Respir. Res. [JOURNAL]
Sun
200 papers
Identification of oxygenation impairment-associated gene networks in ARDS through integrated mRNA and miRNA analysis.
Mitsuyama Y, Matsumoto H, Ebihara T … +3 more , Okuzaki D, Ogura H, Oda J
Respir Res · 2026 May · PMID 42121178 · Full text
BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with high mortality and complex pathophysiology, yet molecularly targeted therapies remain undeveloped. In particular, the microRNA (miRNA)-mRNA regula...
BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with high mortality and complex pathophysiology, yet molecularly targeted therapies remain undeveloped. In particular, the microRNA (miRNA)-mRNA regulatory network underlying ARDS is poorly understood. This study aimed to elucidate the miRNA-mRNA interactions associated with the pathophysiology of ARDS. METHODS: mRNA-Seq and miRNA-Seq were performed in 34 patients with ARDS and healthy controls. Gene and miRNA co-expression modules were constructed using Weighted Gene Co-expression Network Analysis. miRNA-mRNA regulatory relationships were inferred through an integrated analysis of predicted and experimentally validated miRNA targets. Molecular signatures were quantified via single-sample gene set enrichment analysis, and module structure preservation was evaluated in an external pneumonia cohort. RESULTS: A key mRNA co-expression module was identified that exhibited the strongest negative correlation with the P/F ratio, along with a negatively correlated miRNA co-expression module. The miRNA module, centered on miR-361-5p and miR-186-5p, formed a regulatory network broadly controlling gene clusters involved in ubiquitin ligase activity and cellular stress response pathways. This network demonstrated a strong association with the P/F ratio and showed high structural preservation in the external pneumonia cohort. CONCLUSION: A miRNA-mRNA regulatory network linked to impaired oxygenation in patients with ARDS has been identified. The network highlights miRNAs as potential key regulators of disease progression and suggests their utility as biomarkers of disease severity and prospective therapeutic targets.
Identification of plasma exosomal VPS41 chr7:38764322A>I editing as a diagnostic biomarker in lung cancer via a pan-cancer screen.
Li Z, Wu D, Deng P … +6 more , Yang R, Wu J, Pan J, Zou J, Lu J, Yang L
Respir Res · 2026 May · PMID 42121172 · Full text
BACKGROUND: Plasma exosomal RNA has emerged as a promising source of tumor biomarkers for early cancer detection. However, conventional expression-based markers are often limited by the need for stable reference genes. R...
BACKGROUND: Plasma exosomal RNA has emerged as a promising source of tumor biomarkers for early cancer detection. However, conventional expression-based markers are often limited by the need for stable reference genes. RNA editing, as a sequence-specific modification, provides internal, reference-free molecular signals, offering a potential advantage for robust and reproducible biomarker development. METHODS: We performed a two‑stage screening across GEO and Synapse databases to identify candidate RNA editing sites with multi-cancer diagnostic potential. The lead candidate was validated in 30 paired lung cancer tissues. Then the editing was assessed in plasma exosomes from 100 pairs of early‑stage lung cancer patients and healthy controls, as well as an independent set of 172 pulmonary nodule cases (35 benign and 137 malignant). Diagnostic performance was assessed using ROC analysis and 10-fold cross-validation. Bioinformatics and functional experiments were employed to investigate the underlying regulatory mechanisms. RESULTS: We identified VPS41 chr7:38764322A>I as a dysregulated RNA editing site across lung, liver, and gastric cancers. Its editing level was consistently reduced in lung cancer tissues and patient plasma exosomes. This site demonstrated high diagnostic accuracy for early‑stage lung cancer (AUC = 0.763, 95%CI: 0.696-0.829) and effectively distinguished malignant from benign pulmonary nodules (AUC = 0.813, 95%CI: 0.727-0.899). Mechanistically, this editing event, mediated by ADAR2, potentially inhibits VPS41 expression by strengthening miR‑3170 binding. Furthermore, VPS41 was found to promote lung cancer cell proliferation. CONCLUSIONS: Our study identifies VPS41 chr7:38764322A>I as a promising exosomal biomarker with strong diagnostic utility for early lung cancer. By elucidating its potential role in miRNA-mediated regulation, we provide a novel, exosome‑based RNA editing tool for early lung cancer detection.
Interpretable machine learning for predicting in-hospital mortality in COPD ICU patients: a rigorous validation across time and geography.
Li Y, Bu X, Geng Z … +4 more , Dai N, Fu B, Deng R, Fu X
Respir Res · 2026 May · PMID 42121158 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common reason for admission to the intensive care unit (ICU), where accurate risk stratification is crucial for clinical decision-making. This study aimed to...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common reason for admission to the intensive care unit (ICU), where accurate risk stratification is crucial for clinical decision-making. This study aimed to develop and validate machine learning models for predicting in-hospital mortality risk in ICU patients with COPD using multicenter critical care databases, and to evaluate their incremental value and clinical utility. METHODS: This was a multicenter retrospective study utilizing data from three public databases: MIMIC-IV (for model development and internal validation), MIMIC-III (for internal temporal validation), and eICU (for external validation). Patients with a first ICU admission, aged ≥ 18 years, and meeting ICD diagnosis codes for COPD were included; those with an ICU length of stay < 24 h were excluded. The primary outcome was in-hospital mortality. Core predictors were selected through collinearity analysis, the Boruta algorithm, and recursive feature elimination with tenfold nested cross-validation. Twelve algorithms were employed for model development, and cost-sensitive learning was applied to address class imbalance in the training set (MIMIC-IV). Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curves (calibration intercept and slope), Brier score, and decision curve analysis (DCA). The DeLong test was used to compare AUC between models, and the Integrated Discrimination Improvement (IDI) quantified the incremental value of the model relative to the SAPS II score. The SHAP method was used for model interpretation. RESULTS: A total of 7,900 patients from the MIMIC-IV cohort, 1,979 from MIMIC-III, and 8,491 from the eICU cohort were included. Thirteen core predictors were ultimately selected (e.g., SAPS II, respiratory rate, heart rate, blood urea nitrogen, lactate). The CatBoost model demonstrated the best robustness across the three independent validation sets, achieving an AUC of 0.753 (95% CI: 0.722-0.784) in internal validation, 0.731 (95% CI: 0.701-0.760) in temporal validation, and 0.735 (95% CI: 0.718-0.751) in external validation. After calibration, the model's predictive accuracy improved significantly in both MIMIC-III (Brier score decreased from 0.16 to 0.14) and eICU (Brier score decreased from 0.11 to 0.09). DCA indicated a clinical net benefit for the model within the 0.10-0.60 risk threshold range. Compared to the SAPS II score, CatBoost significantly improved discrimination and reclassification in the MIMIC-IV (ΔAUC = + 0.063, P < 0.001; IDI = 0.066, P < 0.001) and MIMIC-III (ΔAUC = + 0.044, P < 0.001; IDI = 0.058, P < 0.001) cohorts. SHAP analysis identified SAPS II, respiratory rate, and blood urea nitrogen as key drivers of risk prediction. An online risk calculator based on this model has been publicly deployed. CONCLUSION: This study successfully developed a CatBoost model for predicting in-hospital mortality in ICU patients with COPD using multicenter data. The model demonstrated good discrimination, calibration, and clinical utility across cross-institutional and cross-temporal validation, with performance superior to the traditional SAPS II score. The online tool, integrated with SHAP explanations, can provide clinicians with individualized risk prediction support.
