ObjectiveBlood eosinophil (EOS) guides corticosteroid therapy in stable chronic obstructive pulmonary disease (COPD), but its prognostic value in COPD exacerbation (ECOPD) remains controversial. This study characterized clinical features and assessed the impact of EOS levels on clinical outcomes in hospitalized ECOPD patients.MethodsWe retrospectively reviewed hospitalized patients with ECOPD between 2018 and 2023. Patients were categorized according to percentage of peripheral blood eosinophil: the eosinophilic group (EOS ≥ 2%) and the non-EOS group (EOS < 2%). The primary outcome was in-hospital mortality, while the secondary outcomes included ICU admission, mechanical ventilation, and length of hospital stay.ResultsAmong 511 patients (EOS group, n = 139; non-EOS group, n = 372), the EOS group had lower levels of inflammatory markers (C-reactive protein and procalcitonin) and a lower detection rate of Gram-negative bacilli, especially Acinetobacter baumannii. The EOS group exhibited significantly lower rates of ICU admission (25.18% vs. 50.27%; P < 0.001) and in-hospital mortality (1.44% vs. 6.72%; p = 0.018). In the multivariable analyses, EOS% ≥ 2% remained associated with lower odds of in-hospital mortality after adjustment for age and heart failure (adjusted OR, 0.225; 95% CI, 0.052–0.971; p = 0.046) and with lower odds of ICU admission after adjustment for age, sex, and heart failure (adjusted OR, 0.357; 95% CI, 0.229–0.556; p < 0.001).ConclusionAmong hospitalized patients with ECOPD, elevated peripheral blood eosinophils were associated with favorable clinical outcomes, especially a reduced risk of ICU admission, as well as a lower systemic inflammation burden.

Background:The beneficial effects of omega-3 fatty acids for patients with chronic obstructive pulmonary disease (COPD) had been observed, including attenuating lung function decline and reducing their respiratory symptom burdens. However, the impact of omega-3 fatty acids on COPD exacerbation-related outcomes remains unclear. This study aimed to evaluate whether reduced serum omega-3 fatty acid levels are associated with a higher risk of future hospital readmission due to COPD exacerbation (ECOPD). Methods:This retrospective cohort study included 88 patients hospitalized for ECOPD between April 2017 and March 2018. Clinical data were collected, and serum omega-3 fatty acid levels were analyzed using liquid chromatography-mass spectrometry (LC-MS). All patients were followed up for a median period of 53.5 months and categorized into two groups based on whether they experienced ECOPD-related readmission during the follow-up period. The clinical characteristics and serum levels of omega-3 fatty acid levels, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), between the two groups were compared. Additionally, patients were categorized into low and high DHA groups based on the median DHA level, and the association between DHA level and ECOPD-related readmission rate was analyzed using a Cox regression model. Result:Patients who experienced ECOPD-related readmission during the follow-up period (n = 36) had lower serum levels of DHA than those who did not experience readmission. The serum levels of EPA did not significantly differ between groups. Kaplan-Meier curve showed that patients in the low-DHA group exhibited a significantly higher ECOPD-related readmission rate compared to those in the high-DHA group (log-rank p = 0.023). Multivariable Cox regression analysis identified low DHA level as an independent risk factor for ECOPD-related readmission. A nomogram based on DHA levels demonstrated good predictive performance. Conclusion:A low DHA level serves as an independent risk factor for ECOPD-related readmission, suggesting DHA may have a potential protective effect to reduce the risk of exacerbation in patients with COPD.

