregulation play an important role in the pathogenesis of COPD. This review summarizes the changes of innate and adaptive immune-related cells during the pathogenesis of COPD, aiming to control COPD airway inflammation and improve lung tissue remodelling by regulating immune dysregulation, for further reducing the risk of COPD progression and opening new avenues of therapeutic intervention in COPD.

Identification of Siglec-1-negative alveolar macrophages with proinflammatory phenotypes in chronic obstructive pulmonary disease.

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, subpopulations of AMs participating in chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a proinflammatory phenotype and are associated with poor clinical outcomes in patients with COPD. Using flow cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1+SSChiFSChi, Siglec-1-SSChiFSChi, and Siglec-1-SSCloFSClo subsets. The Siglec-1-SSCloFSClo subset number was increased in COPD. RNA sequencing revealed upregulation of multiple proinflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1-SSCloFSClo subset. Gene set enrichment analysis indicated that the Siglec-1-SSCloFSClo subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6, and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1-SSCloFSClo subset of AMs displays proinflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes.NEW & NOTEWORTHY Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. We find that Siglec-1-negative alveolar macrophages have a wide range of proinflammatory landscapes and a protease-expressing phenotype. Moreover, this subset is associated with the pathogenesis of COPD and responds to viral stimuli.

Type 2 airway inflammation in COPD.

Globally, nearly 400 million persons have COPD, and COPD is one of the leading causes of hospitalisation and mortality across the world. While it has been long-recognised that COPD is an inflammatory lung disease, dissimilar to asthma, type 2 inflammation was thought to play a minor role. However, recent studies suggest that in approximately one third of patients with COPD, type 2 inflammation may be an important driver of disease and a potential therapeutic target. Importantly, the immune cells and molecules involved in COPD-related type 2 immunity may be significantly different from those observed in severe asthma. Here, we identify the important molecules and effector immune cells involved in type 2 airway inflammation in COPD, discuss the recent therapeutic trial results of biologicals that have targeted these pathways and explore the future of therapeutic development of type 2 immune modulators in COPD.

Association between the Reduced Expression of RECK and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a recently discovered inhibitor of matrix metalloproteinase (MMP). There is a large number of chronic obstructive pulmonary disease (COPD) patients worldwide; however, the role of RECK on COPD has not been studied. This study explored the expression of RECK in COPD patients and its effect on neutrophil function to provide a new scientific basis for the prevention and treatment of COPD. METHOD: Fifty patients with acute exacerbation of COPD and fifty healthy controls were enrolled in the study. RECK was detected in lung tissue, sputum, and plasma of subjects as well as in BEAS-2B cells stimulated with cigarette smoke extract (CSE) by immunohistochemistry, ELISA, and qRT-PCR. Meanwhile, lung function (FEV1%pred) and inflammatory cytokines (IL-6 and IL-8) were examined, and correlation analysis was performed with RECK expression. The effect of RECK on proliferation, apoptosis, migration, and inflammatory cytokines and its potential mechanism was further quantified by neutrophil stimulated with recombinant human RECK protein (rhRECK) combined with CSE using CCK8, flow cytometry, Transwell assay, qRT-PCR, ELISA, and Western analysis. RESULTS: RECK was mainly expressed on airway epithelial cells in normal lung tissue and was significantly diminished in COPD patients. The levels of RECK in sputum and plasma were also significantly decreased in COPD patients. Pearson correlation analysis showed that RECK level in plasma was positively correlated with FEV1%pred (r = 0.458, p < 0.001) and negatively correlated with IL-6 and IL-8 (r = -0.386, -0.437; p = 0.006, 0.002) in COPD patients. The expression of RECK was decreased in BEAS-2B stimulated with CSE. The migration, inflammation, and MMP-9 expression of neutrophils were promoted by CSE, while inhibited by rhRECK. CONCLUSION: RECK is low expressed in COPD patients and negatively correlated with inflammation. It may inhibit the inflammation and migration of neutrophils by downregulating MMP-9.

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

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

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

Astragaloside IV restores Th17/Treg balance via inhibiting CXCR4 to improve chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD. METHODS: To evaluate the effects of AS-IV, CD4+ T cells received different concentrations of AS-IV. CD4+ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4+ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues. RESULTS: AS-IV with concentration exceeding 40 µM inhibited CD4+ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1ß, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression. CONCLUSIONS: AS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts.

BACKGROUND: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). RESULTS: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. CONCLUSIONS: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.).

Potential Mechanisms Between HF and COPD: New Insights From Bioinformatics.

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are closely related in clinical practice. This study aimed to investigate the co-genetic characteristics and potential molecular mechanisms of HF and COPD. HF and COPD datasets were downloaded from gene expression omnibus database. After identifying common differentially expressed genes (DEGs), the functional analysis highlighted the critical role of extracellular matrix and ribosomal signaling pathways in both diseases. In addition, GeneMANIA's results suggested that the 2 diseases were related to immune infiltration, and CIBERSORT suggested the role of macrophages. We also discovered 4 TFs and 1408 miRNAs linked to both diseases, and salbutamol may positively affect them.