Disparate periphery and lung immune microenvironments induced monocyte-macrophage activation as a key factor in anti-synthetase syndrome-associated interstitial lung disease.
Su K, Qi T, He J … +14 more , Zhang X, Liu L, Zhou Y, Gu J, Yi C, Wang J, Wang L, Wang J, Xia J, Jin X, Chang X, Zhang C, Zhang F, Huang J
Respir Res · 2026 May · PMID 42121132 · Full text
BACKGROUND: Anti-synthetase syndrome (ASS) is an autoimmune disease characterized by serum anti-aminoacyl-tRNA synthetase (ARS) antibodies and frequently associated with recurrent and refractory interstitial lung disease...
BACKGROUND: Anti-synthetase syndrome (ASS) is an autoimmune disease characterized by serum anti-aminoacyl-tRNA synthetase (ARS) antibodies and frequently associated with recurrent and refractory interstitial lung disease (ASS-ILD). Its pathogenesis remains poorly understood. METHOD: Paired peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage fluid (BALF) cells from 4 patients with new-onset ASS-ILD were analyzed by single-cell RNA sequencing (scRNA-seq), whereas paired plasma and BALF samples from 11 new-onset ASS-ILD patients underwent Pro-DIA proteomics. Ten patients with idiopathic pulmonary fibrosis (IPF) and 10 healthy donors served as disease and healthy controls (HC) for the proteomics. In vitro experiments were performed to support the multi-omics findings. RESULT: Integrated scRNA-seq (117,960 PBMCs and 91,230 BALF cells) and Pro-DIA proteomics (4,629 plasma and 3,919 BALF proteins) analyses were performed. In ASS-ILD BALF, monocyte-macrophages showed significantly higher cytokine and inflammatory gene module scores compared with IPF and HCs (all P < 2e-16). The proportion of alveolus pro-inflammatory monocyte-macrophages was markedly increased (52.7% vs. 6.2% in IPF and 3.6% in HC). These subsets exhibited upregulated tRNA aminoacylation pathway and elevated multiple ARS gene expressions (adj.P < 1e-5). BALF proteomics also revealed increased ARS-related proteins and inflammatory mediators in ASS-ILD (adj.P < 0.05). In vitro, human histidyl ARS-containing immune complexes (IC) induced higher expression of MHC-I/II, CD80/CD86, pro-inflammatory cytokines, and ARS genes in primary human macrophages compared with control IC. CONCLUSION: Our findings provide novel insights into ASS-ILD pathogenesis and suggest the underlying pathogenicity of ARS containing IC. These results underscore the role of monocyte-macrophage activation in ASS-ILD related immunopathogenesis and pave the way for targeted therapies directed at IC formation and aberrant monocyte-macrophage dynamics.
Effect of airway constriction on ventilation inhomogeneity: multiple-breath washout indices and intrapulmonary reverse flow.
Kim M, Yoon S, Petralia LS … +4 more , Doganay O, Yamakawa M, Brightling C, Gleeson F
Respir Res · 2026 May · PMID 42116140 · Full text
BACKGROUND: Small airway dysfunction is an early and clinically important feature of many respiratory diseases but remains difficult to detect using conventional physiological tests. Multiple-breath washout (MBW) is wide...
BACKGROUND: Small airway dysfunction is an early and clinically important feature of many respiratory diseases but remains difficult to detect using conventional physiological tests. Multiple-breath washout (MBW) is widely used to assess ventilation heterogeneity; however, its sensitivity to the specific location and severity of airway narrowing is not fully understood. METHODS: Nitrogen MBW was simulated using a physiologically realistic computational airway model reconstructed from high-resolution chest CT imaging. Sixty-four airway constriction scenarios were examined, varying systematically by airway generation, constriction ratio, and constricted branch ratio. Standard MBW indices (LCI, S, and S) were evaluated alongside a novel intrapulmonary reverse flow (RF) metric. Sensitivity to airway structural changes was assessed using Spearman's rank correlation and multiple linear regression analyses. RESULTS: MBW indices were predominantly sensitive to severe proximal constriction (Gen 5-9, ≥ 75% severity) with minimal changes observed in distal scenarios. RF showed strong correlations with all MBW indices, particularly S (ρ = 0.93, p < 0.0001), and consistently increased with constriction at any given airway location. Notably, while S has long been regarded as a marker of peripheral convective-diffusive heterogeneity at the acinar level, our findings demonstrate that convective heterogeneities arising from more proximal airway constrictions generate significant RF, which in turn influences the S signal. In multivariable regression, RF emerged as the most sensitive marker of ventilation heterogeneity arising from airway structural alterations, explaining the greatest proportion of variance (Adj. R = 0.933, p < 0.001), exceeding that of S (0.826), LCI (0.732), and S (0.564). CONCLUSIONS: In simulations, RF was sensitive to ventilation abnormalities arising from mild and distal airway narrowing. As a physiologically interpretable, flow-based marker, RF offers a novel and complementary means of enhancing the sensitivity of MBW for the early detection and motivates further experimental and clinical validation. Importantly, by identifying RF as a convective link between central airway narrowing and peripheral washout behaviour, our study suggests that S reflects a broader spectrum of ventilation disturbances than previously assumed, providing a new mechanistic basis for interpreting MBW indices.
