Background: The pathways linking short-term air pollution exposure to hospitalization outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remain poorly understood. This study aims to investigate the associations between air pollutants and both hospitalization risk and prolonged length of stay among patients with AECOPD in Kashgar, and to further explore the potential mediating pathways underlying these associations. Methods: Based on a registry study of patients with AECOPD in Kashgar, China from January 2020 to June 2024, a time-stratified case-crossover design with conditional logistic regression was employed to evaluate the associations between short-term exposure to six ambient air pollutants and the risk of AECOPD hospitalization. Unconditional logistic regression models and LOESS curves were used to examine the relationships between air pollution exposure and length of hospital stay. Furthermore, mediation analyses of twenty-seven blood biomarkers were conducted to explore the potential biological pathways linking air pollutant exposure to hospitalization outcomes. Findings: Ninety-nine percent of patients hospitalized for AECOPD in Kashgar were non-smokers. This study revealed that short-term exposure to NO2 and SO2 was observed significantly associated with an increased risk of AECOPD hospitalization. In particular, SO2 exposure at lag1-2 days showed the strongest association with hospitalization risk. Moreover, exposure to PM2.5, CO, SO2, and O3 was significantly associated with longer hospital stays after adjustment for potential confounders. Furthermore, mediation analysis suggested that hemoglobin, total cholesterol, and several immunological and metabolic biomarkers played important mediating roles in the associations between air pollutants and poor hospitalization outcomes. Interpretation: Short-term exposure to ambient air pollutants, especially NO2 and SO2, may worsen both the incidence and severity of AECOPD. These associations may be partly mediated by alterations in hematological, immunological, and metabolic biomarkers. These findings underscore the importance of reducing air pollution exposure and provide insights into potential biological mechanisms linking air pollution to adverse hospitalization outcomes in patients with AECOPD.

Goblet cell metaplasia is a pathological feature of airway remodelling in chronic obstructive pulmonary disease (COPD). Basal cell clones with goblet cell metaplasia demonstrate high transient receptor potential cation channel subfamily C member 6 (TRPC6) expression, but its biological function remains unclear. TRPC6 expression was analysed by immunostaining in lung tissues and airway basal cells from patients with COPD, and in the airways of mice exposed to cigarette smoke or interleukin-13. In vitro, the role of TRPC6 was assessed by TRPC6 overexpression and depletion in air–liquid interface cultures of human bronchial epithelial cells. In vivo, TRPC6 function was tested by airway TRPC6 depletion and TRPC6 inhibition in mice exposed to interleukin-13. NOTCH signalling was confirmed as a downstream pathway of TRPC6 by performing rescue experiments. TRPC6 expression was increased in the airway epithelium of patients with COPD and in interleukin-13-exposed mice. TRPC6 overexpression in basal cells from patients without COPD promoted their differentiation into goblet cells, while TRPC6 depletion in basal cells from patients with COPD suppressed goblet cell metaplasia in air–liquid interface cultures. TRPC6 function in suppressed goblet cell metaplasia was confirmed in TRPC6 depletion mice and TRPC6 inhibitor-treated mice. NOTCH signalling increased in interleukin-13-exposed control mice and human bronchial epithelial cell air–liquid interface cultures and decreased after TRPC6 inhibition. TRPC6 regulated basal cell differentiation, underscoring its potential as a therapeutic target in COPD. The in vivo experiments used mice exposed to interleukin-13, so its clinical potential requires clarification.

