Respiratory Research[JOURNAL]
Sun
200 papers
Association of metformin with lung function decline and mortality in fibrotic interstitial lung disease: an observational cohort study.
Bevanda L, Mok V, Khor YH … +8 more , Assayag D, Fisher JH, Johannson KA, Kolb M, Manganas H, Marcoux V, Marinescu DC, Ryerson CJ
Respir Res · 2026 Mar · PMID 41826995 · Full text
Many patients with fibrotic interstitial lung disease (ILD) also have comorbid diabetes, for which they take metformin. Metformin use has been shown to have lung fibrosis attenuation potential based on laboratory researc...
Many patients with fibrotic interstitial lung disease (ILD) also have comorbid diabetes, for which they take metformin. Metformin use has been shown to have lung fibrosis attenuation potential based on laboratory research but studies in human populations have yielded inconsistent results. To investigate this, 2,226 patients with fibrotic ILD from the large, prospective Canadian Registry for Pulmonary Fibrosis were analyzed for lung function at baseline and up to 2-year follow up. Joint modeling was used to assess the association of baseline metformin use with longitudinal lung forced vital capacity change and survival (death or lung transplant), adjusting for age, sex, smoking pack-years, baseline lung function, medication use. Results showed that baseline metformin use was not significantly associated with attenuation of forced vital capacity decline in the overall interstitial lung disease cohort, or in the subgroups based on presence of a diagnosis of idiopathic pulmonary fibrosis or diabetes. Kaplan–Meier and Cox analyses suggested a trend toward increased mortality or transplant risk associated with metformin use in all cohorts, although this was not statistically significant after adjustment for other variables. In our study, metformin did not significantly alter lung function decline in fibrotic ILD despite laboratory evidence of antifibrotic properties.
Epidemiological characteristics of six respiratory pathogens in respiratory infections in Fuzhou, China.
Chen S, Jiang L, Zhou H … +4 more , Lunzhu D, Yu L, Shen X, Cao P
Respir Res · 2026 Mar · PMID 41826972 · Full text
OBJECTIVE: To characterize the burden and features of respiratory pathogens infections among patients with Acute Respiratory Tract Infections (ARTIs) in Fuzhou, China. Providing evidence-based guidance for outbreak preve...
OBJECTIVE: To characterize the burden and features of respiratory pathogens infections among patients with Acute Respiratory Tract Infections (ARTIs) in Fuzhou, China. Providing evidence-based guidance for outbreak prevention. METHODS: From December 2023 to February 2025, 10,355 ARTI patients at Fuzhou University Affiliated Provincial Hospital were tested for six pathogens (Influenza A virus (FLUA), Influenza B virus (FLUB), respiratory syncytial virus (RSV), Human rhinovirus (HRV), adenovirus (ADV), and Mycoplasma pneumoniae (MP)) using multiplex PCR. Detection rates and epidemiological characteristics were analyzed. RESULTS: Among enrolled patients, 4,699 (45.37%) tested positive. Overall pathogen detection showed no significant gender difference. However, RSV positivity was higher in males (P =0.046), while MP infection predominated in females (P <0.0001). MP predominated among single infections (14.72%), followed by HRV (13.54%), ADV (9.13%), FLUA (8.93%), RSV (3.43%), and FLUB (2.57%). Major coinfections (>1%) included HRV+MP (2.98%), ADV+MP (2.87%), HRV+FLUA (2.06%), and ADV+HRV (1.64%). These pathogens constituted the primary etiology of pediatric ARTIs. Distinct seasonal patterns emerged: FLUA peaked in spring/winter; FLUB and MP surged in winter; RSV circulated in spring/autumn; ADV prevailed in autumn/winter; HRV was endemic in summer/autumn/winter. HRV positivity correlated inversely with improved air quality (daily index <60). RSV outbreaks exhibited a lagged correlation with precipitation and demonstrated a "compensatory peak" relative to FLUA. Compared to individuals >60 years（y）: Children <7 y had significantly elevated RSV risk; Minors <18 y showed reduced FLUA susceptibility; FLUB risk increased in ages 1-60 y; Those <60 y exhibited higher ADV, HRV, and MP infection risks. Relative to winter: Spring decreased FLUA/B/MP risk but increased RSV/HRV; Summer lowered FLUB/MP risk while elevating RSV; Autumn reduced FLUA/B/ADV/MP risk but heightened RSV/HRV. Multivariate analysis identified age >60 y and RSV/HRV/MP infection as independent risk factors for lower respiratory tract involvement. CONCLUSION: The epidemiology of these six pathogens exhibits significant age-, season-, and climate-dependent variations, necessitating tailored preventive strategies. Enhanced vigilance for lower respiratory complications is warranted in individuals ≥60 y and those infected with RSV, HRV, or MP. These findings provide critical insights for targeted interventions.
Multi-regional radiomics of obstructive sleep apnea based on synthetic MRI.
Chen J, Wen S, Si G … +13 more , Liu W, Wang Z, Li W, Chen J, Deng Y, Chen T, Zhu Y, Cai M, Yuan W, Chen Y, Zou Y, Shi G, Ye J
Respir Res · 2026 Mar · PMID 41821083 · Full text
BACKGROUND: High prevalence and serious complications associated with obstructive sleep apnea (OSA) urge the need for methods that support non-invasive examinations, diagnostic accuracy and pathophysiological insights of...