BACKGROUND:About half of patients with chronic obstructive pulmonary disease (COPD) have hypertension, which significantly worsens prognosis. Yet its critical environmental drivers and vulnerable phenotypes remain unclear. OBJECTIVES:To evaluate associations between size-fractionated particulate matter (PM) and blood pressure, assess differential effects by hypertension status and identify susceptible individuals by smoking and inflammatory phenotypes. METHODS:In this prospective panel study, 82 patients with COPD (42 with hypertension) completed 281 clinical visits. Personal exposure to ambient inhalable PM (PM10), fine PM (PM2.5) and ultrafine particles (UFPs) of 0-7 days was estimated using infiltration factors and time-activity patterns. Inflammatory phenotypes were defined by blood neutrophils and eosinophils. Linear mixed-effect models were applied to evaluate blood pressure changes associated with PM. RESULTS:UFPs and PM2.5, rather than PM10, were significantly associated with increased systolic blood pressure (SBP), whereas diastolic blood pressure (DBP) and pulse pressure showed non-significant changes. The effects appeared earlier after UFP exposure (lag 03d) than PM2.5 exposure (lag 06d), with central responses exceeding brachial responses. Notably, hypertensive individuals exhibited stronger responses to UFPs and PM2.5 exposure, in whom significant elevations were observed in both SBP and DBP. Stratification by smoking status revealed no evidence of effect modification. Comparatively, individuals with an eosinophilic, instead of neutrophilic, phenotype showed heightened susceptibility to PM2.5-related and UFP-related blood pressure increases, particularly in those with hypertension. CONCLUSIONS:Small-sized PM is an important risk factor for blood pressure elevations in patients with COPD, especially among those with hypertension and an eosinophilic inflammatory phenotype. TRIAL REGISTRATION NUMBER:NCT05076630.

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease with complex pathogenesis. Identifying high-risk populations and implementing timely prevention strategies are critical to reducing the disease burden. Single-cell RNA sequencing of lung tissue from control never-smokers, patients with pre-COPD, and COPD patients revealed a novel T cell subset characterized by high expression of metallothionein (MT) genes, designated MT-high T cells. These cells were progressively depleted in the lungs with disease progression. A similar decline was observed in the peripheral blood using flow cytometry, highlighting the potential of these cells to serve as an accessible biomarker of disease progression. Functional analysis indicated that MT-high T cells suppress CD8+ T cell cytotoxic activity, suggesting a key immunoregulatory role in disease pathogenesis. Receiver operating characteristic curve analysis demonstrated the excellent potential of MT-high T cell frequency to predict susceptibility to COPD. These findings establish MT-high T cells as promising biomarkers for identifying individuals at risk for COPD and as novel targets for future therapeutic and prophylactic strategies.

Vascularised lung organoids (vLOs) that faithfully mimic human lung tissue architecture and disease pathology are critical for advancing pulmonary research but remain challenging to generate. Here, we developed a robust self-organisation protocol to produce vLOs with cellular heterogeneity and functional vasculature. The engineered blood vessels within vLOs exhibit lung-specific characteristics. As proof of concept, we applied this platform to model chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH). Using patient-derived vLOs, we demonstrated that cigarette smoke extract (CSE) induces pathological features resembling clinical COPD, including epithelial disruption and inflammatory responses. Furthermore, vLOs generated from a PH patient recapitulated disease-associated vascular remodelling, with RNA-seq revealing dysregulated pathways in endothelial dysfunction. Notably, we identified sodium hydrosulfide (NaHS) as a potential therapeutic candidate, as it attenuated aberrant EndoMT in PH-vLOs. In summary, our study establishes a physiologically relevant vLO system that enables modelling of cell-type-specific disease mechanisms and underscores the broad utility of this platform for mechanistic investigations and precision medicine approaches in respiratory disorders.

Organoid culture represents a sophisticated biological model that surpasses traditional two-dimensional (2D) methods and animal models in physiological relevance and cost-effectiveness. Current organoid systems derive from adult, fetal, and induced pluripotent stem cells, providing innovative platforms for studying organ development, disease pathogenesis, and drug discovery. Recent technological advances now enable respiratory organoids to significantly contribute to respiratory disease research. This review comprehensively synthesizes the development of respiratory organoid models and their applications in studying major respiratory diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and lung cancer. It further evaluates the transformative potential of these models in advancing respiratory disease research. Respiratory organoids uniquely model disease mechanisms and drug responses in human-specific microenvironments, enabling pathogenesis studies of respiratory diseases. They serve as functional platforms for drug screening and personalized therapy development. Future integration of multi-organoid systems with precision medicine promises to redefine respiratory disease research paradigms.