Aerosol deposition in the lung as a biomarker in asthma and chronic obstruction.
Öhrneman H, Malinovschi A, Cai GH … +5 more , Svartengren M, Nicklasson H, Jakobsson J, Wollmer P, Löndahl J
Respir Res · 2026 May · PMID 42116137 · Full text
BACKGROUND: The objective of this study was to explore the potential of Airspace Dimension Assessment (AiDA) to rapidly determine the type and severity of airway obstruction, detect emphysema in individuals with chronic...
BACKGROUND: The objective of this study was to explore the potential of Airspace Dimension Assessment (AiDA) to rapidly determine the type and severity of airway obstruction, detect emphysema in individuals with chronic airflow limitation (CAL), and distinguish it from non-emphysematous obstruction, asthma, and absence of respiratory disease with normal spirometry. METHODS: Among the 744 participants measured with AiDA within the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort, 40 had asthma, and 34 had a CAL (defined by a post-bronchodilator FEV/FVC < 0.7), whereof 12 had CT-detected emphysema. AiDA measurements were compared across these groups and to 111 healthy controls (never-smokers with normal spirometry and no history of respiratory disease). RESULTS: Subjects with CAL had significantly larger distal airspaces radii (median r=298 μm) than controls (r=278 μm, p < 0.001), but no significant difference was observed in asthmatics (r=273 μm, p = 0.79). Subjects with CT-detected emphysema in the CAL group displayed further differentiation from the control (r=349 μm, p < 0.001), while those without emphysema displayed no significant increase. Unlike r, neither low attenuation volume nor 15th percentile density could clearly distinguish between obstruction and radiologist-assessed emphysema. In addition, the zero-second particle recovery (R), which is theorized to reflect conducting airway dysfunction, was decreased in both asthmatics (R = 0.41, p = 0.011), and in the CAL group (R = 0.45, p = 0.020) when compared to controls (R = 0.56). CONCLUSIONS: These findings display AiDA's potential in identifying emphysema as well as obstructive airway disease. The absence of an increased distal airspace radius in asthmatics confirm that r is a measure of the distal airspaces, unaffected by abnormalities in the conducting airways. However, the decreased R in both asthma and CAL suggests that R does reflect conducting airway abnormality.
Robotic-assisted bronchoscopy-guided cryobiopsy for the diagnosis of ground-glass opacity-predominant peripheral pulmonary nodules.
Zhang C, Xie F, Xi H … +4 more , Liu S, Yan L, Xu D, Sun J
Respir Res · 2026 May · PMID 42116052 · Full text
BACKGROUND: The combination of shape-sensing robotic-assisted bronchoscopy (ssRAB) and cryobiopsy may improve the diagnostic yield of ground-glass opacities (GGOs). However, the literature on this approach is limited. Th...
BACKGROUND: The combination of shape-sensing robotic-assisted bronchoscopy (ssRAB) and cryobiopsy may improve the diagnostic yield of ground-glass opacities (GGOs). However, the literature on this approach is limited. This study aims to assess the diagnostic yield and safety of ssRAB integrated with mobile cone-beam computed tomography (CBCT)-guided cryobiopsy for GGO-predominant peripheral pulmonary nodules (PPNs). METHODS: This is a single-center retrospective study of patients suspected to have malignant GGO-predominant PPNs (consolidation-to-tumor ratio ≤ 0.5) who underwent ssRAB integrated with mobile CBCT-guided cryobiopsy between November 2024 and June 2025 at Shanghai Chest Hospital. Clinicodemographic data, nodule characteristics, procedure details, diagnostic performance, and complications were analyzed. The primary efficacy outcome was the diagnostic yield. The primary safety outcome was procedure-related and device-related complications. RESULTS: A total of 55 nodules were biopsied in 40 patients. The mean patient age was 59.2 years, and 75.0% were female. The median nodule size was 12.0 mm (interquartile range, 9.9-16.0) in the largest dimension. Thirty-six nodules were pure GGOs and 19 were mixed GGOs, with 94.5% of nodules lacking a bronchus sign. A tunnel to the target lesion was created in 74.5% of the nodules. The per-nodule diagnostic yield was 87.3%. There were no episodes of major bleeding or pneumothorax. Cryobiopsy provided specimens sufficient for assessment of programmed death-ligand 1 (PD-L1) expression in 11 (84.6%) of 13 patients tested and for genetic testing in all 16 patients (100%) in which it was attempted. CONCLUSIONS: ssRAB integrated with mobile CBCT-guided cryobiopsy had a high diagnostic yield for GGO-predominant PPNs with a favorable safety profile. CLINICAL TRIAL NUMBER: Not applicable.
Comparative evaluation of PEGylated bovine hemoglobin as a perfusate in rat ex vivo lung perfusion.
Zhang J, Zhang X, Yuan H … +3 more , Ou J, Wu G, He J
Respir Res · 2026 May · PMID 42106824 · Full text
BACKGROUND: Ex vivo lung perfusion (EVLP) is pivotal for assessing and preserving marginal donor lungs. While red-blood-cell (RBC)-based perfusates enhance oxygen delivery, they increase pulmonary vascular resistance, th...
