Respir. Res. [JOURNAL]
Sun
200 papers
ERCC6L drives lung adenocarcinoma metastasis: a PJA2/p53 ubiquitination-dependent mechanism.
Jiang L, Zhou H, Liang S … +8 more , Wen Z, Qin J, Lei Z, Li R, Ma Y, Peng S, Zhou Y, Zhong Y
Respir Res · 2026 Apr · PMID 42063149 · Full text
Lung adenocarcinoma (LUAD) is prone to metastasis and exhibits a poor prognosis. The DNA repair-related protein ERCC6L is implicated in tumorigenesis, but its role in LUAD invasion and metastasis remains unclear. The exp...
Lung adenocarcinoma (LUAD) is prone to metastasis and exhibits a poor prognosis. The DNA repair-related protein ERCC6L is implicated in tumorigenesis, but its role in LUAD invasion and metastasis remains unclear. The expression, function, and underlying mechanisms of ERCC6L were investigated using bioinformatics analysis, cellular assays, and animal experiments. ERCC6L was significantly upregulated in LUAD tissues and cell lines, and its high expression was associated with poor overall and recurrence-free survival. Functional experiments demonstrated that ERCC6L overexpression promoted the migration, invasion, and epithelial-mesenchymal transition (EMT) of LUAD cells. Mechanistically, ERCC6L activated the E3 ubiquitin ligase PJA2, which mediated K48-linked polyubiquitination and subsequent degradation of p53, thereby attenuating its tumor-suppressive function. In vivo studies confirmed that ERCC6L knockout suppressed tumor growth, metastasis, and EMT progression by regulating the PJA2/p53 signaling axis. ERCC6L promotes migration, invasion, and EMT in LUAD by facilitating PJA2-mediated ubiquitination and degradation of p53. The ERCC6L/PJA2/p53 axis represents a potential novel therapeutic target for inhibiting metastasis in LUAD.
Alveolar epithelial barrier disruption by FKBP5-mediated necroptosis aggravates lung injury.
Cui J, Liu W, Zhou Y … +5 more , Qiu X, Xiao Y, Wang X, Wang T, Zhang D
Respir Res · 2026 Apr · PMID 42063111 · Full text
Alveolar epithelial barrier damage is a key pathological feature of acute respiratory distress syndrome (ARDS). The glycocalyx and tight junctions are essential for maintaining epithelial barrier function, and their disr...
Alveolar epithelial barrier damage is a key pathological feature of acute respiratory distress syndrome (ARDS). The glycocalyx and tight junctions are essential for maintaining epithelial barrier function, and their disruption exacerbates pulmonary edema. Although FK506-binding protein 51 (FKBP5) regulates inflammatory responses, its mechanistic role in ARDS remains unclear. Here, we show that FKBP5 levels in bronchoalveolar lavage fluid from patients with sepsis-associated ARDS are significantly elevated and positively correlated with disease severity. In a lipopolysaccharide (LPS)-induced ARDS mouse model, Fkbp5 markedly attenuated lung inflammatory injury and reduced damage to the epithelial glycocalyx and tight junctions. Transcriptomic analysis revealed that FKBP5 regulates inflammatory responses through the necroptosis pathway. Both in vivo and in vitro experiments further confirmed that genetic deletion or knockdown of FKBP5 suppresses necroptosis activation, reduces NF-κB signaling, and restores glycocalyx and tight junction integrity. Mechanistically, necroptosis-driven NF-κB activation promotes excessive cytokine production, which in turn damages the epithelial glycocalyx and tight junctions. These findings identify FKBP5 as a potential therapeutic target in ARDS and redefine the alveolar epithelium as an active contributor to the inflammatory microenvironment.
Krüppel-like factor 14 enhances fatty acid oxidation to combat pulmonary fibrosis.
Ren J, Wan R, Zhou S … +6 more , Ma X, Zhu C, Ma J, Chen J, Zhao L, Wu W
Respir Res · 2026 Apr · PMID 42057117 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder with few effective treatments. This study examines how Krüppel-like factor 14 (KLF14) influences fatty acid oxidation (FAO) and fibroblast se...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder with few effective treatments. This study examines how Krüppel-like factor 14 (KLF14) influences fatty acid oxidation (FAO) and fibroblast senescence in IPF. METHODS: A rat model of IPF was induced using bleomycin. Expression levels of KLF14, CPT1A, and related proteins were measured using qRT-PCR and Western blot. Lung tissue histology was examined, and cellular senescence was evaluated using SA-β-gal staining. The transcriptional regulation of CPT1A by KLF14 was confirmed through luciferase reporter assays and ChIP. RESULTS: KLF14 expression was significantly downregulated in the IPF model. Overexpression of KLF14 reduced collagen deposition, attenuated fibroblast senescence, and enhanced FAO by upregulating CPT1A. Mechanistically, KLF14 binds to the CPT1A promoter, promoting its transcription. CONCLUSIONS: KLF14 enhances FAO through CPT1A activation, offering a novel therapeutic strategy for IPF.
The allure and pitfalls of physiological quotients in lung function interpretation.
