Respir. Res. [JOURNAL]
Sun
200 papers
B and T cells in lung tissue are associated with smoking and forced vital capacity in idiopathic pulmonary fibrosis and familial pulmonary fibrosis.
Jaula H, Kreus M, Heikkinen A … +5 more , Leppänen J, Lappi-Blanco E, Vähänikkilä H, Harju T, Kaarteenaho R
Respir Res · 2026 Mar · PMID 41882652 · Full text
BACKGROUND: The exact pathogenesis of idiopathic pulmonary fibrosis (IPF) is unknown, but B and T cells, as part of the adaptive immune system, may play a role. Our aim was to immunohistochemically characterize B and T c...
BACKGROUND: The exact pathogenesis of idiopathic pulmonary fibrosis (IPF) is unknown, but B and T cells, as part of the adaptive immune system, may play a role. Our aim was to immunohistochemically characterize B and T cells in fibrotic lung tissue and to study whether clinical features were associated with the numbers of cells. METHODS: We characterized immunohistochemically the expression of CD20 (a B-cell marker) and CD3 (a T-cell marker) in cells from surgical lung biopsies of patients with IPF (N = 34) and familial pulmonary fibrosis (FPF, N = 16), as well as in noncancerous control tissues from patients who had undergone lung cancer surgery (N = 11). RESULTS: CD20 was expressed in lymphoid cells occurring in aggregates often located near fibroblast foci. In contrast, CD3 expressions was observed in groups of cells and as scattered single cells. The expression of CD20 was higher in patients with IPF than in those with FPF or in the controls. CD3 expression was higher in the patients with IPF and FPF than in the controls. CD20 and CD3 expressions were lower in smokers than in non-smokers or ex-smokers. Higher CD20 expression was associated with a higher forced vital capacity (FVC) in patients with IPF, whereas a high number of T cells was associated with lower FVC in patients with FPF. CONCLUSIONS: Differences were evident between FPF and IPF regarding the expressions of CD20 and CD3. The associations of B and T cells with smoking and lung function are novel observations that merit further investigation.
Protocadherin gamma subfamily A, 3 inhibits the proliferation and metastasis of lung adenocarcinoma by inhibiting transforming growth factor β signaling pathway.
Yang C, Huang Z, Liu S … +4 more , Zheng Z, Dai Z, Dai J, Liu Q
Respir Res · 2026 Mar · PMID 41882650 · Full text
BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent malignancy with poor clinical prognosis, and the specific role of PCDHGA3 in LUAD pathogenesis remains to be fully clarified and understood. METHODS: TCGA, UCSC XENA,...
BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent malignancy with poor clinical prognosis, and the specific role of PCDHGA3 in LUAD pathogenesis remains to be fully clarified and understood. METHODS: TCGA, UCSC XENA, and Human Protein Atlas databases were comprehensively utilized to systematically analyze PCDHGA3 expression levels, clinical prognostic significance, DNA methylation status, and mutation patterns. GO, KEGG, and GSEA enrichment analyses were performed to identify related biological pathways and functions. Western blotting, wound healing assays, cell adhesion assays, CCK8 proliferation assays, and transwell migration assays evaluated PCDHGA3 biological functions. Animal models were employed to validate in vivo effects and mechanisms. RESULTS: PCDHGA3 demonstrated low expression in LUAD tissues. High mutation rates and altered methylation patterns indicated potential involvement in LUAD development. PCDHGA3 overexpression notably inhibited cancer cell proliferation and migration abilities in both in vitro and in vivo models. Moreover, PCDHGA3 overexpression markedly elevated E-cadherin protein levels while substantially reducing N-cadherin, phospho-SMAD2, phospho-SMAD3, and TGFβ protein levels. CONCLUSION: PCDHGA3 inhibits LUAD progression and metastasis by suppressing the TGFβ signaling pathway, providing novel therapeutic insights.
The macrophage entry mechanism of SARS-CoV-2 mediated by surface CD98/TMPRSS11E complex is associated with the cellular tropism toward proinflammatory M1 and pathogenesis.
Wang T, Jiang Y, Teng Y … +11 more , Li J, Gao C, Chi Y, Fang L, Wang N, Chen Z, Zhang W, Cui L, Chao J, Li S, Qiu H
Respir Res · 2026 Mar · PMID 41877147 · Full text
BACKGROUND: Since the emergence of COVID-19, SARS-CoV-2 Omicron variants have demonstrated increased human adaptation. Alveolar and recruited macrophages play a critical role in severe lung inflammation following SARS-Co...
BACKGROUND: Since the emergence of COVID-19, SARS-CoV-2 Omicron variants have demonstrated increased human adaptation. Alveolar and recruited macrophages play a critical role in severe lung inflammation following SARS-CoV-2 infection, yet the mechanisms of viral entry into these immune cells remain incompletely understood. METHODS: Co-IP MS /MS was used to screen for potential SARS-CoV2 receptors in macrophages. Molecular docking, real-time interaction cytometry, and viral infection assays were employed to validate receptor identification. Single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from moderate and severe COVID-19 patients and healthy controls was analyzed to correlate receptor expression with disease severity. Transmission Electron Microscopy (TEM) was utilized to visualize viral particles and membrane fusion events. RESULTS: We identified CD98, a subunit of a heteromeric amino acid transporter, as a novel receptor for the SARS-CoV-2 spike protein. scRNA-seq analysis revealed elevated CD98 expression in pro-inflammatory M1-like macrophages, which were enriched in severe COVID-19 cases. Furthermore, TMPRSS11E, which is upregulated in M1 macrophages, facilitated spike protein cleavage and promoted membrane fusion, as confirmed by TEM. A functional interaction between TMPRSS11E and CD98 was also demonstrated. CONCLUSION: The CD98/TMPRSS11E complex clusters on M1 macrophages, where CD98 serves both as a marker of inflammatory activation and a mediator of viral entry. Reduced spike cleavage efficiency of the Omicron variant correlates with its diminished entry into M1 macrophages. These findings reveal a CD98/TMPRSS11E-mediated entry mechanism that contributes to the tropism of SARS-CoV-2 for pro-inflammatory macrophages and may influence disease pathogenesis.
