Respir. Res. [JOURNAL]
Sun
200 papers
Real-time algorithm-driven ventilation feedback to improve lung-protective ventilation in patients with ARDS (REALVENT-study): study protocol for a multicentre randomised controlled trial.
Su L, Yang Y, Wang Y … +19 more , Lan J, Yue C, Yang M, Pensier J, Zhang S, Yang J, Zhang J, Shao H, Wang Y, Zhao J, Song X, Cao H, Wu H, Cai F, Ma Y, Song Z, Talmor D, Baedorf-Kassis E, Long Y
Respir Res · 2026 Jul · PMID 42401979 · Full text
BACKGROUND: Lung-protective ventilation is a cornerstone of modern mechanical ventilation, yet real-world adherence to lung-protective targets remains suboptimal. While previous studies have established the physiological...
BACKGROUND: Lung-protective ventilation is a cornerstone of modern mechanical ventilation, yet real-world adherence to lung-protective targets remains suboptimal. While previous studies have established the physiological benefits of low tidal volume and driving pressure, clinical implementation is hindered by limited monitoring granularity and lack of real-time actionable feedback. This trial aims to evaluate whether a real-time, cloud-based algorithmic feedback platform can improve lung-protective ventilation delivery and contribute to better clinical outcomes in mechanically ventilated patients with ARDS. METHODS: This multicentre, parallel-group, open-label randomised controlled trial will enrol 208 adult mechanically ventilated ICU patients with ARDS from nine adult ICUs across tertiary academic hospitals and regional referral centres in multiple provinces and municipalities in mainland China. Participants will be randomly assigned in blocks to receive either standard monitoring (Control group) or real-time respiratory mechanics feedback through a cloud-based platform (Intervention group). The intervention group will receive real-time alerts for lasting 72 h and ventilator reports every 24 h, integrating tidal volume, plateau pressure, driving pressure, mechanical power, and detected patient-ventilator asynchrony events. The primary outcome is the lung-protective ventilation achievement rate, defined as compliance with VT < 8 mL/kg predicted body weight, driving pressure < 15 cmH₂O, plateau pressure < 30 cmH₂O, and mechanical power < 17 J/min during the first 72 h after randomisation. Secondary outcomes include ventilator-free days at day 28, ICU length of stay, ventilator-associated complications, inflammatory biomarkers, clinician satisfaction, and predefined safety outcomes, including severe hypoxemia, severe hypercapnia/acidemia, barotrauma, and hemodynamic instability temporally associated with ventilator adjustments. DISCUSSION: This study is, to our knowledge, among the first multicentre randomised controlled trials to evaluate a real-time algorithmic feedback platform designed to enhance lung-protective ventilation. The intervention is designed to provide continuous bedside feedback on ventilation mechanics and may enable more timely and standardised clinical adjustments, with the potential to facilitate lung-protective ventilation delivery. Triaiontl registration ClinicalTrials.gov Identifier NCT07307066 (Registration Date: 2025/12/02).
Identification and functional validation of lactylation-related hub genes in idiopathic pulmonary fibrosis based on multi-omics analysis.
Yue M, Luan R, Ding D … +6 more , Hu X, Tan J, Zhao M, Zhu L, Xue Q, Yang J
Respir Res · 2026 Jul · PMID 42400038 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible interstitial lung disease (ILD) characterized by high mortality and poorly understood pathogenesis. Lactylation, a recently identified post-t...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible interstitial lung disease (ILD) characterized by high mortality and poorly understood pathogenesis. Lactylation, a recently identified post-translational modification (PTM), is closely associated with inflammatory responses and tissue fibrosis in various diseases. However, the expression patterns and potential roles of lactylation, as well as the key regulatory genes involved, have not been fully elucidated in IPF. This study aimed to identify lactylation-related hub genes in IPF through bioinformatics analysis and preliminary functional validation, to explore their therapeutic potential, and to evaluate their binding affinity with clinical drugs, providing a theoretical basis for future research on lactylation mechanisms and targeted interventions in IPF. METHODS: Transcriptomic and single-cell sequencing datasets from lung tissues of IPF patients and healthy controls (HC) were obtained from the Gene Expression Omnibus (GEO) database. Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify IPF-related gene modules. Lactylation-associated hub genes were determined by integrating lactylation-related gene sets with protein-protein interaction (PPI) network analysis. Seurat software and UMAP clustering were employed to identify cell-specific localization of hub genes in lung tissues. Preliminary functional validations, including immunohistochemistry (IHC), Western blotting (WB) for pan-lactylation detection, and gene knockdown assays, were conducted in vitro and in vivo. The CIBERSORT algorithm was applied to analyze immune cell infiltration profiles in IPF tissues. Molecular docking analyses were performed to assess the binding affinity of clinical antifibrotic drugs (pirfenidone and curcumin) with proteins encoded by hub genes. RESULTS: DDX3X, BCLAF1, and NCL were identified as lactylation-related hub genes in IPF and were specifically expressed in macrophages/neutrophils, ciliated epithelial cells, and lung fibroblasts/macrophages, respectively. The level of pan-lactylation was significantly elevated in IPF lung tissues and TGF-β1-stimulated cellular models. These three hub genes were significantly upregulated in IPF tissues compared with HC, and individual knockdown of each gene significantly inhibited alveolar epithelial-mesenchymal transition (EMT) and human fetal lung fibroblast (HFL1) activation. In addition, these hub genes were closely associated with immune microenvironment remodeling in IPF. Pirfenidone and curcumin demonstrated favorable binding affinity with the proteins encoded by these genes. CONCLUSION: The lactylation-related hub genes DDX3X, BCLAF1, and NCL are specifically expressed in distinct cell types within IPF lung tissues, and their upregulation may promote IPF progression by mediating alveolar epithelial EMT, fibroblast activation, and profibrotic immune infiltration, highlighting their potential as therapeutic targets for IPF. Aberrant lactylation activation may contribute to IPF pathogenesis. Pirfenidone and curcumin show promising binding affinity with these hub gene-encoded proteins, providing a theoretical basis for further investigation into lactylation-targeted therapeutic strategies in IPF.