BACKGROUND: Ex vivo lung perfusion (EVLP) is pivotal for assessing and preserving marginal donor lungs. While red-blood-cell (RBC)-based perfusates enhance oxygen delivery, they increase pulmonary vascular resistance, thereby potentially exacerbating perfusion-induced injury. This study compared a novel acellular oxygen carrier, PEGylated bovine hemoglobin (PEG-bHb), against RBC-based and acellular perfusates in a rat EVLP-transplantation model. METHODS: A total of 49 rats were included in this study. Lungs underwent 4 h EVLP with acellular, RBC or PEG-bHb solutions, followed by left-lung transplantation and 2 h reperfusion; unperfused lungs served as controls. Respiratory mechanics, gas exchange, inflammatory cytokines, oxidative-stress markers, tight junction integrity (Occludin), and histology were evaluated. Bulk RNA-sequencing, qRT-PCR, and immunofluorescence for endoplasmic reticulum (ER) stress markers (ATF-6, ATF-4, CHOP and ubiquitin) were employed to explore underlying mechanisms. RESULTS: PEG-bHb demonstrated lower pulmonary vascular resistance and higher dynamic compliance than the RBC group. Inflammatory cytokine (IL-6, IL-1β, TNF-α) and Oxidative markers (MDA, HIF-1α) in lung tissue were reduced compared to acellular and RBC groups. Occludin expression indicated superior alveolar-capillary integrity versus control and acellular groups and parity with RBC group. Post-transplantation, the PEG-bHb group exhibited the least histological injury and the highest IL-10 expression, indicating attenuated early graft damage. Transcriptomic analysis suggested concurrent regulation of endoplasmic-reticulum stress and cytokine pathways; immunofluorescence demonstrated reduced ATF-6, increased ATF-4, and stable CHOP expression. CONCLUSION: PEG-bHb reduced early post-transplant injury by preserving lung compliance, sustaining barrier integrity, and mitigating inflammatory stress during EVLP. It represents a promising candidate for clinical EVLP application.
Compartment-specific phase compensation between pulmonary T-Cell immunity and waning systemic responses in BA.5 breakthrough infection.
Huang P, Mei X, Xu H … +20 more , Wan Q, Wu X, Peng J, Zhou K, Yang G, Cheng L, Bu S, Deng Z, Wu F, Dai C, Chen D, Luo Q, Sun X, Su J, Deng S, Wang S, Liu Y, Ran P, Wang Z, Zhou Y
Respir Res · 2026 May · PMID 42106820 · Full text
BACKGROUND: Spatiotemporal coordination of SARS-CoV-2-specific immunity across pulmonary and systemic compartments is poorly defined, especially how chronic lung diseases modulate this. We hypothesized that profiling vir...
BACKGROUND: Spatiotemporal coordination of SARS-CoV-2-specific immunity across pulmonary and systemic compartments is poorly defined, especially how chronic lung diseases modulate this. We hypothesized that profiling virus-specific T cells (VSTs) and antibodies in respiratory vs. blood samples would reveal compartmentalized dynamics critical for viral control. METHODS: In 64 mild Omicron BA.5 breakthrough-infected participants (30 early [D7], 34 later [D14]), we performed: 1) Paired sputum/PBMCs flow cytometry for CD4⁺/CD8⁺ VSTs; 2) Systemic antibody titration (NAbs, anti-N IgG); 3) Compartmental cytokine profiling; 4) Stratified analysis of GOLD I-II COPD (n = 28) vs controls (n = 36). RESULTS: Pulmonary CD4⁺ VSTs increased 2.8-fold from D7 to D14, contrasting with delayed CD8⁺ VSTs mobilisation, while no sputum-blood VSTs correlations existed in either phase (all P > 0.05). Phase-dependent immune synergy was observed in that early viral control was driven by blood CD8⁺ VSTs-NAbs coordination (CT value: r = 0.43; NAbs: r = 0.41; both P < 0.05), whereas later-phase pulmonary CD4⁺ VSTs expanded reciprocally to waning systemic antibodies (NAbs: r = -0.54, P < 0.01), indicating local compensation. Pulmonary cytokine dominance was evident as sputum IL-1β/IL-6/RANTES inversely correlated with viral titer (CT value) at D7 (all P < 0.05), exhibiting stronger virological associations than their plasma counterparts. Additionally, GOLD I-II COPD patients showed no impairment in viral clearance, NAbs titres, or VSTs magnitudes versus controls (all P > 0.05). CONCLUSIONS: Non-invasive sputum analysis reveals dynamic SARS-CoV-2 immunity: systemic effectors dominate early control, while pulmonary CD4⁺ VSTs compensate during antibody decline, underscoring the need for phase-specific therapeutic regimens targeting distinct compartments.
Quantitative interpretation models for targeted next-generation sequencing in lower respiratory tract infections: a multicenter prospective study.
Jing C, Ding Y, Zhou J … +10 more , Wei J, Wang M, Yuan D, Peng L, Huang Y, Shi X, Wu X, Tao L, Qian Q, Sun W
Respir Res · 2026 May · PMID 42106793 · Full text
BACKGROUND: Lower respiratory tract infections (LRTIs) represent a significant global health burden. While targeted next-generation sequencing (tNGS) offers potential advantages for pathogen detection, its clinical imple...