Anti-heparanase shields against endothelial dysfunction in a rat model of warm pulmonary ischemia-reperfusion.
Magnan V, Hérault A, Fruitier-Arnaudin I … +13 more , Valet M, Dumesnil A, Renet S, Mulder P, Palmier M, Plissonnier D, Chevalier L, Groult H, Billoir P, Piton N, Bellien J, Baste JM, Selim J
Respir Res · 2026 Mar · PMID 41877075 · Full text
BACKGROUND: Primary graft dysfunction (PGD) occurs within the first three days after lung transplantation (LT), primarily due to ischemia–reperfusion (I/R) injury. Heparanase is an enzyme involved in I/R mechanisms. We i...
BACKGROUND: Primary graft dysfunction (PGD) occurs within the first three days after lung transplantation (LT), primarily due to ischemia–reperfusion (I/R) injury. Heparanase is an enzyme involved in I/R mechanisms. We investigated the effects of heparanase inhibition using derivative from λ-Carrageenan referred to as “Carrageenan”, and Heparin on endothelial dysfunction, inflammation, and glycocalyx integrity in a warm I/R rat model. METHODS: Three groups of male Wistar rats were studied: Control (NaCl 0.9%)(n = 14), Heparin (n = 14), and Carrageenan (n = 16). Rats underwent 1 h of left pulmonary warm ischemia. The reperfusion period was 3 h for one subgroup (H3) and 3 days for another (D3). Pulmonary artery endothelium-dependent and independent relaxation to acetylcholine and sodium nitroprusside respectively were analyzed using a wire myograph, with a Sham group (without I/R) for comparison. Pulmonary inflammation markers were assessed by RT-qPCR and immunohistochemistry, while glycocalyx degradation and systemic inflammation markers were evaluated using enzyme-linked immunosorbent assays (ELISA). Data were expressed as mean ± SD for all analyses, except vascular function (mean ± SEM). Normality was assessed using Kolmogorov–Smirnov and Shapiro–Wilk tests. Kinetic data were analyzed using one-way repeated-measures ANOVA or, when non-normal, the Friedman test. Other data were analyzed using one-way ANOVA or the Kruskal–Wallis test for non-normal distributions. Tukey or Dunn’s post hoc tests were applied, respectively, to identify significant differences between groups (p < 0.05). RESULTS: Endothelial dysfunction was observed in the Control and Heparin groups, with reduced pulmonary vasorelaxation to acetylcholine compared to the Sham group, without change in endothelium-independent relaxation. In contrast, Carrageenan preserved endothelium-dependent relaxation. Moreover, Carrageenan reduced macrophage and lymphocyte infiltration, as well as lung inflammation (IL-6 and TNF-α) compared to the Control group at H3. Carrageenan also showed pulmonary anti-inflammatory effects at D3. However, Carrageenan did not reduce circulating levels of markers of glycocalyx degradation or systemic inflammation. CONCLUSION: Carrageenan protects against pulmonary endothelial dysfunction and exerts strong pulmonary anti-inflammatory effects. It may serve as a protective agent against I/R injury in LT, potentially limiting the risk of primary graft dysfunction.
Reduction in microbiota-derived short-chain fatty acids contributes to the pathogenesis of pulmonary arterial hypertension.
Imtiaz H, Liu R, Li QH … +3 more , Zhou CZ, Ying YT, Tan X
Respir Res · 2026 Mar · PMID 41872932 · Full text
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiopulmonary disorder, with growing evidence implicating proinflammatory gut dysbiosis in its pathogenesis. Fast growing broiler chickens (G...
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiopulmonary disorder, with growing evidence implicating proinflammatory gut dysbiosis in its pathogenesis. Fast growing broiler chickens (Gallus gallus) spontaneously develop PAH with histopathological features that closely resemble those of the human disease, providing a robust translational model. METHODS: Gut microbiota composition in PAH-afflicted broilers was compared to that of healthy controls to identify disease-associated microbial alterations. Microbiota depletion was achieved using a broad-spectrum antibiotic cocktail, and oral supplementation with calcium acetate, a short-chain fatty acid (SCFA) salt, was administered to assess therapeutic potential. Pulmonary cytokine expression was measured to evaluate inflammation. RESULTS: PAH-afflicted broilers exhibited gut microbial alterations similar to those observed in human patients, characterized by a reduction in bacterial genera involved in the production of anti-inflammatory metabolites, particularly SCFAs, and an increase in arginine- and tryptophan-producing taxa. Microbiota depletion selectively enriched SCFA-producing bacteria and prevented the onset of PAH. Calcium acetate supplementation significantly mitigated disease progression and reduced pulmonary expression of proinflammatory cytokines. CONCLUSIONS: These findings establish a causal relationship between microbiome-derived metabolites and pulmonary vascular remodeling, supporting SCFA-based interventions as a promising therapeutic strategy for PAH.
Imaging biomarkers of post-COVID dyspnea: insights from machine learning CT patterns and parametric response mapping.
Cohen JG, Estopier-Castillo V, Olivier C … +5 more , Destors M, Ferretti GR, Pépin JL, Tamisier R, Bayat S
Respir Res · 2026 Mar · PMID 41872922 · Full text
BACKGROUND: Dyspnea is one of the most common symptoms in the post-acute phase of COVID-19 pneumonia. Conventional pulmonary function tests and computed tomography (CT) scores often fail to show correlation with symptom...