NSUN2-mediated m5C modification of E2F1 promotes lung adenocarcinoma progression via the RAD54L signaling axis.
Li Y, Chen C, Liu H … +2 more , Zhang Z, Wang C
Respir Res · 2026 Jul · PMID 42399962 · Full text
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, often driven by the hyperactivation of cell cycle and DNA repair pathways. While genomic alterations in these pathways are well-documented, the r...
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, often driven by the hyperactivation of cell cycle and DNA repair pathways. While genomic alterations in these pathways are well-documented, the role of RNA epigenetics in orchestrating these oncogenic signals remains poorly understood. Here, we identify a hierarchical signaling axis driven by the RNA methyltransferase NSUN2 that fuels LUAD progression. We demonstrate that NSUN2 is frequently amplified and overexpressed in LUAD, where it correlates with advanced disease stage and poor patient survival. Mechanistically, NSUN2 catalyzes 5-methylcytosine (m5C) modification of the E2F1 3'-untranslated region (3'-UTR). This modification, recognized by the reader protein YBX1, enhances the translational efficiency of E2F1 transcripts. The resulting accumulation of E2F1 transcriptionally activates the DNA translocase RAD54L, which we redefine as a proactive oncogenic effector essential for cell proliferation, invasion, and in vivo tumorigenesis. Integrated multi-omics and rescue experiments confirm that the NSUN2-mediated translational induction of E2F1 is a prerequisite for RAD54L-driven malignancy. Our findings uncover a novel epitranscriptomic-transcriptional regulatory cascade, establishing the NSUN2-E2F1-RAD54L axis as a critical driver of LUAD and a promising target for therapeutic intervention.
Direct visualisation and measurement of lung microstructure reveal insights into extracellular matrix dysregulation in COPD.
Kong ACW, Havelock T, Bennett M … +18 more , Spalluto CM, Staples KJ, Heinson A, Ostridge K, Burke H, Freeman A, Fazleen A, Welham B, Watson A, Bansal AT, Sand JMB, Rønnow SR, Angermann B, Oberg L, Platt A, Cellura D, Humbert M, Wilkinson T
Respir Res · 2026 Jul · PMID 42393678 · Full text
BACKGROUND: Extracellular matrix (ECM) dysregulation is a key process in the pathology of COPD. However, an inability to characterise ECM remodelling in vivo has limited our understanding of its relationship with functio...
BACKGROUND: Extracellular matrix (ECM) dysregulation is a key process in the pathology of COPD. However, an inability to characterise ECM remodelling in vivo has limited our understanding of its relationship with functional decline and disease mechanisms. We aimed to quantify in vivo ECM remodelling using probe-based confocal laser endomicroscopy (pCLE) and determine associations with physiological, radiological, histological, and serological markers of COPD. METHODS: 16 patients with COPD and 20 controls underwent pulmonary function testing, CT imaging, bronchoscopy, and pCLE. Alveolar morphometrics and elastin linearity scores (ELS) were quantified using a novel automated algorithm. Bronchial biopsies were analysed for elastin and collagen content. Serum biomarkers of elastin and collagen turnover were measured in a combined cohort of 54 COPD patients and 61 controls. RESULTS: Compared with never-smoking controls, current smokers without airflow obstruction demonstrated larger alveolar dimensions including increased alveolar opening area (AOA) (46,282 ± 16,805 vs. 33,549 ± 2,595 μm², p = 0.003). Alveolar dimensions were further increased in COPD, with larger AOA (56,468 ± 11,079 vs. 46,282 ± 16,805 μm², p < 0.001) compared with all controls. COPD was also associated with greater elastin fibre disorganisation (ELS 54.9 ± 6.0 vs. 47.5 ± 10.7, p = 0.032). Across the cohort, ELS correlated with airflow obstruction and surrogate markers of small airway disease. Airway collagen content was increased in COPD and correlated with ELS (r = 0.665, p = 0.005). COPD was associated with higher circulating elastin and collagen degradation biomarkers, including ELP-3, C1M, C6M, and EL-CG (all p < 0.05), which correlated with pCLE morphometrics. CONCLUSION: Using an innovative lung imaging technique, we provide the first objective quantification of in vivo airway elastic fibre disorganisation and demonstrate quantifiable lung microstructural changes that may precede abnormalities detected by established techniques. These quantifiable signals relate to biomarkers of lung ECM turnover, offering a new platform for early disease detection and mechanistic understanding of COPD.
Proteo-metabolomic insights into the progression of chronic obstructive pulmonary disease and lung function decline.
Pang J, Ren X, Hong Q … +16 more , Huang K, Wang J, Li D, Huang X, He R, Jiang J, Li X, Li Y, Wang Z, Xu Y, Xie S, Liang C, Long E, Wang J, Yang T, Wang C
Respir Res · 2026 Jul · PMID 42387628 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive yet preventable respiratory disease, often remaining undiagnosed until significant lung function impairment has occurred. The early, asymptomatic...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive yet preventable respiratory disease, often remaining undiagnosed until significant lung function impairment has occurred. The early, asymptomatic stage, termed "pre-COPD", offers a critical window for intervention, yet its molecular characteristics remain poorly understood. METHODS: We performed integrated proteomic and metabolomic profiling of human lung tissues across the spectrum of COPD (n = 32), including non-diseased controls, individuals with pre-COPD, and patients at varying stages of established disease. Key molecules and pathways involving in the progression of COPD were revealed. The performance of candidate biomarkers for monitoring early-stage lung function decline was validated in serum samples from an independent cohort (n = 158), and a longitudinal cohort from the UK Biobank (n = 21,686). RESULTS: Pairwise comparisons revealed 751 proteins and 1,024 metabolites that were differentially abundant among groups. Pathways such as pyrimidine metabolism and arginine biosynthesis were revealed associated with disease progression. Notably, we identified a core protein-protein interaction network modulated by zinc and copper, two clinically used, orally available trace elements, highlighting their potential as candidate therapeutic agents for COPD. Furthermore, integrative analysis with an independent blood-based cohort and longitudinal data from the UK Biobank uncovered choline as a circulating biomarker that predicts longitudinal lung function decline. CONCLUSION: Our findings define a molecular atlas of pre-COPD, identify actionable therapeutic targets, and propose a readily measurable biomarker for early detection and risk stratification of COPD.