Liu Z, Hu C, Jiang M
Respir Res · 2026 Apr · PMID 42050648 · Full text
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Respiratory tract diseases and lung function in coke oven plant workers: a 50-year global systematic evaluation and meta-analysis.
Khoshakhlagh AH, Ghobakhloo S, Rahimi M … +2 more , Yazdani A, Gruszecka-Kosowska A
Respir Res · 2026 Apr · PMID 42050638 · Full text
This systematic review examines the impact of coke oven emissions (COEs) on workers’ health, with an emphasis on respiratory diseases and mortality. This study aims to investigate the relationship between exposure to pol...
This systematic review examines the impact of coke oven emissions (COEs) on workers’ health, with an emphasis on respiratory diseases and mortality. This study aims to investigate the relationship between exposure to polycyclic aromatic hydrocarbons (PAHs), particulate matter (PM2.5), benzene (C6H6), and coal tar pitch volatiles (CTPV) among coke production workers and their association with respiratory diseases, lung function, lung cancer, and mortality from malignant respiratory diseases. A comprehensive literature search was conducted in Web of Science, Scopus, PubMed, Medline, and Embase up to December 16, 2024, based on the PECO (Population, Exposure, Comparator, and Outcomes) framework. A total of 38 studies met the inclusion criteria. PAHs were the most studied pollutants, with 47% of studies examining their effects in environments like coke oven factories, where workers are at high risk of COPD, asthma, and lung cancer. 37% of the studies focused on lung cancer, highlighting worries about the part contaminants play in the development of cancer in industrial settings. 18% of studies observed non-cancerous diseases such COPD and chronic bronchitis, as well as respiratory symptoms like chronic cough and shortness of breath. Data collection methods differed among research, with questionnaires and interviews constituting the predominant approach (66%), especially for evaluating respiratory diseases such as chronic bronchitis and asthma. This study also assesses the mortality risks associated with coke oven emissions, demonstrating a significant association between such exposure and higher mortality. However, the significant heterogeneity across studies (I-squared value of 98.9%) indicates considerable variation in methodology. This study shows that workers exposed to coke oven emissions and other industrial pollutants face significant health hazards, underlining the need for stricter occupational health and safety standards to safeguard vulnerable populations. The findings also highlight the necessity for continuous health monitoring of workers and improved management of industrial pollutants to prevent chronic respiratory diseases and enhance workers’ quality of life.
Fungal exposure exacerbates allergen-driven asthma in a two-hit mouse model.
Mei S, Zhu L, Zhang K … +7 more , Thakur A, Chen B, Mao X, Duan F, Romero V, Chen Y, Chen J
Respir Res · 2026 Apr · PMID 42050607 · Full text
BACKGROUND: Severe and exacerbation-prone asthma is often triggered by environmental fungi, yet the immunopathologic impact of live spore exposure remains unclear. Traditional murine models using fungal extracts do not r...
BACKGROUND: Severe and exacerbation-prone asthma is often triggered by environmental fungi, yet the immunopathologic impact of live spore exposure remains unclear. Traditional murine models using fungal extracts do not reflect the complexity of inhaled spores during real-world exposures. We sought to establish a clinically relevant model of fungal-driven asthma exacerbation and to define its inflammatory, structural, and molecular features. METHODS: Ovalbumin (OVA)-sensitized mice were challenged intratracheally with live Aspergillus fumigatus or Alternaria alternata spores; spore-only and OVA-only groups served as controls. Airway inflammation and remodeling were assessed by histology and morphometric analysis, including epithelial and peribronchial smooth muscle thickness. Pulmonary mechanics were evaluated using invasive lung function testing. Immune responses were characterized by flow cytometry and cytokine quantification in bronchoalveolar lavage fluid and serum. Tissue inhibitor of metalloproteinase-1 (TIMP1) levels were measured to evaluate matrix-remodeling–associated responses. RESULTS: Live spore exposure alone caused modest inflammation and airway hyperresponsiveness. In contrast, spore challenge in OVA-primed mice elicited a markedly amplified phenotype with dense peribronchial/perivascular infiltrates, extensive goblet-cell metaplasia, epithelial disruption, increased epithelial and smooth muscle thickness, and excessive mucus accumulation. Lung function demonstrated substantial increases in airway resistance and lung elastance, consistent with an exacerbation-like state. Co-challenged mice showed increased frequencies of IL-4⁺ CD4⁺ T cells, an early increase in an ILC2-like Lin⁻CD44⁺CD25⁺ population, and elevated IL-4, IL-13, and IL-17 in bronchoalveolar lavage fluid and serum, indicating a mixed type 2 and type 17 cytokine milieu. TIMP1 was robustly increased and was associated with the most marked inflammatory, remodeling, and physiologic abnormalities. This two-hit model recapitulates key hallmarks of fungus-associated exacerbation-like allergic airway disease and provides a translational platform for testing interventions and evaluating remodeling-linked biomarkers.
Adult life course trajectories of lung function and the development of interstitial lung abnormalities: the CARDIA lung study.