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.

BACKGROUND:Emphysema, a major component of chronic obstructive pulmonary disease (COPD) characterized by progressive alveolar destruction, lacks effective medical therapies. Hepatocyte growth factor (HGF) possesses potent regenerative functions, but its therapeutic potential remains unrealized due to challenges in achieving targeted delivery and sustained lung expression. METHODS:We first assessed associations between HGF expression and emphysema severity using human datasets, lung tissue, and both elastase-induced and cigarette-smoke-induced murine models. We repurposed a clinical-stage SM102 lipid nanoparticles (LNPs) platform to deliver human HGF mRNA in murine models, evaluating therapeutic efficacy via i.t. instillation in the elastase model. After optimizing nebulization, we assessed efficacy in the cigarette-smoke model. We investigated underlying mechanisms via single-cell RNA sequencing (scRNA-seq), which we validated in patient-derived lung organoids. RESULTS:HGF expression displayed a biphasic pattern across the emphysema spectrum, with upregulation in milder disease states and marked reduction in advanced emphysema. i.t. delivery of HGF mRNA LNPs restored lung function and attenuated alveolar destruction in the elastase model. Nebulized delivery achieved efficient pulmonary distribution and demonstrated comparable therapeutic efficacy in the cigarette-smoke model, including improved lung function, reduced inflammation, and decreased apoptosis. scRNA-seq analysis detected enhanced alveolar type II (AT2) cell proliferation and differentiation in the elastase model and human organoids. CONCLUSION:This study provides proof-of-concept evidence for a therapeutic strategy for emphysema. Using a clinical-stage LNPs platform, we demonstrate that HGF mRNA therapy is effective via both direct instillation and optimized nebulization, prompting structural and functional recovery by activating endogenous repair pathways in AT2 cells.

Overexpression of Mucin 5AC (MUC5AC) drives excessive mucus secretion and respiratory obstruction, contributing to mortality in severe asthma and mucous obstructive lung diseases (MOLDs). While siRNA-mediated silencing of MUC5AC expression represents an effective strategy to treat MOLDs, our investigation reveals that intratracheal administration of FDA-approved lipid nanoparticle (LNP) carriers can paradoxically lead to MUC5AC increases due to inflammatory side effects. To address this challenge, we designed noninflammatory LNPs for asthma treatment by (I) developing ionizable cationic lipids with low immunogenicity, (II) incorporating anti-inflammatory natural compound derivatives into LNPs, and(III) reducing the N/P ratio of LNP formulations. After three rounds of screening-evaluating gene silencing efficiency (in vitro and in vivo), LNP physicochemical properties and biosafety─we identify a lead candidate formulation (Formulation 1) that achieves 85% MUC5AC silencing efficiency in vivo, outperforming the integrin αvβ6 ligand-modified siRNA (69%), and demonstrates notably improved biosafety when compared to SM102 LNPs and MC3 LNPs. In house dust mite (HDM)-induced asthmatic mice, siMuc5ac-LNPs effectively alleviate airway inflammation and obstruction with a sustained preventive effect. Moreover, Formulation 1 effectively suppresses MUC5AC secretion in a Chronic Obstructive Pulmonary Disease (COPD) patient-derived organoid model. Collectively, we develop a clinically translatable, noninflammatory siRNA delivery platform with therapeutic potential for asthma and other MOLDs.