Purpose: Early diagnosis is an effective strategy in chronic obstructive pulmonary disease (COPD) prevention. Active case-finding is an effective approach, but traditional tools such as COPD-SQ are limited by outdated data, poor extrapolation, and singular binary prediction. This study aimed to develop an updated, convenient, and interpretable machine learning tool for COPD screening in community participants. Patients and Methods: Data for model training and external validation were obtained from two community-based studies in Guangdong, China. PyCaret and R programming language were used to develop machine learning models. Thirty original items, including demographic data, clinical features, and risk factor data, were initially used. Eleven machine learning classification models were compared, and the least absolute shrinkage and selection operator was further used to shrink predictors. Model performance was evaluated using ROC, AUC, accuracy, sensitivity, specificity, and other metrics. Shapley Additive exPlanations were used to interpret the models. Results: A total of 5381 and 2456 participants from the training and external validation cohorts were included, respectively. In predicting COPD, the AdaBoost model showed the best performance, with an accuracy of 0.846 and an AUC of 0.848. For GOLD classification prediction, the model achieved an overall accuracy of 0.822 and an AUC of 0.816, and identified 83% of moderate-tosevere COPD in the community. In regression analysis, the gradient boosting regression model showed good consistency between predicted and measured FEV1 %pred and FEV1/FVC values. The models also demonstrated good performance in the external validation cohort and were deployed online. Conclusion: We constructed an active case-finding tool with integrated machine learning models for predicting COPD, COPD severity, and lung function parameters using limited clinical data. This tool may help prioritize high-risk individuals for confirmatory spirometry in community settings. Future implementation studies should evaluate its effect on referral efficiency, diagnostic yield, treatment uptake, and long-term outcomes.

Background Depression is a common comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis. However, its association with lung health in individuals with pre-COPD remains unknown. We examined associations of increased depressive symptoms with respiratory symptoms, pre-COPD, and mortality.Methods We analysed data from the National Health and Nutrition Examination Survey (NHANES 2007–2012). Non-COPD individuals with available spirometry and Patient Health Questionnaire-9 (PHQ-9) data were included. Pre-COPD phenotypes included small airway dysfunction (SAD), preserved ratio impaired spirometry (PRISm) and nonobstructive chronic bronchitis (NOCB). Logistic and Cox regression models assessed associations of increased depressive symptoms with respiratory outcomes and all-cause mortality, respectively.Results Among 10 941 participants, increased depressive symptoms were associated with higher risk of PRISm (adjusted OR (aOR) [95% CI] 1.41[1.07,1.85]), NOCB (aOR [95% CI] 1.90[1.49,2.42]), cough (aOR [95% CI] 2.17[1.72,2.73]), phlegm production (aOR [95% CI] 2.86[2.23,3.67]), exertional dyspnoea (aOR [95% CI] 2.53[2.04,3.13]) and wheeze (aOR [95% CI] 1.86[1.51,2.30]). A one-unit increase in PHQ-9 score was also associated with higher risks of respiratory symptoms and pre-COPD. Additionally, increased depressive symptoms were independently associated with higher all-cause mortality risk among participants with pre-COPD, including SAD (aHR [95% CI] 2.85[1.02,7.95]), PRISm (aHR [95% CI] 2.02[1.01,4.01]) and NOCB (aHR [95% CI] 2.45[1.24,4.84]). Similar associations were observed across depression scores and pre-COPD populations.Conclusions Increased depressive symptoms were associated with a higher risk of pre-COPD phenotypes, respiratory symptoms, and mortality. Increased depressive symptoms may be a treatable trait that can help mitigate adverse outcomes in participants with pre-COPD.

This study explores the role of Sulfatase 1 (SULF1) in the progression of Chronic Obstructive Pulmonary Disease (COPD). SULF1, a modifying enzyme involved in various biological processes, was quantified in human serum using ELISA, and its correlation with lung function was analyzed. The in vivo function of SULF1 was investigated through CRISPR-mediated gene knockout (KO) in mice, and SULF1 overexpression was induced via adeno-associated virus (AAV). A COPD model was established by exposing mice to cigarette smoke (CS). Our findings revealed that SULF1 levels were elevated in the serum of COPD patients, where they negatively correlated with the FEV1/FVC ratio and the FEV1/FVC ratio annual decline. In CS-exposed mice, SULF1 expression was downregulated in lung tissues but increased in serum and bronchoalveolar lavage fluid (BALF). SULF1 KO mice exhibited more pronounced emphysematous changes following CS exposure, whereas SULF1 overexpression partially mitigated these lung alterations. Additionally, SULF1 was found to play a protective role in COPD progression through stable binding with Keratin 15 (KRT15). In conclusion, this study elucidates the role of SULF1 in COPD progression, providing novel insights into its pathogenesis and identifying potential therapeutic targets.