Lung ultrasound feature tracking to quantify regional lung strain in mechanically ventilated pigs.
Walters R, Allen MB, Scheen H … +7 more , Reddout-Beam C, Waldrip ZJ, Kollisch-Singule M, Varisco AK, Williams JG, De Luca D, Varisco BM
Respir Res · 2026 Jul · PMID 42387548 · Full text
BACKGROUND: In patients requiring respiratory support, clinicians rely on physical exam, radiologic, laboratory, and ventilator-derived measures for the provision of sufficient support while minimizing ventilator and "wo...
BACKGROUND: In patients requiring respiratory support, clinicians rely on physical exam, radiologic, laboratory, and ventilator-derived measures for the provision of sufficient support while minimizing ventilator and "work of breathing" induced lung injury. Point of care lung ultrasound (LUS) is a widely available tool in hospital and clinic environments. To date, LUS has not been used to evaluate lung strain. METHODS: We collected LUS images in four anesthetized, neuromuscularly blocked, and mechanically ventilated pigs being used for another experiment. A feature tracking tool was developed which tracked echo-bright lung structures in 8-10 s clips obtained in triplicate of the right and left, upper and lower lung fields using tidal volumes of 4, 6, 8, 10, and 12 mL/kg. Pleural lines were manually drawn and a program for quantifying lung strain developed with assistance from Anthropic Claude Artificial Intelligence tool. Structures were identified in inspiratory and expiratory frames and tracked bidirectionally with median strain per clip used for calculations. RESULTS: Triplicate measures of lung ultrasound images in four pigs had a median coefficients of variation of 35% (23-47% IQR) and linear modeling of strain with tidal volumes of 4-12 mL/kg showed positive correlation with R value ranging from 0.89 to 0.97. Strain measurements were similar after bronchial administration of 1.5 M hydrochloric acid. CONCLUSIONS: These findings demonstrate the feasibility of quantifying regional lung strain using LUS and support its further development as a tool for respiratory support management.
Alterations in the fecal virome and bacteriome-virome interplay in IPAH.
Bing Y, Yuan W, Liang L … +9 more , Li J, Chen Y, Feng L, Li X, Li H, Zhong J, Wang L, Tong Z, Liu X
Respir Res · 2026 Jul · PMID 42387526 · Full text
BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiovascular disorder characterized by complex multisystem disturbances. Although alterations in the gut microbiota have been reported...
BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening cardiovascular disorder characterized by complex multisystem disturbances. Although alterations in the gut microbiota have been reported in IPAH, how the gut virome interacts with bacterial communities and host metabolism remains unclear. METHODS: We enrolled 28 patients with IPAH and 30 age-matched healthy controls (HCs). Fecal viromes and bacteriomes were profiled by metagenomic sequencing, and serum metabolomic data were integrated to construct virus-bacterium-metabolite interaction networks. Random forest models were used to evaluate the diagnostic potential of virome features. RESULTS: IPAH patients exhibited markedly reduced gut virome diversity (Shannon, Simpson, and Pielou indices, p < 0.05) and distinct community structures from HCs (p < 0.01). A total of 499 differential viral operational taxonomic units (vOTUs) were identified, accompanied by extensive reorganization of interaction networks. At the phylum level, Hofneiviricota was enriched and Phixviricota depleted, both correlating with clinical indicators. Virus-bacterium associations were markedly increased in IPAH (44,894 vs. 17,920, r > 0.5). Notably, vOTU2967, vOTU1924, and vOTU4522 were elevated and inversely related to Bacteroides, whose depletion was associated with increased lactic acid levels. Mediation analysis confirmed significant indirect virus-bacterium-metabolite effects (p < 0.05). Random forest models based on vOTUs or viral families effectively distinguished IPAH patients from controls, highlighting the exploratory potential of gut virome features for mechanistic insights. CONCLUSIONS: IPAH is characterized by reduced virome diversity, altered viral taxa, and reorganized virus-bacterium-metabolite networks. These findings suggest that gut viruses may influence disease progression by modulating bacterial metabolism, providing a potential avenue for biomarker discovery and therapeutic intervention.
The autonomic nervous system-lung interface in experimental BPD: NPY modulates immune response, alveolar growth and vascular muscularizationin neonatal mice exposed to oxidative stress.
Nies CO, Zeitouny C, Kuiper-Makris C … +15 more , Hirani D, Selle J, Bartz C, Vohlen C, Schmidt J, Janoschek R, Mižik I, Odenthal M, Koningsbruggen-Rietschel SV, Herzog H, Seeger W, Wagner JUG, Dötsch J, Koenig J, Alejandre Alcazar MA
Respir Res · 2026 Jul · PMID 42387502 · Full text
Oxygen supplementation triggers inflammation and disrupts alveolar and microvascular growth in preterm infants, often leading to bronchopulmonary dysplasia (BPD). The autonomic nervous system (ANS) is critical in lung ti...