BACKGROUND: High prevalence and serious complications associated with obstructive sleep apnea (OSA) urge the need for methods that support non-invasive examinations, diagnostic accuracy and pathophysiological insights of OSA. This study aims to develop a Synthetic MRI-based radiomics model for diagnosing and stratifying OSA severity, and to explore its pathophysiological basis through integrated histopathological-transcriptomic analyses. METHODS: This cross-sectional study prospectively collected data at the tertiary hospital between July 2023 and October 2024. Individuals with and without OSA were recruited from the Otolaryngology Head and Neck Inpatient and Outpatient Department, all of whom underwent upper airway SyMRI. All participants were randomly divided into training and a validation set in an 8:2 ratio. The four-class (non-, mild, moderate and severe OSA) radiomics diagnostic model was developed to diagnose OSA and evaluate its severity across three algorithms (logistic regression, support vector machine, and random forest). Model performance was assessed using the receiver operating characteristic (ROC) curve. The underlying pathophysiological connections between radiomic features and OSA were explored by creating radiogenomic maps linking radiomic features with relevant biological pathways using the weighted correlation network analysis (WGCNA). RESULTS: 230 participants were enrolled and divided into four groups by the apnea-hypopnea index (AHI): non-OSA (76 participants, AHI < 5 events/h), mild OSA (28 participants, 5 ≤ AHI < 15 events/h), moderate OSA (53 participants, 15 ≤ AHI < 30 events/h), and severe OSA (73 participants, AHI ≥ 30 events/h). The four-class radiomics diagnostic model demonstrated excellent performance across the three algorithms. In the training set, the average area under curves (AUCs) of the four classes were 0.999, 0.997, 0.988, and 0.995, respectively. In the test set, the average AUCs were 0.968, 0.942, 0.893, and 0.932, respectively. WNGCA and histopathological staining analysis of the soft palates indicated that radiomic features were significantly associated with muscle function and the myocyte areas in soft palates. CONCLUSIONS: SyMRI-based radiomic analysis provides an effective and supportive tool for diagnosing OSA, which can differentiate its severity from a pathophysiological perspective. The pathophysiological relevance of radiomics lies in its ability to capture subtle tissue alterations that are not readily apparent on conventional imaging. CLINICAL TRIAL NUMBER: Not applicable.
Association between anti-citrullinated peptide antibodies and subclinical interstitial lung disease in community-dwelling adults: the multi-ethnic study of atherosclerosis.
Lanz JV, Hughes-Austin J, Podolanczuk AJ … +13 more , Kim JS, Salvatore MM, Robinson WH, Raghu G, Hoffman EA, Newell JD, Watts JR, Nath PH, Sonavane SK, Giles JT, Garcia CK, Barr RG, Bernstein EJ
Respir Res · 2026 Mar · PMID 41821027 · Full text
BACKGROUND: Rheumatoid arthritis-associated autoantibodies have been associated with interstitial lung abnormalities (ILA) among community-dwelling adults. We aimed to determine whether greater numbers of positive anti-c...
BACKGROUND: Rheumatoid arthritis-associated autoantibodies have been associated with interstitial lung abnormalities (ILA) among community-dwelling adults. We aimed to determine whether greater numbers of positive anti-citrullinated protein antibodies (ACPAs) are associated with ILA in community-dwelling adults. METHODS: We performed a period cross-sectional study. We measured 29 ACPAs via Bio-Plex bead array (2003–2005) and ILA on full-lung CTs (2010–2012) in 868 participants enrolled in the Multi-Ethnic Study of Atherosclerosis. A positive ACPA was defined as titer > 75th percentile. We used generalized additive and logistic regression models to examine associations between number of positive ACPA and ILA and tested for effect modification by race/ethnicity. RESULTS: In an adjusted model, each 1 unit increase in log-transformed number of positive ACPA was associated with a 17% decrease in odds of ILA (OR 0.83, 95% CI 0.68–1.01). Race/ethnicity modified the association between log-transformed number of positive ACPA and ILA (interaction p-value 0.03), such that each 1 unit increase in log-transformed number of positive ACPA was associated with a 39% decrease in the adjusted odds of ILA among African American participants (OR 0.61, 95% CI 0.37–0.99) and a 42% decrease in the adjusted odds of ILA among Hispanic participants (OR 0.58, 95% CI 0.36–0.91). There was no significant association between log-transformed number of positive ACPA and ILA among White or Chinese American participants. CONCLUSIONS: In this large population-based multi-ethnic study, an expanded ACPA repertoire was associated with a lower burden of ILA on CT, especially among African American and Hispanic participants.
Integrated multiomics profiling predicts anti-tuberculosis drug-induced liver injury.
Liu Q, Wang C, Si G … +1 more , He J
Respir Res · 2026 Mar · PMID 41803902 · Full text
BACKGROUND: Anti-tuberculosis drug-induced liver injury (ATB-DILI) severely compromises tuberculosis (TB) treatment. We aimed to identify pretreatment predictors via integrated proteomic, metabolomic, and gut microbiome...
BACKGROUND: Anti-tuberculosis drug-induced liver injury (ATB-DILI) severely compromises tuberculosis (TB) treatment. We aimed to identify pretreatment predictors via integrated proteomic, metabolomic, and gut microbiome profiling. METHODS: This prospective multicenter study enrolled 72 adults who were receiving HRZ therapy. Serum, urine, and stool samples were collected before pretreatment. Serum proteins (RBP-4, CHGA, CPB2, ANT3, APOD) were quantified via ELISA. Nontargeted metabolomics (LC-MS) was used to analyze serum/urine, and 16 S rRNA sequencing was used to characterize the fecal microbiota. Liver injury (ALT/TBIL ≥ 2×ULN; RUCAM ≥ 3) was monitored biweekly/monthly. The ATB-DILI (n = 35) and non-ATB-DILI (n = 37) groups were compared statistically. A random forest model was used to integrate significant features (100-fold cross-validation). RESULTS: ATB-DILI developed at a median of 29 days (IQR:14–30) and was predominantly hepatocellular (54.3%). The pretreatment levels of all five proteins were elevated in ATB-DILI patients (p < 0.0001). Serum metabolomics revealed 163 differentially abundant metabolites (137↑/26↓; OPLS-DA R²Y = 0.692, Q²=0.351), and urine metabolomics revealed 106 (42↑/64↓; R²Y = 0.972, Q²=0.364). Beta diversity differed significantly between groups (Adonis P = 0.004), with Catenibacterium/Lactococcus enriched in ATB-DILI. Strong correlations linked the microbiota, metabolites, and liver enzymes. The integrated multiomics model (serum/urine metabolites, microbiome, proteins) achieved superior prediction (AUC = 0.880), outperforming single-platform models (serum metabolites:0.859; urine:0.803; microbiome:0.691; proteins:0.671). CONCLUSION: Pretreatment alterations in serum proteins, host metabolism, and the gut microbiota predict ATB-DILI risk. An integrated multiomics model enables early intervention for personalized TB therapy.