Background:Accelerated lung function decline is an important factor affecting the development and prognosis of chronic obstructive pulmonary disease (COPD), but its clinical characteristics have not been determined. We conduct a retrospective study to assess the clinical characteristics of participants with accelerated lung function decline. Methods:This study was based on the participants of Early Chronic Obstructive Pulmonary Disease (ECOPD) study enrolled in 2019-2020. Participants completed demographic data collection, COPD risk factor questionnaire, chronic respiratory symptom assessment, spirometry, impulse oscillometry (IOS) and computed tomography (CT) scan. We retrospectively sought lung function results from some of those who participated in the COPD epidemiology survey in 2012-2013 to obtain the rate of decline in lung function. Then we calculated the annual rate of decline based on the difference in lung function between 2012-2013 and 2019-2020. Accelerated lung function decline was defined as an annual decline in forced expiratory volume in one second (FEV1) of ≥60 mL. The main results were grouped according to the rate of decline in pre-bronchodilator spirometry, and we also performed sensitivity analysis by grouping the post-bronchodilator spirometry. We examined including chronic respiratory symptoms, the degree of small airway dysfunction (SAD) respectively defined by spirometry, IOS, and CT, and the degree of emphysema, in participants with accelerated and non-accelerated lung function decline. Results:Among 298 participants with spirometry results in 2012-2013, 67 (22.5%) had an accelerated decline in pre-bronchodilator FEV1. Participants with accelerated lung function decline were more likely to have chronic cough, chronic phlegm, and dyspnea (P<0.05) than those with non-accelerated lung function decline. They also had a higher proportion of spirometry-defined SAD, IOS-defined SAD, and CT-defined SAD and the severe degree of SAD. Participants who had an accelerated decline in lung function had more severe emphysema [inspiratory low attenuation area below -950 Hounsfield units: adjusted mean difference =2.5%, 95% confidence interval: 1.2-3.8%, P<0.001]. Results were maintained in sensitivity analyses grouped by the rate of decline in post-bronchodilator spirometry. Conclusions:Participants with an accelerated decline in lung function had more severe chronic respiratory symptoms, structural lung changes, and SAD.

BACKGROUND:The chronic obstructive pulmonary disease (COPD) guidelines recommend selecting initial treatment based on the severity of respiratory symptoms or exacerbation history. However, some patients still experience clinically important deterioration (CID) despite this strategy. Therefore, we aimed to identify the risk factors to guide initial treatment, focusing on mild-to-moderate COPD patients whose annualized CID cannot be controlled by a single-bronchodilator. METHODS:Patients in the tiotropium group from a randomized controlled trial were included. Over 2 years, annualized CID was defined as forced expiratory volume in one second (FEV1) decline at least 100 ml, COPD assessment test (CAT) increasing at least 2 points, or having experienced at least two moderate or one severe acute exacerbations of COPD (AECOPD) in this study. Random coefficients model within a bayesian framework was adapted to estimate the change in FEV1 and CAT scores. The logistic regression analysis was adapted to detect the risk factors. The risk of annualized CID was evaluated using the incidence risk ratio (IRR) for patients with risk factors. RESULTS:Of 312 patients with mild-to-moderate COPD receiving tiotropium, 29.2% still experienced annualized CID. The proportions of patients who developed annualized CID regarding FEV1, CAT, and AECOPD was 20.5, 8.0, and 6.1%, respectively. Post-bronchodilator FEV1:FVC ≤ 60% (OR = 1.73, 95%CI: 1.06-2.84) and smoking pack-years ≥50 (OR = 1.95, 95%CI: 1.11-3.41) were associated with higher risk of experiencing annualized CID. The IRR of annualized CID was increased with more risk factors at baseline. CONCLUSION:Patients with more prominent airflow limitation and higher smoking pack-years warrant intensified initial treatment to control their annualized CID.

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction and defective regeneration, yet the matrix‐derived factors contributing to this process remain poorly defined. We investigated the role of elastin‐derived peptides (EDPs), bioactive fragments generated during cigarette smoke (CS)‐induced elastin degradation, in alveolar epithelial dysfunction. In lung tissues from patients with COPD and in CS‐exposed mice, elevated levels of EDPs were associated with elastic fiber disruption and impaired alveolar type 2 (AT2)‐to‐alveolar type 1 (AT1) differentiation. These observations were supported by histological analyses, single‐cell transcriptomic profiling, and organoid‐based functional assays. In mouse and human alveolar organoids, CS extract and EDPs each suppressed organoid growth and impaired AT2‐to‐AT1 differentiation. Mechanistically, EDPs exposure was associated with activation of TLR4/NF‐κB signaling, and reduced β‐catenin activity, whereas pharmacological inhibition of TLR4 partially restored alveolar epithelial differentiation. Notably, the EDPs‐neutralizing agent TB partially rescued AT2‐to‐AT1 differentiation in organoids and alleviated emphysematous injury in vivo. Together, these findings identify EDPs as an important matrix‐derived mediator of alveolar regenerative failure in COPD and support further evaluation of EDP‐targeted intervention as a potential strategy for promoting alveolar repair.