Oxygen supplementation triggers inflammation and disrupts alveolar and microvascular growth in preterm infants, often leading to bronchopulmonary dysplasia (BPD). The autonomic nervous system (ANS) is critical in lung tissue homeostasis and repair. The sympathetic co-neurotransmitter neuropeptide Y (NPY) emerges as a central regulator of the ANS-organ interface with immune-modulatory function. Here, we studied sympathetic nervous system (SNS) signaling and the contribution of NPY to a hyperoxia-based model of BPD. To this end, neonatal wild-type (WT) and NPY knockout mice (NPY) were exposed to 85% O (HYX) or 21% O (NOX) from birth to postnatal day 14. Prolonged hyperoxia caused a 7-fold increase of tyrosine hydroxylase (TH) protein, an enzyme characteristic for the SNS, and NPY mRNA (> 40-fold) in neonatal WT lungs. The analysis of lung scRNA-seq revealed an upregulation of NPY in alveolar macrophages of WT when compared to WT. In contrast, NPY showed lower amount of TH than WT, indicating reduced sympathetic-associated signaling. Quantitative histomorphometry demonstrated an aggravated hyperoxia-induced alveolar growth arrest and septal thickening in NPY, whereas vascular muscularization and proliferation of vascular smooth muscle cells (SMC) were attenuated compared to WT. Additionally, NPY were protected from hyperoxia-induced CD68 macrophage recruitment, despite exhibiting higher lung expression of Il6 (20-fold) and Il1b (4-fold) than WT. In summary, our data demonstrate a dual role of NPY in neonatal lungs in response to hyperoxia, preserving alveolarization while promoting immune cell recruitment and vascular muscularization, highlighting the importance of ANS-lung interface in lung maturation and injury.
Isoleucyl-tRNA synthetase 1 mutation impairs pulmonary surfactant homeostasis by disrupting alveolar macrophage function.
Zhou W, Dai D, Chen Y … +10 more , Han X, Dong X, Liao Y, Chen T, Wang H, He C, Lu Y, Zheng C, Zhou Y, Qian L
Respir Res · 2026 Jun · PMID 42380998 · Full text
Biallelic isoleucyl-tRNA synthetase 1 (IARS1) variants are associated with an IARS1-related phenotype characterized by growth retardation, intellectual disability, muscular hypotonia, infantile hepatopathy, and interstit...
Biallelic isoleucyl-tRNA synthetase 1 (IARS1) variants are associated with an IARS1-related phenotype characterized by growth retardation, intellectual disability, muscular hypotonia, infantile hepatopathy, and interstitial lung disease. This rare, early-onset disorder is often lethal. Although several variants have been identified in recent years, their pathogenicity and underlying molecular mechanisms remain poorly understood. In this study, we generated Iars1 compound heterozygous mice, which exhibited pulmonary alveolar proteinosis - like lesions, growth retardation, and muscular hypotonia. Lipid metabolomic profiling of these mice revealed dysregulation of cholesterol metabolism pathways. Furthermore, the Iars1 mutation increased surfactant deposition in alveolar macrophages by impairing lysosomal degradation and disrupting lysosome-autophagosome fusion. We also found that partial loss of IARS1 activity interfered with the post-translational processing of cathepsin Z by inhibiting its ubiquitin-mediated degradation. Importantly, exogenous expression of cathepsin Z improved surfactant clearance in macrophages with partial loss of Iars1 activity. Collectively, our findings demonstrate that partial loss of IARS1 activity induces lysosomal dysfunction in alveolar macrophages and promotes pulmonary surfactant accumulation in the alveoli, thereby contributing to the development of pulmonary alveolar proteinosis.
From force to fate: Implications of mechanomemory in lung disease.
Campo-Ortiz de Zárate N, Exojo-Ramírez SM, Albaiceta GM … +1 more , Chacón M
Respir Res · 2026 Jun · PMID 42374439 · Full text
Mechanical cues are increasingly recognized as master regulators of cell behavior in development, regeneration and disease. In fibrotic tissues and solid tumors, aberrant extracellular matrix (ECM) stiffening activates m...
Mechanical cues are increasingly recognized as master regulators of cell behavior in development, regeneration and disease. In fibrotic tissues and solid tumors, aberrant extracellular matrix (ECM) stiffening activates mechanotransduction pathways that reprogram gene expression, metabolism and chromatin architecture. This stiffened microenvironment does not merely act as a transient signal but may also create a mechanotransductive imprint that reinforces signaling pathways, establishing a positive feedback loop that modulates cell behavior through mechanical memory. The concept of mechanomemory, defined as the cellular ability to retain and adaptively respond to past mechanical stimuli, has emerged as a critical player in cell biology offering new insights into how cells interpret and perpetuate biomechanical cues. This "memory" of mechanical stress modulates key processes such as cellular proliferation, epithelial-mesenchymal transition and invasion, contributing to disease progression and resistance against conventional therapies. This review explores the potential role of mechanomemory in the progression of lung diseases. We examine how sustained mechanical signals are encoded through molecular pathways, cytoskeletal adaptations, and epigenetic modifications, leading to persistent pathological cell states. We discuss how this imprinted memory may drive key features of lung disease, including the perpetuation of fibrosis and the acquisition of therapeutic resistance. We propose that targeting mechanomemory could open novel pathways for disrupting the vicious cycle of mechanical stress and lung disease while identifying novel areas for future research.
Necroptosis in alveolar epithelium orchestrates lung ischemia-reperfusion injury: a multi-omics study.
Liang F, Wang T, Lou Z … +11 more , Li J, Yu H, Xu Z, Yu Y, Hu X, Xu X, Wang Y, Chen Y, Zhang W, Lu Y, Wu M
Respir Res · 2026 Jun · PMID 42366351 · Full text
BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a leading cause of early morbidity and mortality following lung transplantation and other cardiopulmonary procedures. It is characterized by acute sterile inflammati...
BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a leading cause of early morbidity and mortality following lung transplantation and other cardiopulmonary procedures. It is characterized by acute sterile inflammation driven by regulated cell death (RCD). While various RCD modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis, have been implicated in lung injury, their relative contributions and distinct activation patterns in LIRI remain poorly defined. METHODS: We employed an integrated multi-omics approach combining transcriptomics and proteomics with histological and functional validations in a murine hilar clamping model of LIRI. Key findings were further corroborated using single-cell RNA sequencing (scRNA-seq) data from human lung transplant recipients. The functional role of necroptosis was validated using pharmacological inhibitors (Nec-1, GSK'872) and Mlkl-deficient (Mlkl) mice. RESULTS: LIRI triggered acute, time-dependent lung injury peaking within 24 h of reperfusion. Although transcriptomic profiling suggested broad activation of multiple RCD pathways, proteomic and biochemical analyses revealed a distinct landscape in our experimental setting: markers of apoptosis, pyroptosis, and ferroptosis were either downregulated or showed no significant positive correlation with injury severity and inflammatory peaks. In contrast, the necroptotic pathway emerged as a highly activated modality. Specifically, necroptosis, marked by phosphorylated RIPK1, RIPK3, and MLKL, was localized primarily in alveolar epithelial cells, correlated strongly with cytokine release and histological lung injury, and preceded the inflammatory response. Pharmacological inhibition or genetic ablation of necroptosis significantly attenuated tissue damage and inflammation. This pronounced necroptotic signature appeared distinct from the broad multi-pathway activation observed in lipopolysaccharide (LPS)-induced lung injury. Translational analysis of human scRNA-seq data further confirmed the selective upregulation of necroptosis signatures in alveolar type 2 (AT2) cells following lung transplantation. CONCLUSION: Our multi-omics analysis identifies necroptosis, particularly in alveolar epithelial cells, as a critical driver of sterile inflammation and tissue injury in the early phase of LIRI. Targeting alveolar epithelial necroptosis may represent a precise and promising therapeutic strategy for lung transplantation and ischemia-reperfusion-associated pulmonary disorders.
Integrated phenotyping identifies reproducible prognostic subgroups in idiopathic pleuroparenchymal fibroelastosis.
Otoshi R, Kitamura H, Oda T … +9 more , Kanzawa A, Okamura K, Niwa T, Baba T, Iwasawa T, Takemura T, Mizuguchi K, Natsume-Kitatani Y, Ogura T
Respir Res · 2026 Jun · PMID 42363231 · Full text
BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by upper-lobe-predominant fibrosis and heterogeneous prognosis. An integrated phenotype classification inco...
BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by upper-lobe-predominant fibrosis and heterogeneous prognosis. An integrated phenotype classification incorporating clinical, radiological and biological markers has not been established. METHODS: We conducted a retrospective observational study of 32 patients with idiopathic PPFE in an exploratory cohort and 37 patients in a separate validation cohort. Unsupervised k-means clustering was performed using % forced vital capacity (%FVC), residual volume/total lung capacity (RV/TLC), serum KL-6 levels, and extent of fibrotic lesions on quantitative computed tomography. Leukocyte telomere length (LTL) was measured using quantitative PCR and age-adjusted. Survival was assessed using Kaplan-Meier and Cox regression models. A simplified prognostic score was constructed using predefined clinical thresholds, and its discriminative performance was evaluated using the concordance index (C-index) with bootstrap-derived confidence intervals. Sensitivity analyses using multiple imputation were performed to assess robustness. RESULTS: Two distinct phenotypic clusters were identified in the exploratory cohort (Cluster 1, n = 15; Cluster 2, n = 17). Cluster 2 showed a severe fibrotic phenotype characterized by lower %FVC, higher RV/TLC, higher KL-6 levels, and greater fibrotic extent, and was associated with significantly worse survival (adjusted hazard ratio, 8.63; 95% CI, 1.06-70.4). Similar phenotypic separation and prognostic differences were reproduced in the validation cohort. The four-variable scoring system reproducibly stratified patients into three risk categories with stepwise prognostic separation in both cohorts. The model demonstrated moderate-to-good discriminative ability, with a C-index of 0.74 (95% CI, 0.59-0.88) in the exploratory cohort and 0.84 (95% CI, 0.74-0.92) in the validation cohort. In contrast, age-adjusted LTL in PPFE was not significantly shorter than in healthy controls and was not associated with survival. CONCLUSIONS: Integrated phenotyping using quantitative CT and clinical indicators identifies reproducible prognostic subgroups in idiopathic PPFE, whereas telomere shortening does not appear to play a major prognostic role. A simple scoring system may provide clinically applicable risk stratification.
Bronchovascular texture pattern on quantitative CT reveals airway and vascular remodeling in post-COVID-19 Lungs.
Zhang X, Rajaraman PK, Comellas AP … +4 more , Hoffman EA, Yang T, Guo J, Lin CL
Respir Res · 2026 Jun · PMID 42363216 · Full text
BACKGROUND: The long-term consequences of COVID-19 remain poorly understood. PURPOSE: To assess CT image-based biomarkers and clinical symptoms in COVID-19 survivors approximately 3-4 years after infection. MATERIALS AND...
BACKGROUND: The long-term consequences of COVID-19 remain poorly understood. PURPOSE: To assess CT image-based biomarkers and clinical symptoms in COVID-19 survivors approximately 3-4 years after infection. MATERIALS AND METHODS: Eighty post-COVID-19 participants (81% infected with the pre-Alpha strain) underwent pulmonary function tests (PFTs) and inspiratory/expiratory CT at approximately 5 months (Visit 1, V1) and 3-4 years (Visit 2, V2) after infection. At V2, participants completed the St. George's Respiratory Questionnaire (SGRQ), Leicester Cough Questionnaire (LCQ), Fatigue Severity Scale (FSS), modified Medical Research Council Dyspnea Scale (mMRC), and a study-specific symptom and medical history questionnaire. Seventy-eight healthy individuals served as controls. Image-based biomarkers included airway diameter, airway wall thickness, functional small airway disease percentage (fSAD%), ground-glass opacity percentage (GGO%), and bronchovascular percentage (Bronchovascular%). RESULTS: Post-COVID-19 participants exhibited normal predicted PFT values, but consistently lower DLCO compared with healthy controls at both visits. At V2, they also reported significantly worse SGRQ scores than the general population, indicating reduced quality of life. Although the elevated fSAD% and GGO% observed at V1 largely resolved by V2, several biomarkers of airway and vascular remodeling persisted, including increased Bronchovascular%, airway narrowing and wall thickening, and a compositional shift from large to small airways and a shift from small to large vessels. Persistent symptoms-such as fatigue, brain fog, cough, and hypertension-were associated with these structural abnormalities. CONCLUSION: Airway and vascular structural abnormalities persisted in COVID-19 survivors 3-4 years after infection and were associated with ongoing symptoms and reduced quality of life.