Grudzinski KM, Liu GY, Colangelo LA … +7 more , Selvan KC, Putman R, Hunninghake GM, Estepar RSJ, Washko G, Kalhan R, Esposito AJ
Respir Res · 2026 Apr · PMID 42050519 · Full text
BACKGROUND: Interstitial lung abnormalities (ILA) are radiologic findings of increased lung density or fibrosis in individuals without clinical interstitial lung disease (ILD) and are associated with increased mortality...
BACKGROUND: Interstitial lung abnormalities (ILA) are radiologic findings of increased lung density or fibrosis in individuals without clinical interstitial lung disease (ILD) and are associated with increased mortality and progression to ILD. Understanding physiologic trajectories of lung function preceding ILA diagnosis may illuminate early mechanisms of lung injury. METHODS: We recruited participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Study, a prospective cohort of adults enrolled at ages 18–30 years and followed longitudinally for 25 years. Percent predicted forced vital capacity (ppFVC) was measured at five study visits over 20 years. Individual ppFVC trajectories were estimated using random coefficient models. Person-specific slopes were incorporated into logistic regression models to examine associations with visually detected ILA on chest CT at exam year 25. Models were adjusted for age, sex, race, body mass index, pack-years of smoking, and study center. RESULTS: Among 3,136 participants with complete data, 57 (1.8%) had ILA at mean age 51 years. In univariable and multivariable models, individuals with ILA had greater cumulative decline in ppFVC over the 20 years preceding diagnosis. Each 10% absolute decline in ppFVC was associated with more than twice the odds of ILA (adjusted OR 2.21, 95% confidence interval 1.47–3.31, p = 0.0001). CONCLUSIONS: Greater longitudinal decline in FVC from early adulthood was strongly associated with the presence of ILA at midlife. These findings suggest that physiologic impairments precede radiologic evidence of subclinical parenchymal lung abnormalities, underscoring the potential of life course lung function trajectories to identify individuals at risk for developing ILD.
Respiratory-physiology modeling of therapeutic hydrogen inhalation: defining the fraction of inspired hydrogen (FiH) and flow-rate requirements.
LeBaron TW, Ohno K, Salomez-Ihl C … +4 more , Cinquin P, Boucher F, Sano M, Kheir JN
Respir Res · 2026 Apr · PMID 42050516 · Full text
BACKGROUND: Molecular hydrogen (H gas) has emerged as a promising therapeutic agent with reported benefits across oxidative stress, inflammation, cardiovascular, and neurodegenerative conditions. Among administration rou...
BACKGROUND: Molecular hydrogen (H gas) has emerged as a promising therapeutic agent with reported benefits across oxidative stress, inflammation, cardiovascular, and neurodegenerative conditions. Among administration routes, inhalation provides direct systemic delivery but has been hindered by a lack of individualization, methodological inconsistencies, misinterpretation of concentration, and safety concerns. We propose that , defined at the airway opening rather than by source gas concentration (H) or flow rate, should be considered the standardized metric for dosing, akin to oxygen therapy. This directly links inspired H at the airway opening to resulting blood concentrations via Dalton’s and Henry’s laws, thereby enabling consistent dosing, interpretation of clinical data, and comparability across studies. METHODS: A targeted analysis of experimental and clinical literature was used to identify H concentration ranges associated with minimum and optimal biological effects. Deterministic respiratory-physiology in silico modeling was then used to estimate the FiH during nasal cannula H administration under practical breathing conditions, accounting for minute ventilation, inspiratory flow dynamics, and duty cycle, and to derive H flow-rate requirements. RESULTS: Evidence indicates that therapeutic effects typically require blood concentrations of ~2–10 µM, corresponding to ~1% FiH; whereas optimal FiH remains elusive with trends favoring 2% over 4% in some settings and possibly the reverse in others. Use of H source gas exceeding 4% introduces intrinsic flammability risk that scales with flow rate, particularly if FiH exceeds 4%, and should be avoided. Modeling suggests that ~200–300 mL/min absolute hydrogen achieves ~1% FiH via nasal cannula in average adults, whereas higher flows (~600–1200 mL/min) may be required for 2–4% and may still fail to reach 1%. Thus, flow rate cannot reliably ensure a precise or therapeutic FiH. In order to truly determine and provide minimum/optimal H concentrations, researchers must measure or estimate and report the specific FiH based on the provided equations. CONCLUSIONS: FiH provides the only physiologically meaningful metric for hydrogen dosing because it determines airway partial pressure and tissue concentrations. Flow rate or device concentration alone cannot predict delivered FiH. Standardizing FiH as the reported dosing metric will improve reproducibility, enable study comparisons, and personalized, safe dosing.
HLA-DRA-mediated inhibition of T-Cell proliferation by differentiated airway epithelium and its disruption in smoking-associated airway inflammation.
Zeng J, Peng L, Yi Q … +3 more , Chen X, Li X, Zhou H
Respir Res · 2026 Apr · PMID 42046125 · Full text
BACKGROUND: HLA-DRA molecule is expressed in human airway epithelial cells (HAECs), but its specific functions remain unclear. This study mainly focused on HLA-DRA molecule’s contribution to the effect of airway epitheli...