Chronic obstructive pulmonary disease (COPD) is a progressive heterogeneous lung disease driving global illness and death, yet reliable biomarkers for its early diagnosis, molecular subtyping and prognosis are lacking. Here, we conduct targeted plasma metabolomic profiling in two independent, deeply phenotyped cohorts comprising 1344 participants across the full spectrum of COPD severity, with 3-year longitudinal follow-up for 651 subjects. Machine learning integration screens metabolite signatures associated with disease presence, clinical subtypes, and longitudinal outcomes. We identify unique plasma metabolic profiles distinguish COPD patients from healthy people and separate emphysema and small-airway-dominant subtypes with high accuracy in test and validation cohorts. A 27-metabolite panel detects early COPD by capturing metabolic shifts prior to lung function loss. Moreover, specific metabolite subsets independently predicted lung function decline, occurrence of acute exacerbations, and dyspnoea severity. Together, plasma metabolomics yields robust multi-purpose COPD biomarkers, offering an accessible strategy for early screening and personalized clinical risk stratification. This study combines plasma metabolomics and machine learning to identify blood biomarkers that improve the diagnosis, classification and prognosis of chronic obstructive pulmonary disease, supporting earlier detection and more precise patient care.

Background Patients with chronic obstructive pulmonary disease (COPD) frequently present with psychological comorbidities, including anxiety and depression, which may contribute to poorer clinical outcomes. However, the prevalence and impact of these mental health conditions in COPD patients have long been underrecognized. Leveraging data from the Chinese Population Health and Multimorbidities Study (CPHMS), a large epidemiological survey on chronic respiratory diseases in China, this study aimed to estimate the prevalence of anxiety and depression comorbidities among community-dwelling COPD patients and to evaluate the diagnostic utility of the COPD Assessment Test (CAT) scale for detecting these conditions in spirometry-confirmed COPD patients. Methods Analytical data were derived from the CPHMS. Comprehensive information on sociodemographic characteristics, lifestyle factors, and health status was collected. COPD-related pulmonary and extra-pulmonary symptoms were assessed using the CAT scale, and anxiety and depression were evaluated via the Hospital Anxiety and Depression Scale. Multivariable logistic regression was employed to identify factors associated with anxiety or depression comorbidities, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the CAT scale. Results Among 3641 spirometry-confirmed community COPD patients, the prevalence of anxiety and depression was 11.07% (95% confidence interval [CI]: 10.05–12.09%) and 14.23% (95% CI: 13.09–15.36%), respectively. Female gender, rural residence, unemployment, lower annual family income, and higher total CAT score, as well as higher scores on both pulmonary and extra-pulmonary symptom subscales of the CAT, were independently associated with an increased likelihood of anxiety and/or depression in COPD patients. The diagnostic yield of the CAT scale for identifying anxiety and depression in COPD patients was evaluated. In the overall COPD patients, the optimal total CAT cut-off value for detecting anxiety was 9 (area under the ROC curve [AUC]: 0.637; 95% CI: 0.607–0.666), and for depression was 7 (AUC: 0.633; 95% CI: 0.607–0.659). Notably, among rural-dwelling COPD patients, the optimal cut-off was 7 for both anxiety (AUC: 0.624; 95% CI: 0.582–0.665) and depression (AUC: 0.616; 95% CI: 0.579–0.653), whereas in urban patients, the corresponding cut-offs were 11 for anxiety (AUC: 0.652; 95% CI: 0.610–0.694) and 10 for depression (AUC: 0.654; 95% CI: 0.618–0.691). Conclusions This study delineated the prevalence of anxiety and depression among community COPD patients and validated the clinical utility of the CAT scale in detecting these psychological comorbidities. Our findings underscore the pressing need for tailored psychological support, particularly for COPD patients residing in rural area of China.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder with rising global morbidity and mortality. Emerging evidence suggests that systemic metabolic alterations, particularly dyslipidemia, contribute to COPD pathogenesis. However, the mechanisms linking lipid dysregulation to pulmonary inflammation and tissue injury remain poorly defined. Untargeted metabolomic profiling was performed on plasma samples from healthy individuals and patients with stage III-IV COPD to identify disease associated metabolic alterations. A high-cholesterol diet (HCD) mouse model, with or without chronic cigarette smoke exposure, was used to examine the impact of systemic cholesterol elevation on lung structure and inflammation. THP-1 derived and bone marrow derived macrophages were employed to assess cholesterol-induced mitochondrial dysfunction, ROS production, and downstream inflammatory signaling. Transcriptomic profiling was conducted to identify key molecular mediators. Plasma metabolomics revealed significant dysregulation of lipid pathways in COPD, with elevated cholesterol levels inversely correlated with lung function. In vivo, HCD feeding induced pulmonary inflammation and further exacerbated cigarette smoke induced alveolar destruction. In macrophages, combined cholesterol loading and cigarette smoke extraction treatment disrupted mitochondrial integrity, reduced respiratory capacity, and increased ROS production. Excess ROS upregulated PPIA, which activated NF-κB signaling and enhanced IL-1β secretion. Silencing PPIA or inhibiting ROS attenuated NF-κB activation and cytokine release. Consistent with these findings, lungs from HCD-fed, cigarette smoke exposed mice exhibited increased PPIA expression and NF-κB phosphorylation, and PPIA levels were elevated in bronchoalveolar lavage fluid from COPD patients. This study identifies a cholesterol-driven metabolic–inflammatory pathway in which mitochondrial dysfunction and ROS-dependent activation of the PPIA–NF-κB axis in macrophages contribute to persistent pulmonary inflammation in COPD. These findings establish a mechanistic link between systemic cholesterol dysregulation and COPD progression and highlight cholesterol metabolism and mitochondrial homeostasis as potential therapeutic targets.