Paradigm shift: from pulmonary vasodilation to cardiopulmonary dual-track therapy-a comprehensive review of pathophysiology and advances in pulmonary hypertension-associated right heart failure.
Chen R, Liu C, Han J … +2 more , Dong J, Zhai W
Respir Res · 2026 Mar · PMID 41792758 · Full text
Pulmonary arterial hypertension (PAH)-induced right heart failure (RHF) remains a major determinant of poor patient outcomes, driven by multifaceted pathophysiological mechanisms including impaired right ventricle-pulmon...
Pulmonary arterial hypertension (PAH)-induced right heart failure (RHF) remains a major determinant of poor patient outcomes, driven by multifaceted pathophysiological mechanisms including impaired right ventricle-pulmonary artery coupling, metabolic reprogramming, mitochondrial dysfunction, chronic inflammation, and gut–lung axis disruption. Traditional therapies focusing solely on pulmonary vasodilation provide symptomatic relief but often fail to halt progressive right heart deterioration. Recent advances underscore a paradigm shift toward cardiopulmonary dual-track strategies that simultaneously reduce right ventricular afterload and directly protect or enhance right heart function. Novel agents such as Sotatercept—an activin signaling inhibitor—significantly reverse vascular remodeling and improve hemodynamics. Metabolic modulators (e.g., metformin), mitochondrial-targeted antioxidants (e.g., Elamipretide), and immunomodulators (e.g., tocilizumab) show promise in correcting bioenergetic deficits and inflammatory activation. Interventional approaches like percutaneous pulmonary artery denervation (PADN) and atrial septostomy serve as effective bridging options, while percutaneous right ventricular assist devices (pRVADs) and extracorporeal membrane oxygenation (ECMO) offer critical circulatory support in end-stage disease. Emerging therapies—including gene editing, cell-based treatments, and exosome technology—hold potential for targeted, personalized intervention. Despite these innovations, challenges persist such as variable treatment responses, long-term safety concerns, and translational inefficiencies. Future efforts should prioritize multi-omics-guided precision medicine, multidisciplinary care integration, and novel technologies like CRISPR/Cas9 to advance disease-modifying therapies and improve quality of life.
Optimized culture of primary human alveolar type II cell-derived 3D organoids from fibrotic lung tissue with phenotypic and metabolic profiling.
Schröder LJ, Rückoldt J, Schubert S … +15 more , Knudsen L, Janciauskiene SM, Werlein C, Knoll M, Engelhardt R, Petzold-Mügge C, Schupp JC, Hoeper MM, Gottlieb J, Ius F, Zardo P, Lindenberg M, Riehle C, Neubert L, Kamp JC
Respir Res · 2026 Mar · PMID 41792753 · Full text
BACKGROUND: Alveolar type II (AT-II) epithelial cells are essential for alveolar repair, immune regulation, and surfactant secretion. Despite their promise for pulmonary disease modeling, limited access and culture metho...
BACKGROUND: Alveolar type II (AT-II) epithelial cells are essential for alveolar repair, immune regulation, and surfactant secretion. Despite their promise for pulmonary disease modeling, limited access and culture methods hinder translational use. We established a patient-derived 3D AT-II organoid system from fibrotic and non-fibrotic lung tissue to maintain AT-II-associated features, enable cryopreservation, and capture disease-associated metabolic alterations. METHODS: HT-II-280+ AT-II cells were isolated by magnetic bead sorting from 63 lung tissues (15 idiopathic pulmonary fibrosis, 26 secondary fibrosis, 22 tumor-distant controls). Cells were expanded as organoids in 3D culture from initial passage 0 up to passage 3. AT-II-associated features were assessed by immunofluorescence, flow cytometry, and transmission electron microscopy. Cryopreserved cells were recovered after ≥ 28 days and tested for viability and organoid-forming capacity. Metabolic profiling was performed using extracellular flux assays. RESULTS: AT-II cells were successfully (~ 80%) isolated and combined with a serum- free feeder-free culturing approach to reproducibly generated alveolospheres with highly efficient colony formation (> 90% in P1), especially in AT-II cells from fibrotic explants. Primary tissue-derived lung organoids display heterogeneous morphologies and sizes, most prominently in fibrotic-derived cultures, as indicated by histology and microcomputed tomography. Culture conditions were optimized to minimize differentiation towards AT-I cells or dedifferentiated epithelial states with partial basaloid features. Expression of key AT-II-associated markers (proSP-C, HT-II-280), and the presence of lamellar bodies were maintained across passages at the population level. Cryopreservation maintained high viability, organoid-forming capacity, and metabolic activity, enabling long-term storage. Fibrotic organoids exhibited disease-associated metabolic reprogramming characterized by a pronounced glycolytic shift with increased ATP production. CONCLUSION: We established a reproducible cell-line-free 3D culture system from primary human AT-II cells of end-stage ILD lungs to generate patient-derived lung organoids. These organoids maintain AT-II-associated features across passages, remain viable after cryostorage, and capture disease-associated metabolic reprogramming. Fibrotic-derived AT-II cells consistently demonstrated a Warburg-like glycolytic phenotype, reflecting increased energy demand. This scalable model in vitro provides a defined resource for mechanistic studies of epithelial dysfunction in pulmonary diseases and supports biobanking for future precision medicine applications.