BACKGROUND: Lower respiratory tract infections (LRTIs) represent a significant global health burden. While targeted next-generation sequencing (tNGS) offers potential advantages for pathogen detection, its clinical implementation is hindered by the absence of validated quantitative interpretation criteria for pathogen discrimination. METHODS: We conducted a multicenter prospective study of 631 patients with suspected LRTIs across five intensive care units in eastern China from January 2022 to March 2025. Bronchoalveolar lavage fluid specimens underwent concurrent tNGS and conventional microbiological testing (CMT). Expert group A established the reference standard by classifying patients into LRTI/non-LRTI categories and identifying clinically significant pathogens based on comprehensive clinical criteria. Expert group B, blinded to tNGS quantitative data, provided qualitative interpretation based solely on detected microorganisms to eliminate any influence from quantitative parameters. Expert group C, blinded to all tNGS data, provided interpretation based on conventional microbiological testing combined with clinical manifestations. Quantitative diagnostic models incorporating reads per kilobase per million mapped reads (RPKM) and pathogen copy numbers were developed using a training cohort (n = 420) and validated in an independent cohort (n = 211). RESULTS: Of 631 patients, 358 (56.7%) met the diagnostic criteria for LRTI. Polymicrobial infections were identified in 77 patients, with the majority co-infected with Acinetobacter baumannii and Pseudomonas aeruginosa. tNGS demonstrated enhanced detection of Gram-negative bacteria, Candida species and Pneumocystis jirovecii, while CMT showed better detection for Aspergillus species. The quantitative models demonstrated excellent discriminatory performance for bacterial pathogens. The sensitivity and specificity for conventional microbiological testing alone were 58.7% and 74.7%. Adding clinical manifestations to CMT resulted in a sensitivity of 68.8% and specificity of 72.0%. In comparison, qualitative tNGS achieved a sensitivity of 78.5% and a specificity of 76.6%, while the model-based algorithm demonstrated the highest diagnostic accuracy with a sensitivity of 82.4% and a specificity of 85.0%. For antimicrobial resistance prediction, tNGS achieved moderate accuracy (AUC 0.715) with high concordance for key antimicrobial resistance markers including KPC, NDM, OXA-48 and mecA. CONCLUSION: We developed and validated quantitative models for tNGS-based pathogen detection in LRTIs, enabling precise discrimination between pathogenic and background organisms. These models represent a significant step forward in the clinical application of tNGS for LRTI diagnosis and antimicrobial resistance detection.
TGM2-TUFM promotes acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC through p62-mediated lipophagy.
Shen J, Gou L, Sun Y … +12 more , Luo P, Hong S, Zhang C, Sun Y, Shen W, Fang J, Zhang Y, Li X, Ying H, Lyu Q, Zhang J, Wei T
Respir Res · 2026 May · PMID 42106683 · Full text
BACKGROUND: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) remains the leading cause of treatment failure in advanced non-small cell lung cancer (NSCLC) patients harboring...
BACKGROUND: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) remains the leading cause of treatment failure in advanced non-small cell lung cancer (NSCLC) patients harboring sensitizing EGFR mutations. This study aims to investigate the underlying resistance mechanisms in EGFR-mutated NSCLC. METHODS: Analyze the differential genes in the transcriptome sequencing data of EGFR-TKi-sensitive and -resistant cell lines, and use the GDC database to analyze the prognosis. qRT‒PCR, western blotting, and immunohistochemistry were used to detect the expression of TGM2 in EGFR-TKI-sensitive and -resistant NSCLC cells and tissue samples. The effects and molecular mechanisms of TGM2 on EGFR-TKI resistance were verified by CCK-8, flow cytometry, western blotting, mouse xenograft models, gene enrichment analysis, and mass spectrometry. RESULTS: Our study found that TGM2 was highly expressed in EGFR-TKI-resistant NSCLC cells and tissue samples. Its increased expression was associated with shorter survival time in NSCLC patients. Transglutaminase 2 (TGM2) overexpression renders EGFR-sensitive mutated NSCLC cells resistant to EGFR-TKIs in culture and in murine xenograft models. Mechanistically, we determined that TGM2 promotes lipophagy and fatty acid oxidation (FAO) by inhibiting the ubiquitin-mediated degradation of elongation factor Tu, mitochondrial (TUFM), thereby contributing to drug resistance in NSCLC. Furthermore, we found that TGM2 promotes the formation of p62 (sequestosome 1) bodies through TUFM, and these p62 bodies bind to lipid droplets (LDs)-associated protein perilipin 2 (PLIN2) to enhance lipophagy, revealing a novel pathway for TGM2-facilitated LD breakdown. Notably, treatment with the autophagy inhibitor chloroquine (CQ) and the FAO inhibitor etomoxir reversed TGM2-mediated EGFR-TKI resistance. CONCLUSIONS: Our study revealed that TGM2 is a potential therapeutic target or biomarker for predicting acquired EGFR-TKI resistance in EGFR-mutated NSCLC.
Correction: A multicenter prospective clinical cohort study of pulmonary cryptococcosis in adult non-HIV-infected patients in a southeastern province of China.
Chen M, Shuyang C, Meng W … +22 more , Huijuan W, Shengyuan Z, Liying Z, Guoxiang L, Zongyang Y, Yanjing Y, Baosong X, Xiujuan Y, Xiangqi C, Lan L, Qunying L, Yuxiong H, Liyu X, Xiaohua L, Xiaohong C, Danmei W, Gongping C, Kaixiong L, Hui S, Li L, Guoqing Y, Wen W
Respir Res · 2026 Apr · PMID 42104465 · Full text
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Development and external validation of an interpretable machine-learning model for HFpEF comorbidity risk in COPD patients.
Cao J, Kang B, Li S … +6 more , Lei Y, Liu D, Li C, Guo W, Zhang B, Xie X
Respir Res · 2026 May · PMID 42104441 · Full text
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) and Heart Failure with preserved Ejection Fraction (HFpEF) frequently coexist, leading to increased hospitalization, mortality, and healthcare burden. Early identi...