OBJECTIVE:To assess the association between personal temperature exposure and oxygen saturation (SpO2) during sleep in chronic obstructive pulmonary disease (COPD) patients, to analyze potential susceptibility factors and to provide a scientific basis for the adoption of effective measures to safeguard the health of susceptible populations. METHODS:In this prospective panel study, 96 stable COPD patients were recruited. From March 2021 to September 2023 in Beijing, all participants completed 202 nights (from 20:00 to 08:00) of dynamic real-time SpO2 monitoring during sleep, simultaneously monitoring personal exposure level to temperature, alongside environmental humidity and other key air pollutant data. Based on previous clinical studies, SpO2 < 90% was defined as desaturation to assess the risk of hypoxic events occurring during sleep. Linear mixed-effects models and generalized linear mixed-effects models were used to analyze the association between personal temperature exposure and SpO2 during sleep, as well as the risk of oxygen desaturation. Interaction models were constructed to evaluate susceptibility factors. RESULTS:During the study, the average personal temperature exposure was (27.5± 2.6) ℃, with a temperature range from 16.5 ℃ to 40.0 ℃. Short-term exposure to personal temperature was associated with a decline in SpO2 and an increased risk of oxygen desaturation during sleep in the COPD patients. The effect of temperature exposure was strongest at lag 0-30 min, with a 0.24% (95%CI: -0.28%, -0.20%) decrease in SpO2, and with an odds ratio (OR) of oxygen desaturation was 1.26 (95% CI: 1.12, 1.42) for each interquartile range (IQR, 6.0 ℃) increase in temperature. Besides, the patients exposed to medium and high humidity levels were more likely to be affected by temperature exposure compared with the patients exposed to low humidity levels. Personal temperature exposure had a stronger effect on SpO2 during sleep in the patients with global initiative for chronic obstructive lung disease (GOLD) Ⅲ-Ⅳ compared with the patients with GOLD Ⅰ-Ⅱ (Pinteraction < 0.05). CONCLUSION:From 16.5 ℃ to 40.0 ℃, personal temperature exposure is associated with SpO2 decline during sleep in COPD patients. There was a significant synergistic amplification between temperature and humidity, patients were more susceptible to damage under high temperature and high humidity conditions. Moreover, patients with poorer lung function are more significantly affected by temperature.

JOURNAL/mgres/04.03/01612956-202612000-00007/figure1/v/2026-07-23T200825Z/r/image-tiff Since air pollution can cause acute exacerbation of asthma, we aimed to investigate the effects of short-term exposure to ambient air pollution on respiratory symptoms and lung function among patients with asthma. A prospective and observational panel study recruited 32 patients with asthma from November 2015 to December 2016. The Asthma Control Test scores and lung function measurements of the patients were repeatedly assessed. Daily ambient air pollution data, including particulate matter (PM2.5 and PM10), sulfur dioxide, nitrogen dioxide, and carbon monoxide, were obtained from nearby central air-monitoring stations. Mixed effects models were used to examine the associations between pollutant exposure and health measurements. Clinical data were repeatedly collected 2 to 13 times each month, totaling 266 visits. Increases in the interquartile ranges of PM2.5 (74.5 μg/m3, 6-day), PM10 (78 μg/m3, 5-day), sulfur dioxide (10 μg/m3, 7-day), nitrogen dioxide (37 μg/m3, 6-day), and carbon monoxide (0.7 mg/m3, 6-day) levels were significantly associated with reductions in Asthma Control Test scores by 3.6%, 2.8%, 3.2%, 3.8%, and 2.9%, respectively. An interquartile range increase of 78 μg/m3 in the 7-day moving average concentration of PM10 was significantly associated with reductions of 3.6% in percentage of predicted forced expiratory volume in 1 second and 6.0% in percentage of predicted forced expiratory flow at 25% of the forced vital capacity, respectively. Short-term ambient air pollution may aggravate respiratory symptoms and cause a decline in lung function among patients with asthma.