BACKGROUND: Dyspnea is one of the most common symptoms in the post-acute phase of COVID-19 pneumonia. Conventional pulmonary function tests and computed tomography (CT) scores often fail to show correlation with symptom severity, highlighting the need for more sensitive imaging biomarkers. Machine-learning–based quantitative CT analysis and parametric response mapping (PRM) can capture subtle structural and functional abnormalities that may be associated with persistent dyspnea. METHODS: We analyzed inspiratory and paired inspiratory–expiratory CT scans of early (3–6 months) post-COVID-19 pneumonia patients. Inspiratory CT images were segmented using a random forest algorithm to quantify lung parenchymal patterns. Paired inspiratory/expiratory scans were co-registered to derive ventilation metrics and PRM-defined functional small airway disease (fSAD), emphysema, emptying emphysema, and normal lung. Associations between imaging metrics and patient-reported dyspnea assessed by a visual analogue scale (VAS) were evaluated using univariable and multivariable linear regression, with adjustment for age, sex, BMI, and smoking history. RESULTS: One hundred twenty-three patients had usable inspiratory CT scans, and 116 patients had paired inspiratory/expiratory scans of sufficient quality for analysis. In the adjusted multivariable models, greater PRM-defined functional small airway disease (fSAD) was positively associated with dyspnea (standardized β = 1.21, p = 0.002). Moreover, a lower standard deviation of dense ground-glass attenuation in the left lung (standardized β = −0.82, p = 0.033) and greater total volume of dense ground-glass opacities (standardized β = 0.71, p = 0.033) were independently associated with dyspnea. CONCLUSIONS: In early post-COVID-19 pneumonia, machine-learning–based CT pattern recognition and PRM revealed that functional small airway disease, and the total volume and heterogeneity of lung dense ground-glass opacities are significantly associated with persistent dyspnea. These findings highlight the potential of quantitative CT to identify pulmonary imaging biomarkers relevant to long COVID symptom burden. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04406324).
The Wnt receptor Frizzled3 (FZD3) drives aggressive phenotypes in small cell lung cancer.
Lu M, Zhu X, Wang C … +9 more , Hou J, Guo J, Zhao J, Qin Z, Wu J, Cao X, Zhang T, Wang D, Ma T
Respir Res · 2026 Mar · PMID 41862898 · Full text
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression and poor prognosis. This study integrates bioinformatics with experimental validation to characteriz...
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression and poor prognosis. This study integrates bioinformatics with experimental validation to characterize the role of Frizzled-3 (FZD3), a Wnt receptor, in SCLC progression. METHODS: We analyzed transcriptomic data from 102 SCLC and 55 normal lung tissues retrieved from the Gene Expression Omnibus (datasets GSE6044, GSE40275, and GSE60052). Differential expression analysis was performed using the limma package, followed by GO and KEGG pathway enrichment analyses. To screen for robust prognostic markers, we employed machine learning algorithms-specifically LASSO and Random Forest-to select hub genes. The prognostic significance of FZD3 was assessed using multivariate Cox regression and Kaplan-Meier survival analysis. Validation assays, including qRT-PCR, Western blotting, and functional assays (proliferation, migration, invasion, and apoptosis), were conducted in SCLC cell lines and clinical specimens. RESULTS: A total of 1,192 differentially expressed genes were identified. Enrichment analysis revealed significant involvement in immune-related pathways and Wnt signaling. FZD3 was selected as a key hub gene and found to be upregulated in SCLC tissues and cell lines. High FZD3 expression was correlated with advanced clinical stage(by Kruskal-Wallis test), and poor prognosis (by Survival analysis). In vitro function assays demonstrated that FZD3 knockdown significantly attenuated SCLC cell proliferation, migration, and invasion while inducing apoptosis. CONCLUSION: FZD3 is frequently overexpressed in SCLC and serves as an independent prognostic indicator for poor survival. Our findings elucidate the oncogenic role of FZD3 in SCLC, highlighting its potential as a therapeutic target and prognostic biomarker.
USP4 promotes non-small cell lung cancer tumorigenesis by antagonizing CNOT4-mediated degradation of PAF1.
Chen S, Wang Y, Han S … +1 more , Zhang B
Respir Res · 2026 Mar · PMID 41857610 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality. This study examines whether the deubiquitinase USP4 promotes NSCLC progression by stabilizing PAF1 and opposing the E3 ligase CNOT4....
BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality. This study examines whether the deubiquitinase USP4 promotes NSCLC progression by stabilizing PAF1 and opposing the E3 ligase CNOT4. METHODS: USP4 and PAF1 expression were examined in NSCLC cell lines and paired tumor tissues by Western blotting and RT-qPCR. Functional studies included USP4 overexpression or silencing, proteasome inhibition, and rescue assays with PAF1. Co-immunoprecipitation and ubiquitination analyses were performed to confirm protein interaction and K48-linked ubiquitin modification. Cellular proliferation was assessed using CCK-8 assays, and the oncogenic role of USP4 in vivo was evaluated through A549 xenograft models co-expressing USP4 and/or CNOT4, followed by histological and Ki-67 analyses. RESULTS: USP4 and PAF1 were concomitantly upregulated in NSCLC cells and tissues, displaying a strong positive correlation. In addition, in-silico analysis of available NSCLC datasets showed that high USP4 or PAF1 expression was associated with poorer overall survival, whereas high CNOT4 expression was associated with better overall survival. USP4 enhanced PAF1 protein stability by directly binding and reducing its K48-linked polyubiquitination, independent of transcriptional regulation. Functionally, USP4 promoted NSCLC cell proliferation and rescued CNOT4-induced PAF1 degradation. In vivo, USP4 expression restored tumor growth and proliferation suppressed by CNOT4, confirming its antagonistic role in tumorigenesis. CONCLUSION: USP4 stabilizes PAF1 by counteracting CNOT4-mediated ubiquitination and degradation, thereby promoting NSCLC progression.