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) and Heart Failure with preserved Ejection Fraction (HFpEF) frequently coexist, leading to increased hospitalization, mortality, and healthcare burden. Early identification of HFpEF risk in COPD patients is critical for timely intervention. AIM: To develop and validate an interpretable machine learning (ML) model for predicting HFpEF risk in COPD patients and to identify key predictors using explainable artificial intelligence techniques. METHODS: This retrospective study analyzed 1,550 COPD patients, divided into COPD-only and COPD-HFpEF groups. Feature selection was performed using LASSO regression, logistic regression, and Boruta random forest. Ten ML models were developed and evaluated on an internal test set, with the best model further validated on an external cohort (n = 69). Model interpretability was assessed using SHapley Additive exPlanations (SHAP). RESULTS: Nine predictors were consistently selected: NT-proBNP, red blood cell count, fibrinogen, cholesterol, arterial PaO₂, inspiratory capacity (IC), IC% predicted, late diastolic mitral inflow velocity (A wave), and CAT score. The XGBoost model achieved the best performance, with an AUC of 0.898 (95% CI: 0.867-0.929) on the internal test set and 0.819 (95%CI: 0.713 - 0.924) on external validation. SHAP analysis identified NT-proBNP as the most influential predictor. CONCLUSION: The developed XGBoost model accurately predicts HFpEF risk in COPD patients and offers clinically interpretable insights into key predictive markers, supporting early identification and stratified management.
Pulmonary infectious complications associated with the addition of cryobiopsy to conventional sampling for peripheral pulmonary lesions: a retrospective study.
Imabayashi T, Matsumoto Y, Uchimura K … +2 more , Furuse H, Tsuchida T
Respir Res · 2026 May · PMID 42104387 · Full text
BACKGROUND: Cryobiopsy is used in addition to conventional sampling during endobronchial ultrasound (rEBUS)-guided bronchoscopy for peripheral pulmonary lesions (PPLs) to improve diagnostic yield. However, the incrementa...
BACKGROUND: Cryobiopsy is used in addition to conventional sampling during endobronchial ultrasound (rEBUS)-guided bronchoscopy for peripheral pulmonary lesions (PPLs) to improve diagnostic yield. However, the incremental risk of procedure-related pulmonary infection remains poorly quantified in routine clinical practice. METHODS: We retrospectively analyzed consecutive patients who underwent rEBUS-guided bronchoscopy for PPLs between January 2019 and March 2022. Patients were categorized into those undergoing combined conventional biopsy and cryobiopsy and those undergoing conventional biopsy alone. Pulmonary infectious complications occurring within 4 weeks after bronchoscopy were assessed. Propensity score matching was performed to adjust for baseline differences and to evaluate the impact of cryobiopsy on pulmonary infectious complications. Sensitivity analyses using overlap weighting were also conducted. RESULTS: After propensity score matching, 756 patients were included in the matched cohort (combined cryobiopsy group: n = 252; conventional biopsy group: n = 504). Pulmonary infectious complications occurred more frequently in the combined cryobiopsy group than in the conventional biopsy group (4.8% vs. 1.8%). Adding cryobiopsy was associated with an increased risk of pulmonary infectious complications (odds ratio, 2.84; 95% confidence interval, 1.15-6.99; P = 0.023), corresponding to an absolute risk increase of 3.0% and a number needed to harm of 33. These findings were consistent in sensitivity analyses using overlap weighting. CONCLUSIONS: Adding cryobiopsy to conventional sampling in rEBUS-guided bronchoscopy is associated with a higher risk of pulmonary infectious complications. These findings provide quantitative evidence to guide patient selection and procedural planning.
Genomic characterization of DNA damage response pathway mutations reveals their adverse impact on EGFR-TKI efficacy in non-small cell lung cancer.
Yang L, Cheng J, Guo X … +8 more , Xiao H, Kuang X, Yang Y, Zhang L, Zhang Q, Wang D, Xu Y, Li M
Respir Res · 2026 May · PMID 42092972 · Full text
BACKGROUND: Although tyrosine kinase inhibitors (TKIs) significantly improve survival outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), tumor clonal evolution un...
BACKGROUND: Although tyrosine kinase inhibitors (TKIs) significantly improve survival outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), tumor clonal evolution under drug pressure inevitably leads to acquired resistance. DNA damage response (DDR) mutations lead to elevated genome instability, but the frequency and impact of DDR gene/pathway mutations on EGFR-TKI treatment efficacy remain unclear. METHODS: A total of 790 NSCLC patients who received high-throughput targeted sequencing at Daping Hospital were retrospectively enrolled to analyze the mutation landscape of DDR genes in NSCLC. Next, 202 EGFR-mutant patients from Daping Hospital and 126 patients from the GENIE database who received first-line EGFR-TKI treatment were further enrolled to explore the association between DDR mutations and clinical outcomes. RESULTS: DDR genes including ATM, MSH3, BRCA2 (> 5%), and pathways including the Fanconi anemia (FA), homologous recombination repair (HRR), and mismatch repair (MMR) exhibited substantial mutation rates (15%). In the Daping cohort, patients with DDR mutations had inferior outcomes when receiving EGFR-TKI treatment (median PFS: 14.9 vs. 10.8 months, P = 0.001) and higher mutation burden. Specifically, FA (HR = 2.314, 95% CI: 1.547-3.549, P < 0.001) or HRR (HR = 2.686, 95% CI: 1.786-4.039, P < 0.001) pathway mutations were independent risk factors for disease progression. Notably, patients with co-occurring TP53 and DDR mutations had the worst outcomes compared to those with either single mutations or wild-type TP53/DDR, and similar findings were validated in the GENIE cohort. CONCLUSION: Our study demonstrates a substantial prevalence of DDR mutations and their association with inferior EGFR-TKI efficacy, highlighting the importance of genomic profiling of DDR mutations to identify this high-risk subpopulation in EGFR-mutant NSCLC.
The integrated analysis of PRDX3 in lung cancer: biomarker potential and therapeutic target prospects.
Kong Q, Zhang L, Gong S … +2 more , Wu Y, Wang J
Respir Res · 2026 May · PMID 42092925 · Full text
BACKGROUND: Lung cancer remains the malignant tumor with the highest global incidence and mortality, posing a severe threat to public health. Peroxiredoxin 3 (PRDX3), a well-characterized ferroptosis biomarker, has been...