Airway inflammation and remodeling are cardinal features of asthma pathogenesis. Genome-wide association studies have shown that several SNPs of KCNJ2, a member of the inwardly rectifying potassium channel family, are associated with asthma in patients. However, the role of KCNJ2 in airway inflammation and remodeling in asthma remains unknown. Here, we demonstrate that the Kcnj2 serves as a critical regulator of airway epithelial inflammation and remodeling. KCNJ2 expression is significantly reduced in the airway epithelium of asthmatic patients, which is associated with goblet cell metaplasia and mucus overproduction. Epithelial cell depletion of Kcnj2 attenuates airway inflammation, Th2 inflammatory response, goblet cell metaplasia, and mucus overproduction in the airways of asthmatic mice. In cultured primary airway epithelial cells of asthmatic patients, KCNJ2 inhibition also hampers goblet cell metaplasia, mucus production, and lung epithelial cell-derived alarmins expression. This process appears to be mediated, at least in part, through inhibition of NLRP3 by restricting Ca2+ influx and K+ efflux, as pharmacological activation of NLRP3 diminishes the KCNJ2 inhibition-ameliorated airway phenotypes. These results provide insight into the role of Kcnj2 in airway inflammation and remodeling in asthmatic conditions.

Spatiotemporal coordination of SARS-CoV-2-specific immunity across pulmonary and systemic compartments is poorly defined, especially how chronic lung diseases modulate this. We hypothesized that profiling virus-specific T cells (VSTs) and antibodies in respiratory vs. blood samples would reveal compartmentalized dynamics critical for viral control. In 64 mild Omicron BA.5 breakthrough-infected participants (30 early [D7], 34 later [D14]), we performed: 1) Paired sputum/PBMCs flow cytometry for CD4⁺/CD8⁺ VSTs; 2) Systemic antibody titration (NAbs, anti-N IgG); 3) Compartmental cytokine profiling; 4) Stratified analysis of GOLD I-II COPD (n = 28) vs controls (n = 36). Pulmonary CD4⁺ VSTs increased 2.8-fold from D7 to D14, contrasting with delayed CD8⁺ VSTs mobilisation, while no sputum-blood VSTs correlations existed in either phase (all P > 0.05). Phase-dependent immune synergy was observed in that early viral control was driven by blood CD8⁺ VSTs-NAbs coordination (CT value: r = 0.43; NAbs: r = 0.41; both P < 0.05), whereas later-phase pulmonary CD4⁺ VSTs expanded reciprocally to waning systemic antibodies (NAbs: r = -0.54, P < 0.01), indicating local compensation. Pulmonary cytokine dominance was evident as sputum IL-1β/IL-6/RANTES inversely correlated with viral titer (CT value) at D7 (all P < 0.05), exhibiting stronger virological associations than their plasma counterparts. Additionally, GOLD I-II COPD patients showed no impairment in viral clearance, NAbs titres, or VSTs magnitudes versus controls (all P > 0.05). Non-invasive sputum analysis reveals dynamic SARS-CoV-2 immunity: systemic effectors dominate early control, while pulmonary CD4⁺ VSTs compensate during antibody decline, underscoring the need for phase-specific therapeutic regimens targeting distinct compartments.