Development and internal validation of a machine learning-based model for predicting 2-year mortality in interstitial lung disease.
Jin X, Yu X, Xiang J … +5 more , Wang X, He M, Zhang C, Sun J, Zhong Z
Respir Res · 2026 Mar · PMID 41851885 · Full text
BACKGROUND: Interstitial lung disease (ILD) is characterized by marked heterogeneity and an overall poor prognosis, with many patients experiencing rapid progression and high short-term mortality. Accurate early risk str...
BACKGROUND: Interstitial lung disease (ILD) is characterized by marked heterogeneity and an overall poor prognosis, with many patients experiencing rapid progression and high short-term mortality. Accurate early risk stratification remains challenging. This study aimed to develop and validate machine learning (ML) models for predicting short-term mortality in ILD and to explore the added prognostic value of nutritional indicators beyond the conventional ILD-GAP score. METHODS: We retrospectively enrolled 670 patients with ILD, including idiopathic pulmonary fibrosis (IPF, 35.1%), connective tissue disease–associated ILD (CTD-ILD, 47.9%), and chronic hypersensitivity pneumonitis (CHP, 17.0%), from a single-center cohort. The primary endpoint was all-cause mortality within 2 years. After data preprocessing and multiple imputation, recursive feature elimination was applied to select optimal predictors. Nine ML models were constructed and optimized using 10 rounds of tenfold cross-validation. Model performance was evaluated by AUC, calibration curves, Precision–Recall curves, and decision curve analysis. The best-performing model was interpreted using SHAP. In addition, the prognostic value of incorporating albumin (ALB) into the ILD-GAP score was assessed. RESULTS: Among the evaluated models, extreme gradient boosting (XGB) achieved the best overall performance. Key predictors included DLCO, age, LDH, ALB, and total protein. Incorporation of ALB into the ILD-GAP model significantly improved performance (AUC increased from 0.813 to 0.892 in the training set and from 0.848 to 0.940 in the testing set). SHAP analysis identified DLCO and albumin as major contributors to the model’s mortality predictions. Restricted cubic spline analyses identified clinically meaningful risk thresholds for these variables. CONCLUSIONS: Machine learning–based models, especially ensemble algorithms, enable accurate and practical prediction of short-term mortality in ILD. Nutritional status, reflected by ALB, provides substantial incremental prognostic value beyond the ILD-GAP score. Integrating routine clinical data with interpretable ML approaches offers an effective strategy for early identification of high-risk ILD patients and supports individualized clinical management.
Blood cell ratio biomarkers of systemic inflammation in chronic obstructive pulmonary disease.
So K, Saferali A, Yun JH … +7 more , Ryu MH, Schiavi E, Castaldi PJ, Ruvuna L, Bowler RP, Curtis JL, Hersh CP
Respir Res · 2026 Mar · PMID 41851771 · Full text
BACKGROUND: Blood eosinophil count is an accepted biomarker for type 2 inflammation in COPD. However, the majority of COPD patients are characterized by non-type 2 inflammation. We aimed to test readily obtainable immune...
BACKGROUND: Blood eosinophil count is an accepted biomarker for type 2 inflammation in COPD. However, the majority of COPD patients are characterized by non-type 2 inflammation. We aimed to test readily obtainable immune cell ratios as biomarkers for clinical phenotypes in the broad COPD population and to determine pathways represented by these ratios using multi-omics data. METHODS: Using complete blood counts with differential collected at the Phase 2 (5-year) visit in the COPDGene Study, we calculated three immune cell ratios previously described in COPD and other diseases: the neutrophil–lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the Systemic Immune-Inflammation Index (SII = NLR*platelets). We tested for associations with COPD outcomes, including lung function, chest CT scan phenotypes, and exacerbations. Blood RNA-sequencing and proteomics data were used to identify genes, proteins and pathways associated with the ratios. RESULTS: In univariate analyses, the three biomarkers were associated with COPD severity measures. In zero inflated Poisson regression models, all three were associated with increased odds of having an exacerbation but were not associated with exacerbation counts. Conversely, the three biomarkers were generally associated with prospective exacerbation counts, but not the zero-inflation term. In logistic regression models, the three biomarkers were significantly associated with having two or more exacerbations in the prior year; however, receiver operating characteristic analyses did not lead to clear cutoff values. Complement and PI3K signaling pathways were enriched across more than one ratio in both the RNA-sequencing and proteomics results. Other inflammatory pathways relevant in COPD appeared in different enrichment sets in either omics data type. CONCLUSIONS: Higher levels of three easily obtained blood cell ratios were associated with COPD severity and exacerbations outcomes; however, there are not clear thresholds which would be required for clinical application. Blood RNA-sequencing and proteomics identified inflammatory pathways associated with the three biomarkers, including targets for COPD therapies currently in human trials.
Single-cell mitophagy signature-based artificial intelligence model enhances prediction of prognosis and immunotherapy response in non-small-cell lung cancer.
Wang MH, Wang Y, Li YT … +5 more , Wusiman D, Lu M, Zhang CY, Li YX, Bi N
Respir Res · 2026 Mar · PMID 41851738 · Full text
BACKGROUND: Non-small-cell lung cancer (NSCLC) exhibits pronounced molecular heterogeneity, and current predictive models rarely incorporate mitochondrial quality-control programs such as mitophagy. We hypothesize that a...