Chronic obstructive pulmonary disease (COPD) is a major public health concern due to its high prevalence, morbidity, and mortality. Although COPD is recognized as a systemic inflammatory disease, the specific circulating inflammatory proteins associated with its development and progression remain poorly understood. We performed a Mendelian randomization (MR) study to investigate the association between circulating inflammatory proteins and COPD risk. Genetic data were obtained from a genome-wide association study of 20,066 COPD cases and 338,303 controls from the FinnGen consortium and circulating inflammatory protein data were derived from a genome-wide association study of 14,824 participants. The inverse-variance weighted method was used as the primary analysis. Depending on the number of available instrumental variables, complementary methods including the Wald ratio, Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were applied to assess robustness. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy using Cochran's Q test, the MR-Egger intercept, MR-PRESSO, and leave-one-out analysis. In addition, cis-acting protein quantitative trait locus -restricted analyses were performed to further reduce potential pleiotropy. Our findings showed that higher genetically predicted levels of CCL28 (odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.69-0.99, P = .0394), CD40 (OR = 0.94, 95% CI: 0.89-0.99, P = .0170), and urokinase-type plasminogen activator (OR = 0.91, 95% CI: 0.85-0.99, P = .0212) were associated with a lower risk of COPD, whereas higher levels of Flt3L (OR = 1.09, 95% CI: 1.01-1.18, P = .0344) and CD6 (OR = 1.06, 95% CI: 1.02-1.12, P = .0099) were associated with a higher risk. Sensitivity analyses showed no evidence of heterogeneity or directional pleiotropy, and leave-one-out analyses indicated that the results were not driven by any single nucleotide polymorphism. These findings suggest that circulating inflammatory proteins, including CCL28, CD40, urokinase-type plasminogen activator, Flt3L, and CD6, may be involved in COPD pathogenesis. Further studies are needed to validate these findings and clarify their potential biological relevance.

Background: Chronic obstructive pulmonary disease is associated with excess cardiovascular morbidity, but the circulating molecular signatures linking chronic obstructive pulmonary disease-related systemic biology with cardiovascular prognosis remain incompletely characterised. Methods: We analysed UK Biobank participants with baseline spirometry, Olink plasma proteomic profiling, and linked health records. Proteins associated with chronic obstructive pulmonary disease were identified using proteome-wide logistic regression. Among participants with chronic obstructive pulmonary disease, these proteins were evaluated for associations with incident cardiovascular and mortality outcomes using Cox models. Pathway enrichment, mediation-consistent analyses, and elastic-net prognostic modelling were performed. Findings: Among 36,728 participants, 6089 had chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease was associated with higher risks of major adverse cardiovascular events, heart failure, atrial fibrillation, and stroke after multivariable adjustment. Proteome-wide analyses identified 1409 chronic obstructive pulmonary disease-associated proteins. Among participants with chronic obstructive pulmonary disease, recurrent prognostic proteins included cardiopulmonary stress, inflammatory, tissue-remodelling, and vascular markers. Protein-enhanced models improved prediction of major adverse cardiovascular events, heart failure, and atrial fibrillation beyond clinical predictors. Interpretation: Chronic obstructive pulmonary disease is characterised by systemic proteomic perturbations that are linked to cardiovascular prognosis. These proteins may help prioritise biological pathways and candidate markers for cardiovascular risk stratification in chronic obstructive pulmonary disease, pending external validation.

Chronic obstructive pulmonary disease (COPD) frequently coexists with extrapulmonary comorbidities, most notably cardiovascular diseases (CVD). However, the mechanisms linking COPD to CVD, particularly atherosclerotic CVD, remain poorly understood. Extracellular vesicles (EVs), as key mediators of inter-organ communication, may participate in this pathological connection. This study aims to determine whether EVs derived from airway epithelial cells (AECs) of individuals with COPD contribute to endothelial dysfunction and atherosclerosis. EVs were isolated from primary airway epithelial cells of COPD patients and matched controls. Their effects on endothelial cell function were assessed in vitro by evaluating inflammation, apoptosis, and monocyte adhesion. ApoE-/- mice were intravenously injected with these EVs to examine their impact on atherosclerotic lesion development. Differentially expressed microRNAs were identified, and the regulatory relationship between miR-141-3p and PDCD4 was validated through molecular assays. Additionally, miR-141-3p supplementation was performed to determine its therapeutic potential in mitigating endothelial injury and atherosclerosis. COPD AECs-derived EVs markedly increased endothelial inflammation, apoptosis, and monocyte adhesion compared with control EVs. In ApoE-/- mice, COPD-derived EVs accelerated the formation of atherosclerotic plaques. Mechanistic analyses revealed that miR-141-3p was significantly downregulated in COPD EVs and directly targeted the 3’ untranslated region of PDCD4 to regulate its transcription, leading to dysregulation of PDCD4/NF-κB signaling in endothelial cells. Restoration of miR-141-3p levels in COPD-derived EVs alleviated endothelial injury and reduced atherosclerotic lesion progression both in vitro and in vivo. This study identifies a previously unrecognized mechanism by which COPD AECs-derived EVs may promote atherosclerotic CVD via miR-141-3p–mediated regulation of PDCD4 and subsequent activation of NF-κB signaling. These findings highlight miR-141-3p as a promising therapeutic target to reduce vascular complications in COPD.