BACKGROUND: Lung cancer remains the malignant tumor with the highest global incidence and mortality, posing a severe threat to public health. Peroxiredoxin 3 (PRDX3), a well-characterized ferroptosis biomarker, has been implicated in lung cancer progression. Accumulating evidence suggests that PRDX3 may serve as a core gene and potential biomarker, which is critical for elucidating pathogenesis, improving diagnostic accuracy, and developing targeted therapeutic strategies for lung cancer. METHODS: To systematically investigate the expression pattern of PRDX3 and its clinical relevance in lung cancer, we integrated multiple bioinformatics tools and public datasets to analyze PRDX3 expression across pan-cancer cohorts, major lung cancer subtypes, and patient subgroups stratified by sex, age, and clinical stage. Furthermore, we evaluated the correlation between PRDX3 expression and immunotherapeutic-related factors, and performed multivariate survival analysis to validate its independent prognostic value. Additionally, protein-protein interaction (PPI) networking and co-expression analysis were employed to explore the functional interactions of PRDX3 with core ferroptosis regulators and immune microenvironment modulators. RESULTS: PRDX3 was significantly upregulated in multiple malignant tumors, including LUAD and LUSC, with minimal variations in expression levels across different sex, age, and clinical stage subgroups. High PRDX3 expression was independently associated with significantly poorer clinical prognosis in lung cancer, particularly in the LUAD subtype. Pathway enrichment analysis revealed that immune activation, immune inhibition, and MHC molecule-related signaling pathways were closely correlated with altered PRDX3 expression in both LUAD and LUSC, with distinct subtype-specific patterns. PPI networking demonstrated that PRDX3 exhibited positive co-expression with core ferroptosis regulators (GPX4, TXN2) and interacted with components of the thioredoxin system (TXNRD2, TXN), indicating its potential involvement in regulating cellular redox homeostasis and ferroptosis. Single-cell analysis further confirmed PRDX3 expression in lung cancer cells and key immune cell subsets (T cells, macrophages), with higher expression levels observed in LUAD than in LUSC. CONCLUSIONS: These correlative findings suggest that PRDX3 may play a pivotal role in lung cancer pathogenesis, potentially through mechanisms involving ferroptosis regulation via interaction with GPX4 and the thioredoxin system, redox homeostasis maintenance, and subtype-specific immune microenvironment modulation. Collectively, PRDX3 represents a promising independent prognostic biomarker for lung cancer, especially for LUAD, and a potential therapeutic target for ferroptosis-based and immunotherapeutic strategies.
IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1ɑ/glycolysis pathway.
Gao Y, Cao L, Huang X … +13 more , Duan G, Lin B, Zhang J, Liu W, Chen C, Li J, Liu M, Li X, Chen H, Liu R, Tang J, Xiao J, Lu Y
Respir Res · 2026 May · PMID 42071231 · Full text
BACKGROUND: IL-36γ coordinates macrophage activation and is essential for defense against Mycobacterium tuberculosis (Mtb), but the mechanisms remains poorly understood. Aerobic glycolysis plays a critical role in macrop...
BACKGROUND: IL-36γ coordinates macrophage activation and is essential for defense against Mycobacterium tuberculosis (Mtb), but the mechanisms remains poorly understood. Aerobic glycolysis plays a critical role in macrophages intrinsic control of Mtb infection. This study aimed to investigate the potential effects of IL-36γ on macrophages energy metabolism transformation from mitochondrial oxidative phosphorylation to aerobic glycolysis in response to Mtb infection. METHODS: The expression of IL-36γ in lung tissues, PBMCs and serum was analyzed using Immunohistochemistry, ELISA and RT-qPCR, while the role and mechanism of IL-36γ on macrophages energy metabolism transformation duing Mtb infection were investigated by RT-qPCR, ELISA, Western blot and colony-forming unit assay. RESULTS: We demonstrated IL-36γ enhanced the aerobic glycolysis, and downregulated the mitochondrial oxidative phosphorylation in Mtb infected macrophages. Furthermore, IL-36γ upregulated the expression of HIF-1α and IFN-γ in macrophages through the NF-κB/ERK/JNK signaling pathway, especially in macrophages infected with Mtb, where it induced the expression of large amounts of HIF-1α and IFN-γ. Moreover, IL-36γ promoted aerobic glycolysis through inducing the expression of HIF-1α in macrophages during Mtb infection. Meanwhile, HIF-1α was required for IL-36γ-mediated control of Mtb infection. Interestingly, the expression of IL-36γ was increased in lung tissues, PBMCs and serum from patients with active pulmonary tuberculosis and correlated with monocytes/macrophages immune response and IFN-γ levels, displayed an appreciable diagnostic value. CONCLUSION: IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1α/ glycolysis pathway. IL-36γ may be a potential treatment target and useful biomarker for tuberculosis.
Qualitative beta-2-adrenoceptor signaling in the regulation of human airway epithelia mucin and cytokine production.
Graumuller F, Cervantes D, Chan TO … +6 more , Schaunaman N, Villalba DR, Dickey BF, Walker JKL, Chu HW, Penn RB
Respir Res · 2026 May · PMID 42067931 · Full text
BACKGROUND: Numerous in vivo studies have demonstrated beta-2-adrenoceptor (βAR) -agonism as permissive in the development of allergic lung inflammation, and have implicated the arrestin-dependent signaling arm of the βA...
BACKGROUND: Numerous in vivo studies have demonstrated beta-2-adrenoceptor (βAR) -agonism as permissive in the development of allergic lung inflammation, and have implicated the arrestin-dependent signaling arm of the βAR in mediating this effect. However, the specific cell type(s) mediating βAR regulation of allergic lung inflammation remain unestablished. METHODS: To explore the potential contribution of airway epithelia in this phenomenon, we compared the ability of ractopamine (RP), recently identified as a Gs-biased beta-agonist, to that of the unbiased/balanced beta-agonist albuterol (ALB), on IL-13-stimulated mucin and cytokine production in human airway epithelia cultures in air-liquid interface (HAE). RESULTS: ALB, which activates both the βAR-arrestin and -Gs signaling pathways significantly augmented IL-13-induced mucin production in HAE. RP, which preferentially signals via Gs/PKA, did not. Although IL-13 stimulated production of numerous cytokines, including IL-1α, IL-1RA, MDC, TGF-α, and GROα, ALB-mediated augmentation of these cytokines was highly variable and not statistically significant. Similarly, RP did not augment the induction of cytokines stimulated by IL-13. Moreover, in contrast to previous studies that reported a requirement of concomitant βAR agonism for IL-13 to stimulate cytokine production, such a requirement was observed only in minority of the (12) cultures examined. CONCLUSIONS: These data implicate arrestin-dependent βAR signaling augmenting airway epithelial mucin production as a contributor to the previously-demonstrated pro-inflammatory effects of βAR agonism in vivo. Moreover, they suggest that beta-agonist effects on the cytokine profile in the allergen-inflamed lung may be influenced by specific asthmatic endotypes and involve cooperativity among multiple cell types.