BACKGROUND: HLA-DRA molecule is expressed in human airway epithelial cells (HAECs), but its specific functions remain unclear. This study mainly focused on HLA-DRA molecule’s contribution to the effect of airway epithelium on T-cell proliferation. METHODS: HLA-DRA expression and its dynamics during airway epithelial differentiation were assessed in human tissues (immunohistochemistry/immunofluorescence) and air-liquid interface (ALI) cultures (TaqMan qPCR, Western blotting, immunofluorescence). We employed a co-culture model to evaluate the regulatory effect of differentiated airway epithelium on T-cell proliferation, with HLA-DRA’s role tested via neutralizing antibodies. The impact of cigarette smoke extract (CSE) on HLA-DRA and T-cell proliferation was examined. We further explored the therapeutic potential of restoring HLA-DRA by overexpressing its transcriptional regulator, POU domain class 2–associating factor 1(POU2AF1, also known as OCA-B or BOB.1/OBF.1). We also validated key findings using public single-cell RNA sequencing data. FINDINGS: Both in vivo and in vitro analyses confirmed that HLA-DRA expression is significantly upregulated during HAEC’s differentiation, with high levels detected in apical ciliated and secretory cells but minimal in basal cells. In the co-culture model, well-differentiated HAECs (ALI-day 21) potently suppressed the proliferation of pre-activated T cells, whereas undifferentiated cells (ALI-day 0) did not. This immunosuppressive effect was contact-dependent and was partially but significantly reversed by pre-treating HAECs with anti-HLA-DRA blocking antibodies. Exposure to CSE downregulated HLA-DRA expression in differentiated HAECs and, concurrently, attenuated their capacity to inhibit T cell proliferation. CSE reduced the expression of the transcription factor POU2AF1, and lentiviral overexpression of POU2AF1 partially rescued HLA-DRA expression in smoke-exposed epithelium. CONCLUSIONS: Our findings indicate a novel immunoregulatory function of airway epithelium, wherein HLA-DRA partially mediates the contact-dependent suppression of activated T cell proliferation, which may contribute to mucosal immune balance. Cigarette smoke disrupts this “epithelial brake” mechanism via downregulation of the POU2AF1–HLA-DRA axis, promoting excessive T cell expansion. These results implicate the POU2AF1–HLA-DRA axis in smoking-associated airway inflammation and highlight its potential as a therapeutic target for immune modulation in chronic airway diseases.
CB2 receptor agonist JWH133 attenuates hyperoxia-induced acute lung injury by inhibiting ferroptosis via GPX4 upregulation.
Chu SJ, Liao WI, Pao HP … +2 more , Wu SY, Tang SE
Respir Res · 2026 Apr · PMID 42046071 · Full text
BACKGROUND: Activation of the cannabinoid type 2 (CB2) receptor has been demonstrated to offer protective effects against various inflammatory conditions and tissue injuries across different organs. Ferroptosis, a form o...
BACKGROUND: Activation of the cannabinoid type 2 (CB2) receptor has been demonstrated to offer protective effects against various inflammatory conditions and tissue injuries across different organs. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been increasingly recognized as a contributor to the severity of acute lung injury (ALI). However, the precise role of CB2 receptor activation in hyperoxia-induced acute lung injury (HALI) remains poorly defined. METHODS: This study investigated the effects of JWH133, a selective CB2 receptor agonist, using both in vivo animal models and in vitro cellular models exposed to hyperoxia conditions. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected at the end of the experiments for analyses, and animal survival rates were recorded throughout the experimental period. Concurrently, mouse lung epithelial cells (MLE-12) were cultured under hyperoxia conditions. To specifically elucidate the role of GPX4, siRNA-mediated knockdown was employed in both animal and cellular models, providing a detailed assessment of its functional relevance. RESULTS: Treatment with JWH133 significantly improved survival rates, reduced pulmonary edema, and markedly decreased inflammatory cytokine levels, oxidative stress markers, and indicators of ferroptosis in hyperoxia-exposed models. Furthermore, JWH133 effectively inhibited NF-κB signaling and reduced cell death in lung tissues, accompanied by enhanced expression of glutathione peroxidase 4 (GPX4). Consistent with these in vivo findings, hyperoxia-exposed MLE-12 cells treated with JWH133 exhibited similar protective effects. Notably, the protective effects of JWH133 were negated when GPX4 expression was silenced using targeted siRNA in both animal and cellular models. CONCLUSION: Our findings suggest that JWH133 confers protection against HALI primarily by upregulating GPX4 expression, highlighting its potential as a promising therapeutic strategy for HALI.
SCFAs inhibited NETosis to alleviate lung inflammation in COPD: a potential role for GPR43.