Abstract Background AECOPD adversely affects patient survival rates and overall quality of life. Irisin is being increasingly recognized for its therapeutic potential in attenuating pulmonary injury, but its underlying mechanism remains unclear. Methods Human lung tissue samples were subjected to IHC analysis for irisin, integrin αVβ5, and GRP78 expression. CSE+LPS-induced mouse and cell models were used to investigate whether irisin protects against emphysema and inflammation by regulating ER homeostasis and AMPK activity via integrin αVβ5. Results In COPD patients, irisin levels are decreased, whereas integrin αVβ5 and GRP78 levels are elevated. Irisin improved lung function and attenuated emphysema and inflammation in mice, and these effects were abolished by cilengitide. Irisin directly bound to integrin αVβ5, maintained ER homeostasis via the PERK/ATF4/CHOP pathway, and activated AMPK. These protective effects were lost upon integrin αVβ5 knockdown. Conclusion These findings suggest that through integrin αVβ5, irisin concurrently maintains ER homeostasis and activates AMPK, thereby alleviating CSE+LPS-induced emphysema and inflammation, suggesting a novel therapeutic direction for the management of AECOPD.

ABSTRACT:Chronic lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, obstructive sleep apnea, asthma, bronchiectasis, and lung cancer, are intricately linked to the aging process. These diseases are characterized by a high prevalence rate and a paucity of effective treatment options. Emerging evidence highlights the critical role of extracellular vesicles (EVs) in the pathogenesis and progression of these diseases. EVs, released by senescent cells, mediate intercellular communication and modulate immune responses through their cargo of microRNAs, proteins, and other molecules. These vesicles contribute to disease progression by promoting inflammation, fibrosis, tissue remodeling, and cellular senescence. Specifically, certain microRNAs, such as miR-21, miR-34a, and miR-570-3p, along with several proteins in EVs, have been identified as key factors influencing these processes. Additionally, EVs play significant roles in immune regulation and have potential anti-inflammatory effects, making them promising candidates for therapeutic applications. Recent advances in the use of EVs as therapeutic agents, including their application in nanotechnology for targeted drug delivery, have demonstrated potential in reducing inflammation, modulating immune responses, and enhancing tissue repair. Understanding the role of EVs in these diseases offers insights into potential therapeutic targets to mitigate disease progression and improve patient outcomes. Future research should focus on standardizing EV isolation and characterization methods, verifying the safety and efficacy of EV-based therapies in clinical trials, and elucidating the complex biological mechanisms of EVs in aging and disease.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and progressive disease, hence greater understanding of its humanistic, economic, and environmental impact is essential for guiding effective management strategies. A systematic literature review (SLR; 2021-2023), complemented with a targeted literature review (TLR; 2013-2023) identified 2039 publications on the economic and humanistic burden of severe COPD. Additionally, an SLR and complementary TLR to evaluate the impact of environmental and sociodemographic factors on COPD (2013-2023), identified 1018 records. All searches were conducted on November 17, 2023. After applying prespecified selection criteria, 50 studies reporting on the humanistic and economic impact of COPD, and six studies on the environmental and sociodemographic impact, were selected. Severe COPD significantly impairs health-related quality of life, exerting effects on physical and psychological well-being, with a progressive decline as COPD worsens from mild to very severe. Evidence indicates that there is a significant burden of disease due to exacerbations of COPD, with their frequency and severity increasing with disease progression, and an increased mortality risk associated with very severe versus severe COPD. The studies reported a high frequency of healthcare resource utilization, including primary care visits, emergency department visits, and hospitalizations among patients with severe COPD, all of which contribute to a significant economic burden, particularly in patients with advanced disease. Environmental factors demonstrated diverse impacts on outcomes for individuals with severe COPD, varying by type of pollutant, disease severity, and patient characteristics. Studies examining the sociodemographic impact of underserved populations on the burden of severe COPD were not identified. Severe COPD is a multifaceted disease that imposes considerable humanistic and economic impact on both patients and healthcare systems. Further work is needed to understand the impact of environmental and sociodemographic factors on the burden of COPD, with such insights ultimately optimizing patient care.