BACKGROUND: Non-small-cell lung cancer (NSCLC) exhibits pronounced molecular heterogeneity, and current predictive models rarely incorporate mitochondrial quality-control programs such as mitophagy. We hypothesize that an artificial intelligence model based on mitophagy-related genes (MRGs) at single-cell resolution could improve prediction of survival and immunotherapy benefit. METHODS: We analyzed single-cell RNA sequencing data from treatment-naïve NSCLC tumors to evaluate the activity of MRGs and identify genes exhibiting differential expression between cells with high versus low mitophagy levels. These differentially expressed genes were then cross-referenced with mitophagy gene sets to pinpoint candidate prognostic markers. Using LASSO regression combined with multiple machine learning classifiers, we constructed a risk model, which was validated in both internal and external cohorts, including a clinical immunotherapy trial. We further examined the relationship between the risk model, immune cell infiltration, and drug sensitivity in silico. The key MRGs were then experimentally validated in A549 cells using qRT-PCR, Western blotting, immunofluorescence, and functional assays for cell migration and wound healing. RESULTS: We quantified the mitochondrial autophagy activity of 18,167 single cells. Differential expression yielded 1,668 genes; intersection with the MRG list produced 39 candidates. A six-gene panel (FOS, CANX, EIF4G1, CALCOCO2, HSP90AB1, and PRKAR1A) emerged from LASSO. Gradient boosting machine (GBM) achieved the optimal cross-validated performance (testing set: AUC = 0.80, validation set: AUC = 0.72). SHAP analysis ranked PRKAR1A and CALCOCO2 as the top risk contributors. Patients classified into the high-MRG-score group exhibited consistently shorter overall survival (OS) across all datasets (HR = 3.66, 95% CI 1.72 − 7.81, P < 0.001). Low-MRG tumors displayed elevated immune and ESTIMATE scores with reduced tumor purity, and achieved a significantly higher objective response rate (35% vs 22%, P < 0.05) and prolonged OS (HR = 1.48, 95% CI 1.07 − 2.05, P = 0.017) with immune checkpoint blockade in the clinical-trial setting. Experimental results showed that knockdown of CALCOCO2 or overexpression of PRKAR1A significantly inhibited A549 cell proliferation and reduced mitochondrial membrane potential (P < 0.05), thereby affecting mitophagy. CONCLUSION: We developed an MRG-based model that reliably stratifies NSCLC patients according to prognosis and identifies those most likely to respond to immune checkpoint inhibitors, providing a framework for integrating tumor metabolic characteristics into personalized therapeutic decisions.
Detecting sleep apnea using non-linear measures of heart rate variability.
Niemi T, Kanniainen M, Nurmo M … +3 more , Pukkila T, Solhjoo S, Räsänen E
Respir Res · 2026 Mar · PMID 41851735 · Full text
BACKGROUND: Sleep apnea is highly prevalent yet frequently underdiagnosed due to the cost and complexity of polysomnography. Heart rate variability (HRV) offers a scalable alternative for early screening, but conventiona...
BACKGROUND: Sleep apnea is highly prevalent yet frequently underdiagnosed due to the cost and complexity of polysomnography. Heart rate variability (HRV) offers a scalable alternative for early screening, but conventional HRV metrics often overlook the multi-scale autonomic disturbances characteristic of apnea. METHODS: We evaluated scale-dependent detrended fluctuation analysis (sDFA), which quantifies how heartbeat-interval correlations evolve across temporal scales, using RR-interval data from Sleep Heart Health Study ([Formula: see text]). The discriminative performance of sDFA was compared with conventional HRV measures across mild, moderate, and severe apnea, and within cardiovascular disease (CVD) subgroups. Propensity score matching was applied for age and body mass index, and analyses were stratified by sex. RESULTS: Across apnea severity levels, sDFA consistently outperformed conventional HRV measures in discriminating individuals with sleep apnea. Performance gains were particularly evident in severe apnea and remained robust in participants with CVD, a subgroup in which traditional HRV metrics showed reduced discriminative ability. sDFA revealed scale-specific signatures of autonomic dysfunction that were not captured by conventional time- and frequency-domain HRV measures. CONCLUSION: Multi-scale analysis of HRV using sDFA enhances the detection of sleep apnea across severity levels and cardiovascular risk profiles. These findings highlight the limitations of conventional HRV metrics and support sDFA as a promising tool for scalable, HRV-based sleep apnea screening, with potential for integration into wearable and ambulatory monitoring systems.
S- nitrosylation of Annexin A2 at Cys133 ameliorates pulmonary arterial hypertension by inhibiting the WNT/β-catenin pathway.
Wande Y, Qianqian C, Yi W … +8 more , Minghui Z, Le Z, Yue G, Xiaomin J, Yichen W, Yang L, Ding G, Hang Z
Respir Res · 2026 Mar · PMID 41851727 · Full text
BACKGROUND: The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which result in pulmonary vascular remodeling, are crucial pathological features of pulmonary arterial hypertension...
BACKGROUND: The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which result in pulmonary vascular remodeling, are crucial pathological features of pulmonary arterial hypertension (PAH). Protein S-nitrosylation (SNO), which is a modification by which a nitric oxide (NO) group is added to a cysteine residue, has been shown to play a critical role in PASMC proliferation and PAH, but the underlying mechanism remains largely unknown. METHODS: Using a combination of membrane and nuclear localization analyses, iodoTMT switch assays, molecular biology techniques, and in vitro and in vivo approaches, we investigated the effects of ANXA2 SNO at cysteine 133 (Cys133) on PASMC proliferation and migration in PAH. RESULTS: ANXA2 protein expression was increased in PASMCs from rats with PAH. ANXA2 knockdown significantly inhibited excessive PASMC proliferation and migration. Additionally, inhibiting ANXA2 or conditionally knocking down ANXA2 in PASMCs ameliorated pulmonary vascular remodeling in experimental models of PAH. Moreover, we found that the NO donor S-nitrosoglutathione (GSNO) mediated the SNO of ANXA2 at Cys133 under hypoxic conditions. S-nitrosylated Cys133 (SNO-Cys133) of ANXA2 inhibited hypoxia-mediated PASMC proliferation and migration by regulating the subcellular localization of ANXA2 in cells. In addition, SNO-Cys133 of ANXA2 regulated the WNT pathway by inhibiting ANXA2 phosphorylation at Tyr24. Finally, SNO-Cys133 of ANXA2 ameliorated pulmonary vascular remodeling and improved RV function in vivo. CONCLUSIONS: SNO-Cys133 of ANXA2 suppressed ANXA2 relocation and the WNT pathway to ameliorate pulmonary vascular remodeling in PAH.