Tang S, Cai L, Hao Y … +5 more , Jiang Q, Luan X, Fang X, Li Z, Zhu J
Respir Res · 2026 Apr · PMID 42046064 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and poses a significant socioeconomic burden attributable to its high mortality and morbidity. Short-chain fatty aci...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and poses a significant socioeconomic burden attributable to its high mortality and morbidity. Short-chain fatty acids (SCFAs), as the key metabolites produced by gut microbiota, have been considered to be involved in the regulation of pulmonary inflammation. However, the underlying bridging mechanisms through the gut-lung axis remain elusive. METHODS: To delineate cellular heterogeneity during COPD progression, we profiled lung tissues from rats at distinct stages (Days 0, 7, 14, and 28) using scRNA-seq, followed by bulk transcriptomic analysis to pinpoint critical dysregulated pathways. Gas chromatography-mass spectrometry (GC-MS) was employed to quantify the differential SCFA levels. The protective effects of SCFAs against pulmonary inflammation in COPD were evaluated via pulmonary function testing, HE staining, and ELISA. Flow cytometry, Western blotting, immunofluorescence and scanning electron microscopy were employed to explore the mechanism of SCFAs regulating neutrophil extracellular trap (NET) formation in vitro and in vivo. Finally, metagenomic sequencing was applied to investigate the impact of SCFAs on gut microbial communities. RESULTS: ScRNA-seq demonstrated the intense immune activation during the progress of COPD, characterized by neutrophil accumulation exceeding 50% of cellular composition on the 14th day in the lung tissue. Transcriptomic analysis further pinpointed neutrophil-driven NETosis as the key pathogenic pathway. The results of GC-MS showed the significant downregulation of SCFAs represented by acetic acid and propionic acid in COPD. Exogenous supplementation with SCFAs (acetic acid and propionic acid) activated the key receptor GPR43, suppressed the expression of NETs marker proteins (NE, MPO, and CitH3) and attenuated inflammatory cytokine levels in COPD rats. Rescue experiments with NETs inducers/inhibitors and GPR43 agonists/antagonists further elucidated the regulatory mechanisms of SCFAs/GPR43 axis in COPD inflammation. Furthermore, metagenomic sequencing revealed that SCFAs reshaped the intestinal flora in COPD by enriching the abundance of beneficial bacteria. CONCLUSION: As one of the key receptors for gut microbiota-derived SCFAs, GPR43 may be involved in the process by which SCFAs alleviate pulmonary inflammation in COPD through regulating NET formation. These findings provide valuable experimental evidence for promoting the clinical translation of therapeutic strategies characterized by gut microbiota and their metabolites.
Unsupervised comprehensive CT imaging clusters reveal distinct morphological phenotypes in asthma: insights from two prospective cohorts.
Hayashi Y, Tanabe N, Sato A … +18 more , Hirano T, Iwamoto H, Maetani T, Shiraishi Y, Sakamoto R, Sunadome H, Fukatsu-Chikumoto A, Otani T, Higaki N, Amano Y, Okimoto T, Yamane M, Yokoyama A, Date H, Sato S, Hattori N, Matsunaga K, Hirai T
Respir Res · 2026 Apr · PMID 42046063 · Full text
BACKGROUND: Asthma is a heterogeneous disease with diverse underlying structural abnormalities. Comprehensive evaluation of computed tomography (CT)-derived features may uncover novel morphological phenotypes with clinic...
BACKGROUND: Asthma is a heterogeneous disease with diverse underlying structural abnormalities. Comprehensive evaluation of computed tomography (CT)-derived features may uncover novel morphological phenotypes with clinical relevance. This study aimed to identify and validate the morphological phenotypes of asthma using comprehensive inspiratory and expiratory CT features and assess their associations with clinical outcomes. METHODS: We analyzed two independent prospective asthma cohorts (Kyoto asthma cohort, n = 223; PACTAS study, n = 94) and a cross-sectional healthy control cohort (n = 88). Quantitative CT measures—airway morphology, mucus plugs, parenchyma, extrapulmonary structures, and pulmonary arteries—were quantified. Unsupervised clustering using these parameters was performed separately in each asthma cohort. Associations with lung function, type 2 inflammation, symptom burden, and exacerbations were examined. RESULTS: Four reproducible morphological phenotypes were identified. Cluster 1 (airway remodeling) was characterized by reduced airway lumen area (LA), and lower total airway count (TAC), along with higher mucus plug scores and elevated small airway dysfunction (SAD%) measured from inspiratory and expiratory lung density. Patients were older, had a longer asthma duration, and exhibited a lower forced expiratory volume in 1 s to forced vital capacity ratio (FEV₁/FVC). Cluster 2 (airway dilatation) showed enlarged LA, higher modified Reiff scores, and increased TAC. Patients tended to be younger, with a shorter disease duration and preserved lung function. Cluster 3 (metabolic abnormality) was characterized by reduced pectoralis muscle density and higher body mass index, and included predominantly female patients. This cluster was associated with a lower %FVC and greater symptom burden. Cluster 4 (parenchymal-dominant) consisted mainly of male smokers with emphysematous changes and higher SAD%, who exhibited lower FEV₁/FVC. Across both cohorts, Clusters 2–4 had exacerbation rates similar to or higher than in Cluster 1 in both unadjusted and adjusted analyses. CONCLUSIONS: Comprehensive CT-based clustering revealed four reproducible morphological phenotypes of asthma—airway remodeling, airway dilatation, metabolic abnormality, and parenchymal-dominant—each associated with distinct structural and clinical features. These findings underscore the morphological heterogeneity of asthma and suggest that CT-based phenotyping may support more precise phenotype-specific treatment strategies.
ABTB1 modulates EGFR signaling and confers icotinib sensitivity in lung adenocarcinoma.