Decoding the ubiquitination-immunity axis in idiopathic pulmonary fibrosis: diagnostic insights and therapeutic implications.
He W, Feng C, Liu M … +4 more , Qin H, Wu Y, Deng C, Zhu X
Respir Res · 2026 Mar · PMID 41792712 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. Emerging evidence suggests that ubiquitination-related genes (URGs) may contribute...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. Emerging evidence suggests that ubiquitination-related genes (URGs) may contribute to IPF pathogenesis, although their diagnostic and immunological significance remains poorly understood. METHODS: Three bulk RNA sequencing (RNA-seq) datasets (GSE110147, GSE53845, and GSE32537) and one single-cell RNA-seq dataset (GSE122960) were obtained from the Gene Expression Omnibus database. GSE110147 and GSE53845 were merged as the training cohort to construct a URG-based diagnostic model using least absolute shrinkage and selection operator (LASSO) regression, while GSE32537 and GSE122960 served as external validation cohorts. Immune cell infiltration was assessed using the CIBERSORT algorithm. A bleomycin-induced mouse model of pulmonary fibrosis was used to validate hub URG expression. The pro-fibrotic role of ubiquitin D (UBD) was evaluated in vitro using Cell Counting Kit-8 (CCK-8), wound healing, and transwell assays in mouse primary lung fibroblasts (PLFs). Transwell-based neutrophil migration assays were used to assess the impact of UBD expression in PLFs on neutrophil infiltration. RESULTS: We developed a robust six-gene diagnostic signature with high predictive accuracy in both training and validation cohorts. Immune infiltration analysis revealed strong correlations between hub URGs and specific immune cell types. Among them, UBD showed the most significant upregulation in fibrotic lungs and was positively associated with neutrophil infiltration. Functional assays demonstrated that UBD silencing attenuated transforming growth factor β1 (TGFβ1)-induced fibroblast activation. Moreover, UBD knockdown significantly increased the expression levels of Cxcl2 and Cxcl3 in PLFs and promoted neutrophil migration. CONCLUSION: This study highlights the diagnostic and immunological relevance of URGs in IPF and identifies UBD as a key pro-fibrotic factor and neutrophil infiltration regulator, offering novel insights into IPF pathogenesis and potential therapeutic targets.
An improved precision-cut lung slices technique for pulmonary vasoconstriction.
Luo S, Liao P, Song X … +5 more , Yue X, Wu X, Xiao R, Zhu L, Hu Q
Respir Res · 2026 Mar · PMID 41792711 · Full text
BACKGROUND: This study presents an improved technique for precision-cut lung slices to overcome the challenge of identifying pulmonary arteries in hypoxic pulmonary vasoconstriction. METHODS: The innovation employs the c...
BACKGROUND: This study presents an improved technique for precision-cut lung slices to overcome the challenge of identifying pulmonary arteries in hypoxic pulmonary vasoconstriction. METHODS: The innovation employs the connexin 40 immunofluorescence staining to precisely identify pulmonary arterial endothelium. RESULTS: The results of the experiments demonstrated that the refined protocol successfully differentiated between pulmonary vessels, trachea or bronchus, and bronchial arteries in precision-cut lung slices. This differentiation was accomplished by administrating a cell tracer into the pulmonary circulation to aid in identifying specific structure. Furthermore, this study accurately distinguished pulmonary arteries from veins using CX40 immunostaining. CONCLUSIONS: This study validates the accuracy and reliability of the improved precision-cut lung slices method in evaluating hypoxic pulmonary vasoconstriction particularly in pulmonary arteries.
Multi-omics integration identifies associations between large high-density lipoprotein and lung function, asthma, and COPD: evidence from genetic and population-based analyses.
Zhang M, Liu Q, Ju L … +4 more , Zheng Y, Dou K, Chen W, Guo Y
Respir Res · 2026 Mar · PMID 41792706 · Full text
BACKGROUND: Metabolomic signatures of lung function and chronic inflammatory respiratory diseases have been associated with potential early disease processes. We aimed to investigate the genetic correlations and causal r...
BACKGROUND: Metabolomic signatures of lung function and chronic inflammatory respiratory diseases have been associated with potential early disease processes. We aimed to investigate the genetic correlations and causal relationships of plasma metabolites with lung function and chronic respiratory inflammatory diseases. METHODS: Leveraging large-scale genome-wide association study (GWAS) summary-level data and individual-level data from UK Biobank, we applied linkage disequilibrium score regression (LDSC) for genetic correlation analysis, Mendelian randomization (MR) for causal inference, cross-trait meta-analysis for identifying shared genetic loci, and transcriptome-wide association studies (TWAS) for gene-level association analysis to examine the genetic and observational associations, causal relationships and shared genes of metabolites with lung function, asthma, and chronic obstructive pulmonary disease (COPD). RESULTS: High-density lipoprotein (HDL) profiles consistently showed significant genetic correlations with lung function measurements, asthma, and COPD, especially large HDL profiles (L-HDL- [cholesterol, cholesteryl esters, total lipids, particles, and phospholipid]). The genetic correlations (rg) of large HDL profiles with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) ranged from 0.12 to 0.20, and with asthma and COPD ranged from − 0.27 to -0.10 (P < 0.05/249). In MR analysis, genetically elevated large HDL profile levels (per unit) showed a significant association with increased FEV1 (mL, β coefficient ranged from 11.81 to 14.64, P < 0.05/6) and decreased risks of asthma and COPD (odds ratio ranged from 0.94 to 0.95, P < 0.05/6). Six shared genes at chr17q12 were identified in priority metabolites with lung function, asthma, and COPD. CONCLUSIONS: Our findings revealed significant associations of HDL profiles with lung function, asthma, and COPD, and provided evidence supporting potential causal relationships of HDL size and large HDL profiles in explaining these associations.