The GAP43/RAC1 axis drives glycolytic reprogramming and progression in lung adenocarcinoma.
Li K, Shen C, Li Y … +2 more , Zhang Q, Guo J
Respir Res · 2026 Mar · PMID 41851687 · Full text
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and poses a significant threat to public health. Traditional treatments often lead to poor prognoses and tumor recur...
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and poses a significant threat to public health. Traditional treatments often lead to poor prognoses and tumor recurrence. Glycolysis plays a crucial role in the initiation and progression of LUAD, making it an important area of research for the development of new therapeutic strategies. METHODS: In this study, we analyzed the Cancer Genome Atlas (TCGA) data to assess GAP43 expression and prognostic value in LUAD. Functional roles were investigated using GAP43 knockdown and overexpression cell lines through proliferation, apoptosis, colony formation, wound healing, and Transwell assays. The nude mouse xenograft tumor model was used to validate the effects of GAP43 knockdown on tumor growth in vivo. RAC1 was identified as a downstream target via gene set enrichment analysis (GSEA) and correlation analysis. Glycolytic activity (glucose uptake, ATP/lactate production, OCR/ECAR) and related protein expression were measured, and GAP43-RAC1 interaction was examined by co-immunoprecipitation. RESULTS: GAP43 expression was significantly upregulated in LUAD tissues compared with normal tissues and that high GAP43 expression was associated with poor overall survival (OS) and progression-free survival (PFS). GAP43 knockdown significantly inhibited the proliferation, migration, and invasive capabilities of LUAD cells in vitro and suppressed tumor growth in vivo. Conversely, its overexpression promoted malignant behavior of tumor cells. Mechanistically, GAP43 promoted the transcription of RAC1 by binding to the transcription factor CREB1, thereby enhancing aerobic glycolysis and facilitating the malignant progression of LUAD. CONCLUSIONS: The results of this study suggest that GAP43 may serve as a potential therapeutic target for LUAD. The GAP43/RAC1 axis plays a crucial role in regulating glycolysis and malignant phenotypes in LUAD cells, offering new insights for the clinical management of LUAD.
Exosomes derived from bone marrow mesenchymal stem cells alleviate sepsis-induced ARDS via inhibition of HOXA9-mediated glycolysis in alveolar macrophages.
Hu S, Wang Y, Zhou W … +5 more , Zhu L, Chen Y, Li Q, Lv X, Yang H
Respir Res · 2026 Mar · PMID 41845452 · Full text
BACKGROUND: Pulmonary injury in sepsis often develops into acute respiratory distress syndrome (ARDS), in which the polarization state of alveolar macrophages (AMs) is a central pathogenic factor. Bone marrow mesenchymal...
BACKGROUND: Pulmonary injury in sepsis often develops into acute respiratory distress syndrome (ARDS), in which the polarization state of alveolar macrophages (AMs) is a central pathogenic factor. Bone marrow mesenchymal stem cell-derived exosomes (BMSCs-exo) have demonstrated therapeutic potential in septic ARDS through metabolic modulation, yet the specific mechanisms remain unclear. This study investigated whether BMSCs-exo attenuate ARDS by regulating AM polarization via glycolysis inhibition and clarified the role of HOXA9. METHODS: BMSCs were identified using flow cytometry and trilineage differentiation. BMSCs-exo were characterized by transmission electron microscopy, nanoparticle tracking analysis and Western blot. An in vitro septic model was established by stimulating MH-S cells with lipopolysaccharide (LPS, 1 µg/mL). In vivo, ARDS was induced in C57BL/6 mice using either LPS (10 mg/kg) or cecal ligation and puncture (CLP), followed by caudal vein injection of BMSCs-exo. Glycolysis and macrophage polarization were evaluated with Western blot, RT-qPCR, and immunofluorescence. RESULTS: BMSCs-exo treatment improved survival in septic mice, alleviated pulmonary inflammation and edema, suppressed glycolysis in AMs, and restored M1/M2 balance. In vitro, BMSCs-exo downregulated glycolysis-associated markers in LPS-stimulated MH-S cells, suppressed M1 polarization, and facilitated M2 polarization. Notably, knockdown of the HOXA9 gene significantly diminished the ability of BMSCs-exo to suppress glycolysis and M1 polarization in MH-S cells. CONCLUSION: BMSCs-exo mitigate sepsis-induced ARDS by inhibiting HOXA9-mediated glycolysis and re-establishing AM polarization homeostasis, supporting their potential as a promising therapeutic approach for ARDS.
Smoking-induced dysregulation of transposable elements in the small airway epithelium.
Rostami MR, Strulovici Y, Kaner RJ … +2 more , Crystal RG, de Mulder Rougvie M
Respir Res · 2026 Mar · PMID 41845375 · Full text
BACKGROUND: Transposable elements (TE) are mobile sequences in the human genome that change location, have variable expression and function as cis-regulating elements that modify the expression of the transcriptome. Base...