Background Airway remodelling precedes airflow obstruction in COPD. Pi10 assumes a consistent fixed slope between airway wall thickness and lumen perimeter across individuals. PiSlope comprehensively quantifies airway wall thickening, which is associated with increased acute exacerbation and mortality risk. Whether PiSlope is associated with respiratory prognosis in participants with preserved spirometry is unknown. Methods Participants with preserved spirometry with complete baseline questionnaires, spirometry and chest computed tomography were enrolled from a 3–year prospective Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort study and divided into four groups by PiSlope quartile (Q) (Q1: PiSlope ≥0.4946, Q2: 0.4550≤ PiSlope <0.4946, Q3: 0.4149≤ PiSlope <0.4550, Q4: PiSlope <0.4149). Clinical outcomes included lung function decline and risk of airflow obstruction progression. Results 1140 participants with preserved spirometry were included and 1067 (93.6%) completed at least one follow-up lung function assessment. One standard deviation decrease in PiSlope was associated with accelerated decline in pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) (adjusted difference 5 mL·year −1 , 95% CI 1–9 mL·year −1 ; p=0.007) and post-bronchodilator FEV 1 (adjusted difference 4 mL·year −1 , 95% CI 0–9 mL·year −1 ; p=0.033), and increased airflow obstruction risk (unadjusted: OR 1.21, 95% CI 1.01–1.36, p =0.038; adjusted: OR 1.13, 95% CI 0.87–1.32, p=0.307). Q2–Q4 had accelerated decline in pre-bronchodilator FEV 1 and FEV 1 % predicted, compared with Q1 (all p<0.05). The third-year risk of airflow obstruction progression was higher in Q2 (adjusted OR 2.40, 95% CI 1.13–5.08; p=0.022), Q3 (adjusted OR 1.71, 95% CI 0.77–3.82; p=0.188) and Q4 (adjusted OR 2.04, 95% CI 0.92–4.53; p=0.078) than in Q1. Conclusion Lower PiSlope was associated with faster lung function decline and increased airflow obstruction risk in participants with preserved spirometry, but the association between PiSlope and progression to airflow obstruction was not significant after adjustment.

BACKGROUND:Ensifentrine, a novel phosphodiesterase 3/4 inhibitor, was shown to significantly improve lung function and reduced COPD exacerbations in previous trials in Western populations. However, efficacy and safety data on its use in Chinese participants with COPD remain limited. RESEARCH QUESTION:Is nebulized ensifentrine effective and safe compared with placebo for the treatment of COPD in Chinese participants? STUDY DESIGN AND METHODS:A phase III, multicenter, randomized, double-anonymized, placebo-controlled trial was conducted between March 2023 and March 2025. The study enrolled participants with moderate to severe symptomatic COPD randomized to the ensifentrine group or the placebo group (5:3) over 24 weeks. Participants were stratified according to maintenance therapy and smoking status. The primary end point was lung function improvement measured by FEV1 area under the curve at 0 to 12 hours. Other end points included quality of life, symptoms, and exacerbations. RESULTS:Overall, 525 participants were included in the analysis, with 45.9% receiving concomitant maintenance therapy. Ensifentrine significantly improved average FEV1 area under the curve at 0 to 12 hours vs placebo (110 mL; 95% CI, 69-151 mL; P < .0001). Lung function improvement was consistent across clinically relevant subgroups, including participants with and without maintenance therapy, as well as participants with moderate and severe COPD. Ensifentrine significantly improved Transition Dyspnea Index score and showed improvements in Evaluating Respiratory Symptoms and St. George's Respiratory Questionnaire scores vs placebo. Ensifentrine treatment tended to reduce the rate of moderate to severe exacerbations and increased the time to first exacerbation. Adverse event rates were similar between the ensifentrine and placebo groups. INTERPRETATION:Ensifentrine was shown to significantly improve lung function and showed efficacy benefits in symptoms and quality of life improvement in Chinese individuals with COPD. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT05743075; URL: www. CLINICALTRIALS:gov.