Plasma proteomic and machine learning models for differentiating idiopathic pulmonary fibrosis and connective tissue disease-associated interstitial lung disease: findings from a prospective cohort.
Wu CS, Lai DW, Chen YC … +3 more , Yu YH, Yang LY, Fu PK
Respir Res · 2026 Mar · PMID 41787510 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) with limited treatment options and poor prognosis. Differentiating IPF from connective tissue disease–associated I...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) with limited treatment options and poor prognosis. Differentiating IPF from connective tissue disease–associated ILD (CTD-ILD) is clinically challenging due to overlapping features, and reliable circulating biomarkers are lacking. Recent studies suggest that multi-marker proteomic models combined with machine learning may enhance diagnostic precision and prognostic assessment in fibrotic ILDs. METHODS: We prospectively analyzed plasma samples from Taiwanese patients with fibrotic ILDs (IPF, n = 22; CTD-ILD, n = 66) using the Olink inflammation panel (92 proteins). Differentially expressed proteins were identified and subjected to integrative network analyses. Predictive classification models were developed using generalized linear modeling (GLM), decision tree, and random forest approaches. Prognostic relevance was evaluated with Kaplan–Meier and Cox regression analyses, and findings were validated in public transcriptomic datasets. RESULTS: Among 92 proteins profiled, 23 showed significant differences between IPF and CTD-ILD. Four candidates—MMP-10, FGF-19, ADA, and TWEAK (TNFSF12)—consistently emerged as key discriminatory markers. The GLM model incorporating FGF-19, ADA, and TWEAK achieved the highest diagnostic accuracy (AUC 0.870; sensitivity 0.97; specificity 0.82), outperforming decision tree and random forest models. Transcriptomic validation confirmed TWEAK downregulation in ILD lung tissues and in TGF-β1–stimulated fibroblasts, linking it to canonical profibrotic signaling. Survival analysis showed significantly worse outcomes in IPF versus CTD-ILD (log-rank p < 0.001), with MMP-10 associated with poor prognosis (HR 2.08, p = 0.007) and TWEAK with favorable prognosis (HR 0.04, p < 0.001). CONCLUSIONS: This study identifies distinct plasma proteomic signatures that differentiate IPF from CTD-ILD and highlights TWEAK as both a diagnostic and prognostic biomarker. A multi-marker GLM model demonstrated excellent diagnostic performance, supporting the clinical utility of plasma proteomics combined with machine learning to improve disease classification and risk stratification in fibrotic ILDs. CLINICAL IMPLICATION: Integrating plasma proteomics with machine learning enables development of a multi-marker model that enhances diagnostic accuracy and prognostic evaluation in fibrotic interstitial lung diseases, supporting more precise disease classification and risk stratification in clinical practice.
A lung microbial signature for postoperative recurrence in stage I-II non-small cell lung cancer.
Gu C, Qi Y, Xie Y … +10 more , Yang L, Wang G, Zhou J, Ren J, Liu S, Zhu G, Li W, Hu W, Chen Y, Liu D
Respir Res · 2026 Mar · PMID 41787488 · Full text
BACKGROUND: Postoperative recurrence remains a prevalent and lethal threat to survival in early-stage non-small cell lung cancer (NSCLC), affecting approximately 20% of patients within five years. While emerging evidence...
BACKGROUND: Postoperative recurrence remains a prevalent and lethal threat to survival in early-stage non-small cell lung cancer (NSCLC), affecting approximately 20% of patients within five years. While emerging evidence implicates the lung microbiota and microbiota-related metabolites in carcinogenesis, their prognostic value for predicting NSCLC recurrence remains underexplored. METHODS: Using preoperative bronchoalveolar lavage fluid from 72 patients with stage I–II NSCLC (17 recurrence and 55 non-recurrence), we performed microbial 2bRAD-M sequencing to profile bacterial, fungal, and archaeal communities, along with untargeted metabolomics. Recurrence-associated microbial signatures were identified through machine learning approaches and network analysis. RESULTS: Patients with recurrence exhibited significantly reduced alpha diversity, shorter recurrence-free survival but enhanced microbial interactions compared with recurrence-free controls. We identified two predictive microbial signatures (32-species and 30-genus) that significantly outperformed conventional clinical factors, achieving mean area-under-the-curve of the receiver operating characteristic curve values of 0.92 (species-level) and 0.81 (genus-level), respectively. Notably, four potential recurrence-related drivers, namely the genera Paenibacillus, Cupriavidus, and Pseudomonas, along with the species Pseudomonas aeruginosa, were significantly increased in recurrence patients and associated with poorer survival. An integrated metabolomic analysis revealed that two microbiota-related metabolites, indole-3-lactic acid and pyridoxal, potentially mediated elevated recurrence risk through the tryptophan and vitamin B6 metabolic pathways. CONCLUSION: These findings elucidate the prognostic role of microbiota and metabolites in the lower respiratory tract of early-stage NSCLC, and highlight their dual potential as biomarkers and intervention targets.
HDAC6 inhibition reprograms endothelial and macrophage responses to protect the lung in endotoxemia.
Li Y, Wang Y, Li W … +1 more , Yu J
Respir Res · 2026 Mar · PMID 41787468 · Full text
BACKGROUND: Endotoxemia causes pulmonary barrier disruption, endothelial dysfunction, and myeloid-mediated inflammatory responses leading to sepsis-associated acute lung injury. Histone deacetylase 6 (HDAC6) regulates cy...