Contribution of host-related immune factors to frequency and severity of infections in lung transplant recipients.
Kufa J, Schneiderova P, Genzor S … +5 more , Trajerova M, Jakubec P, Mizera J, Zurkova M, Kriegova E
Respir Res · 2026 May · PMID 42067865 · Full text
BACKGROUND: Lung transplantation (LTx) is associated with an increased risk of infection, causing notable morbidity and mortality at all phases post-transplantation. The contribution of host-related immune factors to sus...
BACKGROUND: Lung transplantation (LTx) is associated with an increased risk of infection, causing notable morbidity and mortality at all phases post-transplantation. The contribution of host-related immune factors to susceptibility to post-LTx infections is not fully understood. METHODS: The circulating blood profile, serum cytokine profiles and 28 functional single nucleotide polymorphisms in cytokine genes were investigated in 103 lung transplant recipients (LTRs) (men/women: 65/38; mean [95% confidence interval {CI}]: 5.4 [4.7-6.1] years post-LTx) using cytometry and MassARRAY genotyping; the frequency and severity of viral, bacterial and fungal infections were evaluated. RESULTS: In total, 62 (60.2%) LTRs had frequent/severe infections requiring inpatient care (FSI) and 41 (39.8%) had infrequent infections managed in the outpatient setting (IO). We identified rs1800587 AA (IL1A), rs1143634 AA (IL1B), rs16944 GG (IL1B), rs1800795 CG/GG (IL6) and rs1800797 AG/GG (IL6) as being associated with susceptibility to frequent/severe infections in LTRs. A combination of ≥ 2 IL1/IL6 risk variants was present in 53.2% of patients with frequent/severe infections compared with 17.1% with infrequent infections, increasing the likelihood of severe/frequent infections 5.5-fold (95% CI 2.17-13.6; p < 0.001). Moreover, patients with severe/frequent infections exhibited distinct changes in immune cell composition and cytokine profiles between 6- and 12-months post-LTx compared with others. CONCLUSION: Our data demonstrated that LTRs carrying IL1/IL6 risk variants and exhibiting limited post-LTx immune reconstitution were substantially more susceptible to frequent/severe infections. These findings highlight the value of combining immunogenetic profiling with longitudinal immune monitoring to improve infection risk stratification and guide personalised post-LTx care.
Blood eosinophil counts and postoperative outcomes in early-stage lung cancer: a retrospective cohort study.
Mugutso E, Freund O, Pitrou I … +8 more , Ghatak A, Roux C, Jacobson S, Stetco JR, Kutzkel S, Bar-Shai A, Smith B, Ezer N
Respir Res · 2026 May · PMID 42067843 · Full text
BACKGROUND: Lung cancer resection is curative but associated with postoperative morbidity and mortality. This study evaluated whether elevated blood eosinophil count (BEC) was associated with postoperative outcomes in ea...
BACKGROUND: Lung cancer resection is curative but associated with postoperative morbidity and mortality. This study evaluated whether elevated blood eosinophil count (BEC) was associated with postoperative outcomes in early-stage lung cancer. METHODS: This was a retrospective cohort study of consecutive adult patients undergoing lung resection for stage I and II non-small cell lung cancer in a large tertiary referral center from September 2017 to June 2021. Data were drawn from the institution's Data Warehouse. The primary outcome was 90-day healthcare utilization defined as emergency department visit or hospital readmission. Secondary outcomes were postoperative complications, index hospitalization length of stay, and 1-year survival. Preoperative 90-day BEC was categorized by a threshold of 200 cells/µL. Covariates were age, sex, smoking status, Charlson Comorbidity Index, chronic obstructive pulmonary disease (COPD), asthma, tumor size, nodal status, surgical approach, and blood results (white blood cells, hemoglobin, and creatinine). The main analyses were validated by a second international cohort. Log-Poisson with robust variance estimation and Cox proportional hazards regression models were fit for primary and secondary outcomes. Analyses were replicated for BEC thresholds of 150 and 300 cells/µL. RESULTS: Among 715 patients undergoing lung resection (median age = 69 years, 42% male, 29% with COPD), 146 patients (20%) had high preoperative BEC ≥ 200 cells/µL. BEC ≥ 200 cells/µL was associated with a higher rate of 90-day healthcare utilization:19% vs. 14% for BEC < 200 cells/µL. This association remained after adjustment (Risk Ratio [RR], 1.52; 95% Confidence Interval [CI], 1.02-2.25) and the validation cohort (RR, 2.23; 95% CI, 1.06-4.69). BEC as a continuous measure was also associated with the primary outcome in both cohorts: RR, 2.15 (95% CI, 1.49-3.12) and RR, 1.42 (95% CI, 1.10-1.94), respectively. BEC ≥ 200 cells/µL was associated with higher probability of death 1 year post-surgery (adjusted Hazard Ratio, 2.41; 95% CI, 1.08-5.35). There was no difference in the risk of postoperative pulmonary complications between high and low BEC (RR, 0.86; 95% CI, 0.58-1.27). CONCLUSIONS: Elevated preoperative BEC was associated with higher risk of postoperative healthcare utilization and lower 1-year survival after lung cancer resection among patients with or without respiratory disease.
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