Fibroblast activity biomarkers are associated with mortality in severe COVID-19: a post-hoc analysis of a phase 2 clinical trial.
Breisnes HW, Simões FB, Frederiksen P … +10 more , Nielsen SH, Leeming DJ, Cahn T, O'Shea C, Hove K, Layton M, Karsdal MA, Bay-Jensen AC, Sand JMB, Mukherjee S
Respir Res · 2026 Jun · PMID 42351128 · Full text
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease characterised by systemic inflammation and lung tissue damage. In injured lungs, fibroblast activity increases in response to tis...
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease characterised by systemic inflammation and lung tissue damage. In injured lungs, fibroblast activity increases in response to tissue insult and has been shown to be prognostic in fibrotic disease. This study investigated whether fibroblast activity is associated with mortality in severe COVID-19. METHOD: Severe COVID-19 patients were enrolled in the randomised, sequential, multicentre, placebo-controlled, double-blind study Otilimab in severe COVID-19-related disease (OSCAR; NCT04376684). In this post-hoc analysis, serum samples from 242 placebo-treated patients were analysed on days 1, 7, and 14, alongside serum from 20 healthy controls. Two serological biomarkers reflecting fibroblast activity, PRO-C3 and PRO-C6, were quantified using ELISAs. RESULTS: Patients who died or experienced respiratory failure had higher PRO-C3 and PRO-C6 serum levels on day 1 compared with healthy controls (p < 0.0001 and p = 0.053, respectively) and recovering patients (both p < 0.0001). Levels gradually increased over 14 days, with the sharpest increase seen at the last measured timepoint before death. High PRO-C3 and PRO-C6 levels on day 1 were associated with increased risk of mortality (hazard ratio [HR]: 2.93, 95% confidence interval [CI]: 1.6-5.4, p = 0.0006 and HR: 3.88, 95% CI: 1.96-7.70, p = 0.0001, respectively). CONCLUSION: Elevated PRO-C3 and PRO-C6 levels, and their increase shortly before death, were strongly associated with mortality in severe COVID-19. These findings highlight fibroblast activity as a key driver of poor outcomes and suggest that PRO-C3 and PRO-C6 could serve as early prognostic biomarkers to identify high-risk patients and guide future disease management strategies.
Blood transcriptomic endotyping of COPD identifies a neutrophil-driven inflammatory endotype reflected by the neutrophil-to-lymphocyte ratio.
Song Y, Kim W, Jung JY … +2 more , Sa JK, Park J
Respir Res · 2026 Jun · PMID 42351125 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is molecularly heterogeneous, yet clinically deployable approaches for blood-based endotyping remain limited. We aimed to identify blood transcriptomic COPD endoty...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is molecularly heterogeneous, yet clinically deployable approaches for blood-based endotyping remain limited. We aimed to identify blood transcriptomic COPD endotypes and evaluate whether the neutrophil-to-lymphocyte ratio (NLR), derived from a routine complete blood count, is associated with a neutrophil-driven inflammatory endotype and could serve as a clinically accessible surrogate biomarker. METHODS: Whole-blood RNA sequencing was performed in a prospective multicentre Korean COPD cohort. After quality control, 492 samples underwent unsupervised consensus clustering. The final analysable cohort comprised 481 participants with valid NLR values and complete spirometry, including 285 with confirmed COPD (post-bronchodilator FEV₁/FVC < 0.70) and 196 symptomatic at-risk individuals (post-bronchodilator FEV₁/FVC ≥ 0.70 with respiratory symptoms). Clinical, radiologic and laboratory features were compared across clusters with Benjamini-Hochberg false discovery rate correction. Associations between NLR and the inflammatory K1 endotype were assessed using multivariable logistic regression with multiple imputation by chained equations and receiver operating characteristic analyses with Harrell optimism-corrected bootstrap resampling. External validation of the K1 signature and the NLR-K1 association was performed in the COPDGene cohort (n = 3,785). RESULTS: Four reproducible blood transcriptomic endotypes were identified: K1 (23.5%), a neutrophil-driven inflammatory subtype enriched for IL-6/TLR5-NFkB signalling; K2 (18.9%), a hypoxia-vascular subtype; K3 (47.4%), a metabolically preserved subtype; and K4 (10.2%), a tissue remodelling subtype. NLR strongly identified the inflammatory K1 endotype (adjusted OR 2.89, 95% CI 2.23-3.74; optimism-corrected AUC 0.86, 95% CI 0.82-0.89).Performance was highest in symptomatic at-risk individuals without fixed airflow obstruction (AUC 0.90, 95% CI 0.85-0.95). A two-threshold framework derived from the discovery cohort (NLR < 1.76 for rule-out; NLR ≥ 2.58 for rule-in) showed strong transferability in COPDGene, where NLR achieved an AUC of 0.88 (95% CI 0.87-0.89) for signature-derived K1. Higher NLR was associated with neutrophilic markers including IL1R2 and MMP9, supporting the biological coherence of the NLR-K1 relationship. CONCLUSIONS: The NLR was strongly associated with a transcriptomically defined neutrophil-driven COPD endotype and may provide a clinically accessible surrogate marker for inflammatory stratification using routine blood testing. These findings support the translational potential of blood-based endotyping but remain hypothesis-generating pending prospective outcome-based validation.