Li SY, Xia L, Xu P … +5 more , Li GH, Yang BC, Wu JX, Zhang FX, Lian JB
Respir Res · 2026 Apr · PMID 42046060 · Full text
BACKGROUND: Icotinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used in the treatment of EGFR-mutant lung adenocarcinoma (LUAD). However, heterogeneous responses...
BACKGROUND: Icotinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used in the treatment of EGFR-mutant lung adenocarcinoma (LUAD). However, heterogeneous responses and the development of resistance limit durable clinical benefit. The molecular regulators that modulate EGFR signaling output and influence cellular sensitivity to icotinib remain incompletely defined. METHODS: An integrative discovery framework was implemented by combining genome-wide CRISPR–Cas9 functional screening under icotinib selection pressure with RNA sequencing analyses performed under basal and icotinib-treated conditions. Candidate regulators were prioritized through multi-layer integration of functional dependency, transcriptional response, and disease-context expression data. Clinical associations were evaluated using public LUAD datasets. Functional validation was performed using cell proliferation assays, dose–response analyses, and biochemical approaches. Protein interaction and signaling mechanisms were examined using immunoprecipitation–mass spectrometry, co-immunoprecipitation, immunofluorescence, and molecular docking analyses. RESULTS: Integrated functional and transcriptomic analyses identified ABTB1 as a candidate regulator associated with icotinib response. ABTB1 expression was reduced in LUAD and correlated with aggressive tumor features and unfavorable overall survival. Functionally, ABTB1 overexpression enhanced cellular sensitivity to icotinib, as evidenced by suppressed proliferation, leftward shifts of dose–response curves, and reduced IC50 values. Proteomic profiling identified EGFR as a prominent ABTB1-associated protein, which was further validated by biochemical and spatial co-localization analyses. Mechanistically, ABTB1 overexpression attenuated EGFR phosphorylation and downstream STAT3 and NF-κB signaling, accompanied by coordinated transcriptional remodeling of gene programs related to stress response, inflammatory signaling, and cell fate regulation. CONCLUSIONS: This study identifies ABTB1 as a non-mutational regulator of EGFR signaling that modulates cellular sensitivity to icotinib in LUAD. By integrating functional screening, transcriptomic network analysis, and mechanistic validation, our findings reveal a receptor-proximal control layer shaping icotinib response and highlight ABTB1 as a potential biomarker and modulatory factor in icotinib-treated LUAD.
Long-term health outcomes in elderly COPD patients with long COVID: a 2-year prospective cohort study.
Li S, Zhao H, Zhang M … +6 more , Yuan T, Li X, Shen Z, Qin C, Li Y, Pan M
Respir Res · 2026 Apr · PMID 42045916 · Full text
BACKGROUND: Elderly chronic obstructive pulmonary disease (COPD) patients often face long-term adverse health issues post-COVID-19, but longitudinal and comprehensive assessments are limited. The study aimed to assess 2-...
BACKGROUND: Elderly chronic obstructive pulmonary disease (COPD) patients often face long-term adverse health issues post-COVID-19, but longitudinal and comprehensive assessments are limited. The study aimed to assess 2-year trajectories of both self-reported symptoms and lung function in elderly COPD patients after SARS-CoV-2 infection and to explore potential molecular mechanisms underlying long COVID progression through serum proteomic analysis. METHODS: This longitudinal cohort study followed up elderly COPD patients at 1, 1.5, and 2 years post-COVID-19. Patients were assigned to the Control or Long-COVID group based on the presence of new-onset and significant fatigue. They completed questionnaires, pulmonary function tests, routine laboratory tests, and serum proteomic analysis. RESULTS: Patients in the Long-COVID group consistently experienced a heavier symptom burden throughout the follow-up period, including lower EQ-VAS scores, higher mMRC and CAT scores, and experienced more frequent adverse events. Several parameters of both pulmonary ventilation function and small airway function were lower in the Long-COVID group at 1-year and 1.5-year follow-ups. Although not statistically significant, the Long-COVID group showed slightly poorer diffusion capacity at all three follow-up visits. The phenomenon of lung function improvement at the 1.5-year follow-up, which was conducted in summer, was not observed in the Long-COVID group. Additionally, at the 2-year follow-up, serum proteomic analysis revealed upregulation of blood coagulation and platelet activation, as well as complement system dysregulation in patients with long COVID. Proteins associated with coagulation and thrombosis (FLNA, FN1, ITGA2B, FGB, and ITGB3) and complement system (C8A, C8B, VTN, C3, and CFH) were identified as hub differentially expressed proteins (DEPs). CONCLUSION: Elderly COPD patients with long COVID showed a persistently greater symptom burden and more frequent adverse outcomes, even up to two years post-infection. These individuals exhibited worse pulmonary ventilation function, particularly at the first and second follow-up visits, along with slightly lower diffusion capacity throughout all three follow-up visits. Disordered coagulation, platelet activation, and complement system may be the underlying molecular mechanisms and therapeutic targets.
Integration of blood protein-metabolic profiles via machine learning to enable the accurate early detection of non-small cell lung cancer.