INTRODUCTION:Exercise intolerance serves as a prognostic marker for poor respiratory outcomes in mild-to-moderate COPD. However, the longitudinal change in exercise tolerance and its association with disease progression remains unknown. We aimed to explore the association of longitudinal change in exercise tolerance with disease progression in mild-to-moderate COPD. METHODS:This community-based, prospective cohort study was conducted in China from 2019 to 2024. The participants completed baseline questionnaires, spirometry, chest computed tomography, and cardiopulmonary exercise testing (CPET), and underwent annual acute exacerbation assessment and spirometry over 3 years. Participants were categorized by the longitudinal change in peak oxygen uptake from baseline to 3 years into groups with non-declined or declined exercise tolerance. RESULTS:Overall, 213 participants with mild-to-moderate COPD who completed baseline and 3-year CPET were analyzed, including 131 (61.5%) with exercise tolerance decline. For every 5% longitudinal decrease in exercise tolerance, there was greater progression of air trapping (adjusted difference = 0.18%/year, 95% CI 0.01-0.34, P = 0.033) and a faster decline in postbronchodilator FEV1 (adjusted difference = -4.2 ml/year, 95% CI -8.3 to -0.1, P = 0.044). Compared with the non-declined exercise tolerance group, the group with exercise tolerance decline demonstrated greater progression of emphysema (adjusted difference = 0.40%/year, 95% CI 0.10-0.69, P = 0.008) and air trapping (adjusted difference = 1.26%/year, 95% CI 0.41-1.84, P = 0.002). CONCLUSIONS:The longitudinal decrease in exercise tolerance over 3 years was associated with accelerated lung function decline and air trapping progression, suggesting it may be a marker associated with disease progression in mild-to-moderate COPD.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene–environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework—integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization—to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = –0.038 to –0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = –22.1 mL/year per standardized unit; ECOPD: –0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber–related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.

Background Small airway dysfunction (SAD), as assessed by impulse oscillometry (IOS) (IOS-SAD), exhibits temporal variability and its long-term fluctuations may be linked to distinct clinical phenotypes. We investigated the associations of long-term variability in IOS-SAD with adverse clinical outcomes among participants with and without chronic obstructive pulmonary disease (COPD). Methods The baseline and 2-year follow-up data from the early COPD cohort were retrospectively analysed. SAD was defined based on the following criteria: difference from R5 to R20 (R5-R20) >upper limit of normal (ULN) (R5-R20-SAD), or reactance at 5 Hz (X5) ULN. Individuals were classified into three groups based on SAD variability over three visits at 2-year follow-up: (1) consistent SAD (SAD at every visit), (2) inconsistent SAD (SAD at some, but not all, visits) and (3) never SAD (no SAD at any visit). Differences in the rate of spirometric lung function decline and exacerbation rate were compared across long-term IOS-SAD variability groups in participants with and without COPD. Results In individuals with COPD, the consistent and inconsistent SAD groups assessed were associated with a faster spirometric lung function decline and a higher risk of exacerbations. In individuals without COPD, the consistent R5-R20-SAD group was associated with a faster decline in spirometric lung function and progression towards COPD. Conclusions SAD, even diagnosed once, characterises an airway behaviour with a higher proportion of higher risk of moderate or severe exacerbations. Consistent SAD was associated with accelerated spirometric lung function decline, increased exacerbation risk and progression to spirometry-defined COPD. Trial registration number ChiCTR1900024643.