Blood-based targeted sequencing of microbial cell-free DNA in severe pneumonia-associated sepsis.
Huang H, Ye X, Gu D … +10 more , Huang E, Yu X, Ai L, Deng J, Guo P, Liu H, Chen Y, Wang R, Luo Y, Chen P
Respir Res · 2026 Jun · PMID 42343345 · Full text
BACKGROUND: Bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) improves pathogen detection in severe pneumonia-related sepsis, but sampling is invasive and prone to false-positive results....
BACKGROUND: Bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) improves pathogen detection in severe pneumonia-related sepsis, but sampling is invasive and prone to false-positive results. Blood is easier to obtain, and broad-spectrum targeted NGS (tNGS) of microbial cell-free DNA may offer a practical alternative to BALF-based testing. We evaluated the diagnostic and prognostic value of blood-based bstNGS. METHODS: In this retrospective cohort, 122 adults with suspected severe pneumonia-related sepsis and paired BALF and blood samples underwent BALF-mNGS, blood-bstNGS and blood-mNGS. Pathogens were adjudicated using a composite clinical reference. We assessed blood-BALF concordance, compared diagnostic performance across methods, and examined whether blood-bstNGS could down-weight likely false-positive BALF-only detections and stratify prognosis. RESULTS: BALF-mNGS identified 414 microorganisms; 51% were adjudicated as causative or possibly causative, corresponding to 85.24% of patients. Among these pathogenic microorganisms, blood-bstNGS detected 45.02%, significantly more than blood-mNGS (22.27%), and nearly all pathogens detected by blood-mNGS were also detected by blood-bstNGS. Against the clinical reference, blood-bstNGS showed higher sensitivity (63.46%) than blood-mNGS (35.58%), conventional microbiological tests (CMTs) (49.04%), and blood culture (9.62%). Organisms detected only in BALF but not in blood were less likely to be classified as causative. Patients with concordant blood-bstNGS and BALF-mNGS profiles had significantly lower 30-day and 90-day mortality. CONCLUSIONS: In severe pneumonia-related sepsis, blood-bstNGS provides sensitive, non-invasive pathogen detection. It acts as a complementary tool rather than a replacement for BALF-mNGS, offering an important diagnostic alternative when BALF is unavailable and improving specificity and prognostic utility when used in combination.
Identification and validation of SPP1 as a prognostic biomarker in interstitial lung disease subtypes by single-cell sequencing.
Ji T, Li Y, Zhang S … +6 more , Zhang C, Xie W, Wang S, Liu Q, Xu H, Dai J
Respir Res · 2026 Jun · PMID 42337746 · Full text
BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders with diverse clinical trajectories, highlighting the need for reliable biomarkers for prognostic assessment and risk stratification. ME...
BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders with diverse clinical trajectories, highlighting the need for reliable biomarkers for prognostic assessment and risk stratification. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on explanted lung tissue from 3 patients with idiopathic pulmonary fibrosis (IPF) and 3 control subjects. Secreted phosphoprotein 1 (SPP1) was identified and further validated in serum samples from two ILD cohorts comprising 74 patients with IPF and 92 with idiopathic inflammatory myopathy-associated ILD (IIM-ILD), as well as 56 healthy controls (HCs). Patients with IPF were further classified as acute exacerbation (AE) or stable IPF, and patients with IIM-ILD as rapidly progressive (RP) or stable IIM-ILD. The association between serum SPP1 levels and 1-year all-cause mortality was assessed using Cox proportional hazards models. RESULTS: scRNA-seq demonstrated that SPP1 expression was markedly upregulated in explanted lungs from IPF patients compared with controls. Serum SPP1 levels were significantly higher in patients with ILD than in HCs (P < 0.001), and were further elevated in AE-IPF (P < 0.001), RP-IIM-ILD (P < 0.001), and anti-melanoma differentiation-associated gene 5-positive IIM-ILD (P = 0.015). The 1-year mortality rates were 35.1% in patients with IPF and 31.5% in those with IIM-ILD. In multivariable Cox analyses, serum SPP1 was an independent predictor of 1-year mortality in the overall ILD cohort (hazard ratio [HR] 1.007, 95% confidence interval [CI] 1.002-1.012, P = 0.005), as well as in the IPF (HR 1.015, 95% CI 1.003-1.027, P = 0.012) and IIM-ILD (HR 1.007, 95% CI 1.001-1.012, P = 0.022) subgroups. CONCLUSIONS: Serum SPP1 may serve as a potential biomarker for risk stratification and prognostic assessment in IPF and IIM-ILD.
Antisense oligonucleotides targeting Ninjurin1 ameliorate the pathology of lead- and cadmium-induced chronic obstructive pulmonary disease in mice.
Sim JY, Ahn JH, Kim J … +6 more , Min HY, Kim J, Seo D, Watts JK, Shin M, Lee HY
Respir Res · 2026 Jun · PMID 42337738 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder driven not only by tobacco smoke (TS) but also by environmental toxicants, including particulate matter (PM) and heavy...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder driven not only by tobacco smoke (TS) but also by environmental toxicants, including particulate matter (PM) and heavy metals such as lead (Pb) and cadmium (Cd). Although oxidative stress and inflammatory cell death are central to COPD pathogenesis, effective disease-modifying therapeutic targets remain limited. Here, we identify that nerve injury-induced protein 1 (Ninjurin1, Ninj1), a damage-responsive cell adhesion molecule implicated in inflammatory cell death, as a previously unrecognized mediator of toxicant-induced COPD-like pathology. METHODS: We designed and screened a panel of 22 2'-O-methoxyethyl (2'-MOE) gapmer antisense oligonucleotides (ASOs) targeting Ninj1. Cell type-specific knockdown efficiency was assessed by flow cytometry and real-time PCR. The therapeutic efficacy of lead candidates was evaluated by histopathological analysis, immunofluorescence, and molecular readouts of inflammation and tissue injury in a murine COPD model induced by long-term inhalation of a mixture of Pb and Cd (Pb/Cd). ASO safety was further assessed both in vitro and in vivo, including acute and chronic toxicity studies. RESULTS: Ninj1 expression was markedly upregulated in the lungs of mice following exposure to TS components (NNK and BaP), particulate matter (PM), or Pb/Cd. Intratracheal delivery of Ninj1-targeting ASO attenuated hallmark COPD-associated features, including alveolar airspace enlargement, mucus hypersecretion, oxidative stress, matrix metalloproteinase activity, and fibrotic lesions, without evidence of overt systemic toxicity. CONCLUSIONS: These findings establish Ninj1 as a critical mediator of chronic lung inflammation and a translationally relevant therapeutic target, highlighting Ninj1-directed ASO therapy as a promising strategy for the treatment of environmental toxicant-induced respiratory diseases.