Shi H, Sun J, Wei H … +8 more , Tang J, Zhou X, Li H, Wang J, Li L, Sun F, Zhao J, Zhang S
Respir Res · 2026 Apr · PMID 42045902 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC) poses a major threat to human health due to its high morbidity and mortality. Early accurate diagnosis and differential diagnosis from other respiratory diseases, are pivota...
BACKGROUND: Non-small cell lung cancer (NSCLC) poses a major threat to human health due to its high morbidity and mortality. Early accurate diagnosis and differential diagnosis from other respiratory diseases, are pivotal to improving patient prognosis. This study aimed to construct an NSCLC diagnostic model based on multidimensional datasets by leveraging machine learning (ML) driven feature selection and classification algorithms, clarifying the diagnostic value of blood protein metabolic profiles, and provide a novel non-invasive diagnostic scheme for clinical practice. METHODS: A total of 144 lung cancer patients (LC), 132 healthy controls (HCs), and 130 patients with other respiratory diseases (ORDs) were recruited from three medical centers. A panel of 26 serum protein metabolism indicators and demographic variables was included as candidate features. Five feature-selection algorithms were used to identify core variables from the high-dimensional data. Ten ML classifiers were subsequently constructed, and their performance was comprehensively evaluated using metrics such as the area under the receiver operating characteristic curve (AUC), accuracy, positive precision, negative precision, positive recall, negative recall, F1 score, and Cohen’s kappa. Moreover, SHapley Additive exPlanations (SHAP) analysis was performed to decipher key predictive factors. RESULTS: Significant differences were observed in 21 serum protein metabolic indicators across the LC, HC, and ORD cohorts (p < 0.05). Among the tested algorithms, LightGBM emerged as the superior model for early detection of NSCLC, outperforming logistic regression, SVM, and ANN. It yielded the highest performance metrics, including an AUC of 0.867, positive recall of 0.977, and F1 score of 0.807. Notably, the model minimized both missed and false-positive diagnoses-a crucial factor for clinical utility-while demonstrating robust generalizability (AUC > 0.840 across all datasets). Furthermore, SHAP analysis identified age as the top predictor of NSCLC, followed by Glu, His, ApoB, FN, ApoA2, and Arg. CONCLUSIONS: In this study, a stable, high-performance LightGBM model for NSCLC diagnosis was developed, and key clinical metrics and probability-based outputs were optimized. This model is expected to enhance early detection and differential diagnosis, thereby helping reduce lung cancer morbidity and mortality.
Tracking the evolution of biomarker efficacy in SARS-CoV-2: a global meta-analyses series.
Shuvo MR, Schwiening M, Avramidis N … +12 more , Soares F, Feng O, Abreu S, Veale N, Thomas W, Thompson AAR, Samworth RJ, Morrell NW, Semple MG, Baillie K, Marciniak SJ, Soon E
Respir Res · 2026 Apr · PMID 42045892 · Full text
BACKGROUND: Sophisticated prognostic scores have been proposed for SARS-CoV-2 but do not always perform consistently. We performed this systematic review to discover why and to investigate the impact of vaccination and v...
BACKGROUND: Sophisticated prognostic scores have been proposed for SARS-CoV-2 but do not always perform consistently. We performed this systematic review to discover why and to investigate the impact of vaccination and viral variants. METHODS: We searched the PubMed database for the keywords ‘SARS-CoV-2’ or ‘Covid19’ with ‘biomarker’ and ‘mortality’ for the baseline tranche (01/12/2019–30/06/2021) and either ‘SARS-CoV-2’ or ‘Covid19’ with ‘biomarker’ and either ‘vaccination’ or ‘variant’ from 01/12/2020 to 31/10/2023. To aggregate the data, the library in R was used, and a random effects model fitted to obtain pooled AUCs and 95% confidence intervals. RESULTS: We screened 4,688 potential source manuscripts and included 144 in the final analyses. Biomarker effectiveness varies significantly by geographical region. Admission CRP levels were a good prognostic marker for mortality due to wild-type virus in Asian countries, with a pooled area under curve (AUC) of 0.83 (95%CI 0.80–0.85), but only an average predictor of mortality in Europe/Northern America, with a pooled AUC of 0.67 (95%CI 0.63–0.71, < 0.0001). The same pattern applies to D-dimer and IL-6. Notably, urea and troponin had pooled AUCs ≥ 0.78 regardless of location, implying that end-organ damage at presentation was a key prognostic factor in wild-type SARS-CoV-2 infection. CRP, D-dimer, and IL-6 have generally declined in effectiveness in the vaccinated and variant cohorts. We note a significant lag from the pandemic advent to data availability and that the type of data varied considerably between studies. CONCLUSION: Biomarkers and prognostic scores should be tailored to populations. It is imperative that the infrastructure for collecting clinical data should be put in place ahead of a future pandemic so that data harvesting, collation and analysis can occur in a robust and timely manner to aid clinical decision making. TRIAL REGISTRATION: This study was registered with PROSPERO (CRD42022366893). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03656-9.
Cardiovascular components of the COTE index predict acute exacerbations and healthcare costs in patients with chronic obstructive pulmonary disease: a nationwide linked cohort study.