BACKGROUND: Transposable elements (TE) are mobile sequences in the human genome that change location, have variable expression and function as cis-regulating elements that modify the expression of the transcriptome. Based on the knowledge that the small airway epithelium (SAE) is the first site of early pathology caused by cigarette smoking, we hypothesized that smoking alters the expression of TE in the SAE and some smoker dysregulated SAE TE are associated with dysregulation of the SAE transcriptome. METHODS: RNA-Seq of cigarette smokers (n = 20) and nonsmokers (n = 26) and single cell RNA-seq (scRNA-seq) analysis of n = 3 smokers and nonsmokers all with normal lung function, was performed to quantify expression of TE. RESULTS: Compared to nonsmokers, cigarette smokers had 111 downregulated and 191 upregulated differentially expressed TE in the SAE. scRNA-seq showed that intermediate and differentiated club, mucus and ciliated cells had the highest number of dysregulated TE in smokers. Among the smoking-upregulated gene-TE pairs, genes involved in epithelial differentiation (EGF, MUCL1, MEP1A), immune responses and inflammation (IRGM, LUCAT1, LINCO1258), and tumorigenesis (AKR1B15). Conversely, smoking-downregulated gene-TE pairs included genes important for maintaining epithelial differentiation (DAPK1, CD81-AS1) and regulating immune functions (BTNL8, LTF, CFH, C4BPA, CCL17). Smoking-induced dysregulation of TE in the SAE of cigarette smokers in intermediate and differentiated cells was associated with dysregulation of genes in the SAE transcriptome. CONCLUSIONS: Understanding the impact of smoking on TE-mediated gene regulation may lead to the identification of new therapeutic targets for smoking-related lung diseases.
A new tunable 3D alveolospheres model from human alveolar epithelial type 2 cells (AEC2) with reduced heterogeneity for studying cigarette smoke extract exposure.
Guecamburu M, Pavot A, Legrix A … +20 more , Jeannière C, Belaroussi Y, Thumerel M, Samaniego E, Begueret H, Maucort G, Decoeur F, Dupuy JW, Raymond AA, Esteves P, Grassion L, Dournes G, Berger P, Maurat E, Raasch K, Latouille E, Studer V, Dupin I, Henrot P, Zysman M
Respir Res · 2026 Mar · PMID 41845362 · Full text
RATIONALE: Three-dimensional (3D) organoid models, such as alveolospheres, are unique tools for investigating the mechanisms underlying emphysema. However, high inter-organoid heterogeneity hampers consistent results in...
RATIONALE: Three-dimensional (3D) organoid models, such as alveolospheres, are unique tools for investigating the mechanisms underlying emphysema. However, high inter-organoid heterogeneity hampers consistent results in emphysema research and drug testing. OBJECTIVES: To develop a tunable 3D alveolosphere derived from human primary type II alveolar epithelial cells (AEC2) for modeling alterations linked to cigarette smoke exposure. METHODS: AEC2 (HTII-280+) were isolated from 52 lung samples from both COPD and non-COPD patients, then cultured in 3D, comparing Matrigel to preformed photopolymerized hydrogel microwells of adjustable size and stiffness. Topological and phenotypic characterization were performed on days (D)1, 7, and 14. Lamellar bodies (LBs) were quantified using artificial intelligence (AI) analysis of transmission electron microscopy (TEM) serial block-face images. Chronic exposure to 1% or 5% cigarette smoke extract (CSE) was performed for 5 consecutive days. RESULTS: Compared to Matrigel-based spheroid cultures, alveolospheres generated in microwells display reduced heterogeneity in size. Such alveolospheres were maintained in culture for 14 days and exhibited central lumen formation from D7 to D14. Across different hydrogel stiffness, a stiffness of 5 kPa was found to best support long-term organoid maintenance. The presence of tight junctions (TEM, ZO-1 immunostaining) suggested an auto-organization. AEC1 markers (P2XR4, PDPN) increased from D1 to D14 while AEC2 markers (ABCA3, SFTPA, SFTPC) persisted over time, in qPCR. TEM indicated surfactant synthesis, and AI-driven LB quantification revealed a decrease in LB-containing cells over time. CSE exposure resulted in cell death, architectural disorganization, oxidative stress, and inflammation. Similarly, alveolospheres derived from COPD patients showed increased expression of inflammatory and cell death markers. CONCLUSION: This standardized and adjustable 3D alveolosphere model, derived from human primary AEC2, successfully reproduces key native alveolar features. Exposure to CSE provides a relevant platform for studying responses to cigarette smoke exposure.
A novel quantitative method for CT assessment of bronchiectasis using AI-based airway segmentation and upper limits of normal airway caliber.
Tanabe N, Sato A, Maetani T … +8 more , Sakamoto R, Fukui M, Masuda I, Kanasaki M, Handa T, Sato S, Morita S, Hirai T
Respir Res · 2026 Mar · PMID 41840608 · Full text
BACKGROUND: Bronchiectasis represents a growing global health burden. While computed tomography (CT) is essential for diagnosis, current criteria rely on broncho-arterial ratios and visual assessments, which are subject...
BACKGROUND: Bronchiectasis represents a growing global health burden. While computed tomography (CT) is essential for diagnosis, current criteria rely on broncho-arterial ratios and visual assessments, which are subject to inter-observer variability and can be confounded by pathological changes in arterial caliber. This study aimed to develop a novel quantitative method for assessing bronchiectasis by incorporating artificial intelligence-based airway segmentation and establishing location-specific upper limits of normal (ULN) for airway dimensions derived from healthy controls. METHODS: We analyzed chest CT scans from 459 healthy non-smokers who participated in a lung cancer screening program. Of these, 445 were used to calculate sex- and height-specific ULN values, while 14 served as independent controls for comparison with 14 patients clinically diagnosed with bronchiectasis. Following automatic segmentation of airway trees using previously-established artificial intelligence-based quantitative CT image analysis software, we extracted centerlines. At each point along the airway centerline, we measured the cross-sectional radius and the distance from the lobar bronchus origin. The ULN for airway radius was defined as the 95th percentile of measurements from healthy controls, stratified by sex and height. In patients with bronchiectasis, airways exceeding the ULN were classified as bronchiectatic, and bronchiectatic airway volume percentage (BEV%) was calculated. RESULTS: Male sex and height, but not age, were significantly associated with lobar bronchus radius. Location-specific ULN values were established for all five lobes as a function of distance from lobar origins, stratified by sex and height. BEV% was significantly higher in patients with bronchiectasis compared to matched controls (p < 0.001) and strongly correlated with the Reiff score (rho = 0.722, p = 0.004). CONCLUSION: This study established a novel reproducible approach for quantifying bronchiectasis using AI-based airway segmentation and location-specific normative airway dimensions without relying on broncho-arterial ratios. This method potentially enhances diagnostic accuracy and disease monitoring in the management of bronchiectasis.