Mechanical ventilation activates PERK/eIF2α and NOD1 pathways that contribute to NF-κB-driven inflammation in VILI.
Ling M, Jiang Y, Cakir U … +8 more , Lu K, Liao X, Yang G, Ji L, Meng T, Huang C, Ye L, Pan L
Respir Res · 2026 Jun · PMID 42337589 · Full text
BACKGROUND: Ventilator-induced lung injury (VILI) is characterized by acute lung damage and NF-κB-driven cytokine production during mechanical ventilation. However, the upstream signals that initiate and exacerbate NF-κB...
BACKGROUND: Ventilator-induced lung injury (VILI) is characterized by acute lung damage and NF-κB-driven cytokine production during mechanical ventilation. However, the upstream signals that initiate and exacerbate NF-κB-driven inflammation remain poorly understood. Although endoplasmic reticulum (ER) stress is implicated in VILI, how ER stress pathways interact with innate immune sensors to promote inflammation is incompletely defined. Here, we investigate the roles of NOD1 and the ER stress-responsive PERK/eIF2α pathway in a VILI mice model. METHODS: C57BL/6 mice were subjected to high-tidal volume (HTV) ventilation for 4 h to establish an in vivo model of VILI. To investigate the role of NOD1 in VILI, Nod1-knockout (Nod1-KO) mice were generated. To further determine the involvement of the PERK pathway, wild-type and Nod1-KO mice were treated with PERK inhibitor GSK2606414 prior to HTV ventilation. Lung injury was evaluated using H&E staining, wet/dry ratio, and analysis of bronchoalveolar lavage fluid (BALF) for total protein concentration and inflammatory cell counts. Inflammatory cytokine levels were quantified by ELISA. Relative proteins expression was analyzed by immunoblotting and immunofluorescence. RESULTS: HTV ventilation induced lung histopathological damage, alveolar-capillary barrier dysfunction, and increased levels of IL-1β, IL-6, and TNF-α, along with upregulation of NOD1 and the ER stress marker GRP78. Genetic deletion of Nod1 attenuated lung injury and inflammatory cytokine release, associated with reduced GRP78 abundance and decreased NF-κB activation. In parallel, HTV increased phosphorylation of PERK and eIF2α, and pharmacological inhibition of PERK with GSK2606414 ameliorated lung injury and inflammation while suppressing NF-κB activation, without altering NOD1 protein abundance. Notably, combining NOD1 deficiency with PERK inhibition produced more pronounced protection against HTV-induced lung injury than either intervention alone, whereas the reduction of NF-κB readouts did not further deepen under the combined condition. CONCLUSIONS: HTV-induced inflammatory lung injury is associated with activation of both NOD1 and PERK/eIF2α signaling. Mechanistically, these pathways contribute to NF-κB-associated inflammatory responses and lung injury in VILI. Notably, the greater protection observed under combined NOD1 deficiency and PERK inhibition, despite a plateau in NF-κB readouts, suggests that additional injury mechanisms beyond NF-κB may also be involved.
H3K18 lactylation promotes allergic airway inflammation in asthma via a CSF1/CSF1R/MAPK autocrine axis.
Hu M, Chen Y, Huang H … +8 more , Zhuo J, Zhong H, Liu D, Yu Q, Du Y, Zhang J, Cai S, Dong H
Respir Res · 2026 Jun · PMID 42337539 · Full text
BACKGROUND: Metabolic reprogramming of airway epithelial cells is a hallmark of asthma, yet the mechanisms by which altered metabolism drives inflammation remain largely unknown. Histone lactylation, a recently identifie...
BACKGROUND: Metabolic reprogramming of airway epithelial cells is a hallmark of asthma, yet the mechanisms by which altered metabolism drives inflammation remain largely unknown. Histone lactylation, a recently identified metabolism-derived epigenetic modification, may provide a mechanistic link. METHODS: Clinical specimens and single-cell RNA sequencing (scRNA-seq) were analyzed to map the metabolic landscape of asthma. Histone lactylation in airway epithelial cells was assessed by western blotting and immunofluorescence. Functional roles of histone lactylation were evaluated via modulation of glycolysis, lactate availability, or P300 expression. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were performed to identify transcriptional targets of H3K18 lactylation (H3K18la). RESULTS: Glycolysis and histone lactylation, particularly H3K18la, were significantly elevated in the airway epithelial cells of asthma. Inhibition of glycolysis or P300 knockdown attenuated the inflammatory response by suppressing histone lactylation; whereas lactate supplementation exacerbated inflammation by promoting histone lactylation. H3K18la accumulated at the CSF1R promoter, directly enhancing its transcription and establishing a CSF1/CSF1R/MAPK autocrine positive feedback axis that positions airway epithelial cells as an upstream driver and inflammatory amplifier in allergic airway inflammation. CONCLUSION: This study defines a glycolysis-histone lactylation-CSF1R signaling axis that links epithelial metabolic reprogramming to sustained inflammatory gene activation in asthma, highlighting histone lactylation as a potential therapeutic target for allergic airway inflammation.
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