Chronic inflammation is a crucial driver in the development of chronic obstructive pulmonary disease (COPD) and its comorbidities, such as skeletal muscle dysfunction. Heightened IL-36 expression in the lung and systemic circulation has been observed in patients with COPD, but the potential role of IL-36 in COPD still needs further exploration. Herein, we established a COPD model through long-term cigarette smoke (CS) exposure in mice with or without IL-36R deletion. Elevated IL-36 cytokines were observed in the lung and peripheral blood of CS-exposed wild-type mice. IL-36R gene deficiency attenuated CS-induced lung parenchymal destruction and airway inflammation, as evidenced by decreased secretion of inflammatory mediators, such as IL-6, IL-1β, TNF-α and MMP9, and a diminished Th1/Tc1- and Tfh-biased immune response. In addition, skeletal muscle dysfunction was alleviated in CS-exposed mice by IL-36R deletion. Further investigations indicated that CS treatment induced the expression of IL-36 cytokines and IL-36R in C2C12 myotubes and skeletal muscles, and that IL-36 cytokines could upregulate FBXO32 and TRIM63 expression by activating NF-κB p65 pathway, thereby leading to skeletal muscle atrophy in an endocrine and autocrine/paracrine manner. Our findings provide evidence for a critical role of the IL-36/IL-36R signaling in the pathogenesis of CS-induced COPD and comorbid skeletal muscle dysfunction.

BACKGROUND:Asthma frequently coexists with other diseases associated with poor asthma control and low quality of life. Asthma exacerbation refers to severe episodes of disease worsening. Few studies have focused on identifying multimorbidity patterns in asthma and assessing their effects on asthma exacerbation. OBJECTIVE:To identify distinct multimorbidity patterns associated with asthma exacerbation in an older cohort and evaluate their impact on prognosis. METHODS:We performed a mini batch K-means clustering analysis of the comorbidities of 849 patients with asthma in this retrospective cohort study. Logistic regression analysis was performed to quantify independent associations between the identified phenotypes and outcomes. RESULTS:We identified four multimorbidity patterns in patients with asthma. Clusters 1 (n = 232; 27.33%), 2 (n = 122; 14.37%), 3 (n = 149; 17.55%), and 4 (n = 346; 40.75%) were characterized by predominantly allergic, predominantly respiratory, predominantly cardiometabolic, and fewer comorbidities, respectively. Cluster 2 was at significantly increased risk of intensive care unit admission (odds ratio [OR] = 2.30), noninvasive ventilation (OR = 2.68), mechanical ventilation (OR = 1.93) and 1-year emergency department revisits for asthma (OR = 3.10). Cluster 3 had the highest risk of 1-year readmission for comorbidities (OR = 2.53) and 1-year emergency department revisit for comorbidities (OR = 1.84). CONCLUSIONS:We identified four multimorbidity patterns associated with clinical characteristics and adverse outcomes in patients at risk for asthma exacerbation. Comorbidities can be recognized as treatable traits that can minimize the risk of future exacerbations and the adverse effects of asthma.