BACKGROUND: Endotoxemia causes pulmonary barrier disruption, endothelial dysfunction, and myeloid-mediated inflammatory responses leading to sepsis-associated acute lung injury. Histone deacetylase 6 (HDAC6) regulates cytoskeletal dynamics and inflammatory signaling; however, its cell-type-specific effects in inflammatory lung injury remain undetermined. METHODS: We conducted single-cell RNA sequencing in a mouse endotoxemia model to investigate the effects of HDAC6 inhibition on endothelial and macrophage responses. Key findings were confirmed using histology and bulk RNA sequencing studies. RESULTS: In endothelial cells, lipopolysaccharide induced inflammation and STAT pathway activation. HDAC6 inhibition with CAY10603 suppressed these changes, lowered inflammatory and apoptotic scores, and maintained endothelial cells toward earlier pseudotime states. Concurrently, HDAC6 inhibition via CAY10603 treatment restored angiogenesis-associated gene expression (Acadl, Adrb2, Cd24a, Ecm1, and Ptgs1). In macrophages, CAY10603 treatment suppressed lipopolysaccharide-induced interferon, inflammasome, and IL-6/JAK/STAT3 signatures and downregulated key gene expression (Isg15, Ifit1/2, Lcn2, Txnip, and Irf1), maintaining them in less activated states. These findings correlated with reduced alveolar congestion and leukocyte infiltration and suppressed inflammation signatures. CONCLUSIONS: Selective HDAC6 inhibition suppresses endothelial activation and macrophage inflammatory programs while promoting angiogenic transcriptional programs, supporting further evaluation of HDAC6-targeted strategies for sepsis-associated lung injury.
Platelet-specific P2Y receptor deficient mice have suppressed pulmonary leukocyte recruitment in response to lipopolysaccharide.
Pan D, Lino-Alvarado A, Amison RT … +6 more , Oralman T, Evans R, Baker O, Cocks G, Page CP, Pitchford SC
Respir Res · 2026 Mar · PMID 41787372 · Full text
A role for the P2Y1 receptor (P2Y1R) in platelet-driven inflammation has been established using a pharmacological approach, limited to an acute 4 h time span. Nucleotide-structure P2Y1R antagonists have restricted experi...
A role for the P2Y1 receptor (P2Y1R) in platelet-driven inflammation has been established using a pharmacological approach, limited to an acute 4 h time span. Nucleotide-structure P2Y1R antagonists have restricted experimental use due to inadequate pharmacokinetics, and an inability to decipher global versus cell specific effects in vivo. The creation of a conditional knock out (platelet) P2Y1R transgenic mouse model was designed to overcome these restrictions.A homozygous P2Y1 LoxP mouse colony was created using CRISPR/Cas9 technology, and crossed with a hemizygous P2Y1 LoxP with PF4-cre to provide offspring that are homozygous for P2Y1 LoxP flanked allele, and hemizygous for the PF4cre (platelet P2Y1−/−) and offspring homozygous for P2Y1 LoxP flanked allele, but non-carriers for PF4cre (control mice). Animals were intranasally administered LPS to induce pulmonary inflammation to assess the influence of phenotype on leukocyte recruitment.24 h post intranasal LPS administration; pulmonary neutrophil and platelet recruitment were significantly suppressed, despite the fact that neutrophils retained the ability to migrate to fMLP ex vivo. Circulating platelet and leukocyte numbers were not different between control and platelet P2Y1−/− animals. Tail bleeding times revealed the platelet P2Y1−/− mice had a severe bleeding phenotype.The platelet specific P2Y1−/− mouse model confirms the importance of platelet P2Y1R in the regulation of inflammatory responses. A 60–70% inhibition of leukocyte recruitment over an extended time period was observed compared to previous pharmacological studies. Platelet P2Y1−/− mice will help further elucidate the mechanisms by which P2Y1R regulate platelet activation during inflammation.
UC-MSCs-derived exosomal circFOXP1 alleviates allergic rhinitis through EZH2/EGR1/Blimp-1 axis.
Li P, Yu B, Zeng J
Respir Res · 2026 Mar · PMID 41776607 · Full text
BACKGROUND: Allergic rhinitis (AR) is a frequently diagnosed allergic disease with high prevalence worldwide. However, the understanding of AR pathogenesis remains limited. METHODS: qRT-PCR, RNA fluorescence in situ hybr...
BACKGROUND: Allergic rhinitis (AR) is a frequently diagnosed allergic disease with high prevalence worldwide. However, the understanding of AR pathogenesis remains limited. METHODS: qRT-PCR, RNA fluorescence in situ hybridization (FISH), IHC or western blot were used to detect the expression of circFOXP1, EZH2, EGR1, Blimp-1 and other molecules. Flow cytometry and ELISA assay were employed to Th1/Th2 cell ratio and cytokine secretion, respectively. Umbilical cord-derived mesenchymal stem cells (UC-MSCs)-derived exosomes were isolated and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot. Bioinformatics analysis, RNA pull-down, RIP, ChIP and luciferase assays were used to examine the direct association among circFOXP1, EZH2, EGR1 and Blimp-1. The in vitro findings were validated in ovalbumin (OVA)-induced AR mouse model. RESULTS: circFOXP1 was downregulated, while EGR1 and Blimp-1 were upregulated in the peripheral blood and nasal mucosa of AR patients. This was accompanied with Th1/Th2 imbalance. hnRNPA2B1 mediated the packaging of circFOXP1 into exosomes, and UC-MSCs-derived exosomal circFOXP1 was internalized by CD4+ T cells. Silencing of circFOXP1 counteracted UC-MSCs-derived exosomes-suppressed Th2 differentiation of CD4+ T cells. Mechanistic experiments showed that EGR1 was a transcriptional activator of Blimp-1. circFOXP1 triggered epigenetic repression of EGR1 to transcriptionally suppress Blimp-1 through recruiting EZH2. In AR mice, UC-MSCs-derived exosomal circFOXP1 protected against the impairments, possibly via EZH2/EGR1/Blimp-1 axis. CONCLUSION: UC-MSC-derived exosomal circFOXP1 alleviated allergic rhinitis, suggesting a role for the EZH2/EGR1/Blimp-1 axis in regulating Th2 differentiation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03604-7.