Cleavage and inactivation of poly(ADP-ribose) polymerase in peripheral blood mononuclear cells of patients with acute respiratory distress syndrome.
Santos SS, Ascenção K, Zuhra K … +11 more , Martins V, Leite GGF, de Oliveira Cavalcanti Peres Rodrigues L, Hayashi JY, Brunialti MKC, Pecze L, Liaudet L, Vukovic J, Sridharan G, Salomão R, Szabo C
Respir Res · 2026 Mar · PMID 41840597 · Full text
Olaparib, the first clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, may be repurposed for non-oncological conditions such as acute respiratory distress syndrome (ARDS), where PARP-1 inhibition has show...
Olaparib, the first clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, may be repurposed for non-oncological conditions such as acute respiratory distress syndrome (ARDS), where PARP-1 inhibition has shown benefits in preclinical models. We investigated the expression and functional status of PARP-1 and the effects of olaparib in peripheral blood mononuclear cells (PBMCs) from ARDS patients and healthy controls. PBMCs from healthy volunteers (N = 8) and ARDS patients (N = 8) were isolated via Ficoll gradient. PARP-1, cleaved PARP (cPARP), and PAR polymers were assessed by Western blotting. Cytokine production was measured in plasma and in PBMC supernatants after 1 h preincubation with olaparib (10 µM) or vehicle, followed by LPS (100 ng/ml) stimulation for 4 h. Cellular bioenergetics were analyzed using Seahorse XFe24 after H2O2 (100 µM, 2 h) with or without olaparib pretreatment. Control PBMCs showed a lymphocyte-predominant population with mostly full-length PARP-1. In ARDS Day 1 samples, PARylated proteins increased and PARP became downregulated. By Day 8, PARylation decreased and full-length PARP-1, as well as cleaved PARP-1 were detectable. Olaparib treatment of the cells did not alter the LPS-induced cytokine responses. Exposure of healthy PBMCs to oxidative stress suppressed cellular bioenergetics, and this effect was attenuated by olaparib. However, in ARDS PBMCs, which were already bioenergetically suppressed, oxidative stress had no further effect, and olaparib was without protective effect. Thus, in PBMCs isolated from ARDS, olaparib’s cytoprotective effect is no longer detectable, likely due to PARP-1 inactivation and degradation.
Telomere damage-mediated senescence in alveolar epithelial type II cells but not in macrophages aggravates inflammation in acute lung injury.
Hildebrand CB, Öztürk S, Ye JL … +5 more , Wedekind D, Maus UA, Bär C, Mühlfeld C, Brandenberger C
Respir Res · 2026 Mar · PMID 41826998 · Full text
Severity of acute lung injury (ALI) increases with age and is associated with enhanced inflammation in older individuals (inflamm-aging), characterized by increased expression of pro-inflammatory cytokines. Telomere dama...
Severity of acute lung injury (ALI) increases with age and is associated with enhanced inflammation in older individuals (inflamm-aging), characterized by increased expression of pro-inflammatory cytokines. Telomere damage can cause irreversible cell cycle arrest, known as cellular senescence, that may promote pro-inflammatory signaling and exacerbate ALI. Therefore, we investigated the role of telomere damage-mediated senescence in alveolar epithelial type II (AEII) cells and macrophages in injury and inflammation of lipopolysaccharide (LPS)-induced ALI in mice.Cell type-specific deletion of Trf1 (telomeric repeat-binding factor 1) was achieved using tamoxifen-inducible Cre-loxP mouse models driven by the Sftpc (surfactant protein c) promoter for AEII cells or Lyz2 (lysozyme 2) promoter for macrophages to induce telomere damage in respective cell types. Mice without Trf1 deletion were used for comparison, as well as naturally aged mice. After tamoxifen injections, ALI was induced by intranasal application of 2.5 mg LPS/kg body weight. Control mice received saline. The severity of ALI, as well as cell type-specific molecular responses, were assessed using functional, immunological, histological and transcriptomic investigations.Telomere damage-mediated senescence in AEII cells resulted in an increase in inflammatory BALF cells and cytokines and a decline in lung function 72 h after LPS exposure, compared to mice without Trf1 deletion in AEII cells. Transcriptomic analysis revealed that Trf1-deleted AEII cells exhibited specific cell cycle inhibition, as well as an elevated DNA damage response (DDR), in both control and LPS-treated Sftpc-Cre mice. Trf1 deletion in macrophages triggered an augmented DDR without affecting LPS-driven lung inflammation compared to mice without Trf1 deletion. Control mice with Trf1 deletion of both Cre-loxP mouse models did not show signs of inflamm-aging. Additional comparison with old mice revealed that global aging causes a much greater severity in ALI than Trf1 deletion in lung cells.The findings demonstrate that telomere damage-mediated senescence in AEII cells promotes inflammation in the late exudative phase of ALI, while Trf1 deletion in macrophages did not cause an aggravation of ALI. The results also suggest that additional mechanisms of aging beyond pulmonary telomere damage and cellular senescence, such as global inflamm-aging, contribute to the severity of ALI in old age.
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