CFTR activity in nasal potential difference of adults with idiopathic bronchiectasis.
Tümmler B, Schulz A, Minso R … +4 more , Alfeis N, Tamm S, Rademacher J, Ringshausen FC
Respir Res · 2026 Mar · PMID 41776502 · Full text
BACKGROUND: Multiple documented underlying etiologies may lead to bronchiectasis, but the European Bronchiectasis Registry found that in 38% of patients the cause is unknown, referred to as idiopathic. We wanted to resol...
BACKGROUND: Multiple documented underlying etiologies may lead to bronchiectasis, but the European Bronchiectasis Registry found that in 38% of patients the cause is unknown, referred to as idiopathic. We wanted to resolve the role of CFTR dysfunction in people with idiopathic bronchiectasis by nasal potential difference (NPD) measurements. METHODS: NPD was examined in people with cystic fibrosis (CF), healthy controls, 40 people with idiopathic bronchiectasis recruited from the local outpatient clinic and in 60 people with idiopathic bronchiectasis with the suspected etiology of CF who had been referred from 2010 – 2022 to our electrophysiological laboratory to make a diagnosis by NPD. RESULTS: The unselected MHH cohort and the preselected diagnostic cohort of people with idiopathic bronchiectasis matched in their basal NPD potential with healthy controls. Conversely, after inhibition of the sodium conductance with amiloride, the distribution of the CFTR-mediated depolarization potential upon exposure to chloride-free solution and isoproterenol was in between those of healthy controls and CF patients with exocrine pancreatic insufficiency and overlapped with that of patients with exocrine pancreatic sufficiency. This intermediate phenotype was characteristic for the whole study population of 100 people with idiopathic bronchiectasis irrespectively of whether clinical features of CFTR dysfunction had been recognized before in an individual. Taking the Sermet Score that was developed to discriminate patients with CF from non-CF patients by NPD, the bronchiectasis population was significantly distinct from both healthy people and people with CF. CONCLUSIONS: A CFTR activity of the nasal surface epithelium in the lower quartile is typical for people with idiopathic bronchiectasis, but further CFTR-independent inherited susceptibilities and external insults are necessary to materialize the emergence of bronchiectasis. TRIAL REGISTRATION: Clinical trial number: not applicable.
Reduced gastrointestinal iron uptake in pulmonary arterial hypertension: a prospective cross-sectional study.
Repsold L, Harutyunova S, Grünig E … +9 more , Benjamin N, Xanthouli P, Egenlauf B, Florea A, Shaukat M, Sparla R, Mertens C, Muckenthaler MU, Eichstaedt CA
Respir Res · 2026 Mar · PMID 41772585 · Full text
BACKGROUND: Iron deficiency (ID) is common in patients with pulmonary arterial hypertension (PAH) and is associated with worse clinical outcomes. The etiology of ID in PAH is poorly understood. The aim of this study was...
BACKGROUND: Iron deficiency (ID) is common in patients with pulmonary arterial hypertension (PAH) and is associated with worse clinical outcomes. The etiology of ID in PAH is poorly understood. The aim of this study was to systematically determine whether differences in oral iron absorption exist between PAH patients with and without chronic ID compared with healthy controls. METHODS: This single-center prospective, cross-sectional cohort study enrolled 45 subjects: 15 PAH patients with chronic ID, 15 PAH patients without ID and 15 healthy age and sex matched controls. Chronic ID was defined by either recorded ID anemia or clinical indication for i.v. iron supplementation in the past 3 years. Plasma iron levels and transferrin saturation (TSAT) were measured before and after a standardized oral iron absorption test with 200 mg ferrous iron. Additional iron and inflammation laboratory parameters were determined. Hepcidin and erythroferrone levels were measured using enzyme-linked immunosorbent assay, and tumor necrosis factor alpha and ferroportin expression were determined by quantitative polymerase chain reaction. RESULTS: Both PAH groups showed a similar increase of plasma iron and TSAT after 3 h. The increase in plasma iron and TSAT was significantly lower in both PAH groups (with chronic ID: 71.5 (IQR 44.1–188.8) µg/dl; 22 (IQR 14–49) %; without ID: 86.0 (IQR 27.9–105.6) µg/dl; 26 (IQR 11–42) %) compared to healthy controls (154.1 (IQR 129.0–181.5) µg/dl; 45 (IQR 34–54) %, p = 0.015 and p = 0.031, respectively). CONCLUSIONS: This study is the first to demonstrate a significantly reduced gastrointestinal iron uptake in PAH patients compared to healthy age and sex matched controls. Interestingly, PAH patients with chronic ID showed similar iron uptake levels as those without, suggesting that factors other than iron stores, such as chronic inflammation, may impair iron absorption in this patient population.
The identification of RNA splicing aberrations and their potential regulatory network in Chinese non-small cell lung cancer.
Yan Y, Meng H, Guo H … +2 more , Wei S, Cheng S
Respir Res · 2026 Mar · PMID 41772579 · Full text
BACKGROUND: Alternative splicing contributes to the carcinogenic process of non-small cell lung cancer. Although extensive efforts have characterized cancer-associated alternative splicing events, the upstream regulators...
BACKGROUND: Alternative splicing contributes to the carcinogenic process of non-small cell lung cancer. Although extensive efforts have characterized cancer-associated alternative splicing events, the upstream regulators governing these aberrant splicing events remain poorly understood. METHODS: Here, we integrated multi-omics data from 22 lung adenocarcinoma, 13 lung squamous cell carcinoma and matched adjacent normal tissues of Chinese patients. We aimed to identify cancer-associated splicing events, construct regulatory networks of RBP, miRNA and DNA methylation on them and dissect carcinogenic pathways at integrated multi-omics layers in lung adenocarcinoma and squamous cell carcinoma, respectively. RESULTS: We identified that immune-suppression pathways and oxidative phosphorylation specifically promote the progression of adenocarcinoma and squamous cell carcinoma, respectively. ATP5F1C exon 9 inclusion in adenocarcinoma and LTBP3 exon 25 exclusion in squamous cell carcinoma, involved in proliferation, invasion and metastasis, are key splicing events with therapeutic potential. Furthermore, we proposed miR-4521-PABPC5-ATP5F1C, miR-4423-3p-IGF2BP3/miR-944-RBMS3-LTBP3 as upstream regulatory axes potentially driving these events. Notably, genome-wide CpG methylation exhibited widespread association with distant splicing events, potentially playing a trans-regulatory role by disrupting splice factor (BCL11B, RUNX1, RUNX2) binding near CpG sites and inhibiting RBMS3 transcription. CONCLUSIONS: Our findings shed light on the potential functional impact and multi-layer regulation of cancer-associated splicing events, offering novel insights for splicing-switching therapies to improve non-small cell lung cancer treatment and prognosis.
Integrated network toxicology and multi-omics analysis reveals the role of tobacco-specific carcinogen NNK in idiopathic pulmonary fibrosis pathogenesis.
Lai Y, Kuang Z, Zhou W … +11 more , Zhou A, Jiang J, Zhang X, Liu S, Hou L, Li X, Cui W, Wang Z, Duan M, Zhang C, Duan C
Respir Res · 2026 Feb · PMID 41764494 · Full text
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific nitrosamine that has been widely recognized as a major carcinogen contributing to smoking-related lung diseases. Although its involvement...
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific nitrosamine that has been widely recognized as a major carcinogen contributing to smoking-related lung diseases. Although its involvement in lung cancer has been extensively studied, the underlying pathogenic mechanisms by which NNK contributes to the development of idiopathic pulmonary fibrosis (IPF) remain unclear.In this study, potential IPF-related targets of NNK were identified through integrating multiple public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to uncover key biological processes associated with NNK-induced IPF. Weighted gene co-expression network analysis (WGCNA) combined with machine learning approaches was employed to screen for core regulatory genes. Furthermore, molecular docking and 100-nanosecond molecular dynamics simulations were utilized to assess the binding interactions between NNK and candidate target proteins. Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were also performed to validate gene expression patterns and characterize the immune microenvironment.A total of 204 overlapping targets associated with both NNK exposure and IPF were identified, which were predominantly enriched in the biological processes of oxidative stress, cell cycle regulation, and the FoxO signaling pathway. Six hub genes (BCHE, CD38, MMP7, PLA2G2A, ST6GAL1, and TIMP1) were identified as potential key diagnostic biomarkers.This study suggests that NNK may contribute to IPF progression through multiple mechanisms, including disrupting redox homeostasis, activating fibrotic signaling pathways, and modulating the immune microenvironment. The identified core genes and associated pathways provide novel insights into the molecular mechanisms underlying smoking-related IPF and offer promising targets for future therapeutic strategies.
Multi-ancestry genome-wide association study and meta-analysis of lung function decline.
Patchen BK, Zhang J, Gaddis N … +34 more , Bartz TM, Chen J, Debban C, Leonard H, Nguyen NQH, Seo J, Tern C, Allen R, DeMeo DL, Fornage M, Melbourne C, Minto M, Moll M, O'Connor GT, Pottinger T, Psaty BM, Rich SS, Rotter JI, Silverman EK, Stratford J, Zhang C, Barr RG, Cho MH, Gharib SA, Manichaikul A, North K, Oelsner EC, Simonsick EM, Tobin MD, Yu B, Choi SH, Dupuis J, Cassano PA, Hancock DB
Respir Res · 2026 Feb · PMID 41764487 · Full text
BACKGROUND: Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genet...
BACKGROUND: Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline. METHODS: We conducted genome-wide association study (GWAS) analyses of decline in FEV1, FVC, and FEV1/FVC in 52,056 White (N = 44,988), Black (N = 5,788), Hispanic (N = 550), and Chinese American (N = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in two independent COPD-enriched cohorts were tested for replication. RESULTS: We identified 361 distinct genome-wide significant (p < 5E-08) variants for one or more of the FEV1, FVC, and FEV1/FVC decline phenotypes, which overlapped with previously reported genetic signals for pulmonary traits. Four variants, or 10.3% of variants available for replication testing, were nominally associated (p < 0.05) with at least one decline phenotype in COPD-enriched cohorts. Gene-level analysis of GWAS results implicated 38 genes, many with consistent associations across ancestries or decline phenotypes. Annotation class analysis revealed enrichment of regulatory processes for corticosteroid biosynthesis and metabolism. Drug repurposing analysis identified 43 approved compounds targeting eight implicated genes. CONCLUSIONS: Our GWAS meta-analyses identified numerous genetic loci associated with lung function decline. These findings contribute knowledge to the genetic architecture of lung function decline, provide evidence for a role of corticosteroids in the etiology of lung function decline, and identify drug targets meriting further study for potential repurposing to slow lung function decline and mitigate lung disease.
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