Kwon E, Yoon WS, Moon JY … +4 more , Hwang YI, Yoo KH, Kim YY, Kim Y
Respir Res · 2026 Apr · PMID 42026638 · Full text
BACKGROUND: The COPD-specific CO-morbidity Test (COTE) index is an established predictor of mortality in patients with chronic obstructive pulmonary disease (COPD), but its prognostic value for acute exacerbations and he...
BACKGROUND: The COPD-specific CO-morbidity Test (COTE) index is an established predictor of mortality in patients with chronic obstructive pulmonary disease (COPD), but its prognostic value for acute exacerbations and healthcare costs remains unclear. In particular, the impact of cardiovascular diseases on these clinical outcomes is poorly understood in Asian patients with COPD. Therefore, we aimed to assess the associations between baseline cardiovascular diseases within the COTE index and acute exacerbations and healthcare costs over a 1-year follow-up. METHODS: We analyzed data from 2,474 patients with stable COPD from the Korean COPD Subgroup Study linked to the national Health Insurance Review and Assessment Service claims. Associations between baseline cardiovascular components within the COTE index and clinical outcomes were assessed using zero-inflated negative binomial and gamma regression models. To further evaluate the independent effect of cardiovascular components, stratified analyses by COTE risk group were performed. RESULTS: Comorbidities were highly prevalent (95.4%), with cardiovascular diseases being the most common. Among cardiovascular disease, myocardial infarction (MI) and ischemic stroke were significant predictors of severe exacerbations during the 1-year follow-up. Higher COTE index was significantly associated with increased healthcare costs. Notably, ischemic stroke, coronary artery disease (CAD) and congestive heart failure showed the strongest association with higher healthcare costs. In stratified analyses, MI and ischemic stroke predicted severe exacerbations only in the high-risk COTE group, whereas CAD and ischemic stroke were linked to increased healthcare costs across all COTE groups. CONCLUSIONS: Baseline cardiovascular comorbidities within the COTE index are independently associated with severe exacerbations and increased healthcare costs in patients with COPD over a 1-year follow-up. Collectively, these results support the clinical utility of the COTE index, especially cardiovascular diseases, in identifying high-risk patients for exacerbations and healthcare costs in COPD.
The dynamic landscape of alternative splicing during silicosis progression.
Luo J, Ou S, Wang X … +6 more , Wang YY, Yang L, Jiang J, Xu J, Zhu G, Chen S
Respir Res · 2026 Apr · PMID 42026633 · Full text
BACKGROUND: Silicosis is a severe occupational pulmonary fibrosis disease caused by silica dust inhalation, characterized by persistent inflammation and progressive fibrosis. While transcriptomic studies have identified...
BACKGROUND: Silicosis is a severe occupational pulmonary fibrosis disease caused by silica dust inhalation, characterized by persistent inflammation and progressive fibrosis. While transcriptomic studies have identified numerous genes dysregulated, molecular mechanisms extend beyond mere changes in gene expression levels. Recent evidence suggests that post-transcriptional regulatory mechanisms, particularly alternative splicing (AS), may play crucial roles in fibrotic processes. However, AS dynamics and functional significance in silicosis remain largely unexplored. METHOD: To investigate AS in silicosis pathogenesis, we analyzed RNA sequencing (RNA-Seq) data from a mouse model, delineating the dynamic landscape of gene expression and AS events across disease stages. AS events were classified into two categories: those correlated with and independent of gene expression changes. We integrated single-cell RNA sequencing (scRNA-seq) data to precisely map the cell type-specific expression patterns of these events. Through this analysis, we identified critical AS events, whose dynamic regulation and functional relevance during silicosis progression were validated using in vivo and in vitro models. RESULTS: A total of 26,232 high-confidence AS events were identified, with Skipping Exon (SE) being the predominant type (75.6%, 19,832/26,232). These splicing events were derived from 7,524 parental genes, with 72% (5,422) harboring at least two events, indicating widespread splicing complexity. 1,363 (5.2%) high-confidence events were significantly regulated across disease stages, with 88 Differentially Expressed Alternative Splicing (DEAS) events exhibiting a substantial splicing shift (absolute delta Percent Spliced In (PSI) greater than 0.2). Strikingly, only 11.4% (10/88) of these DEAS events showed concordant gene-level changes, while a substantial proportion (88.6%, 78/88) occurred despite stable gene level expression. Parental genes were enriched in silicosis-related pathways, including smooth muscle cell migration, actin bundle assembly and the small GTPase-mediated signal transduction. Integrated scRNA-seq helped map expression to specific cell types and prioritize validation targets. The dynamic regulation of three top targets, including Clec4e- Retained Intron (RI), Wdr37- Alternative First Exon (AFE), and Tns3-AFE, was validated in mouse models. In vitro functional experiments showed that Clec4e isoforms (RI and non-RI) possess distinct functional properties; dysregulation of Clec4e-RI may relieve inflammatory inhibition. These results suggest a potential regulatory role of AS reprogramming in silicosis pathogenesis and indicate Clec4e splicing events as a possible target for inflammation regulation. CONCLUSION: This study presents a landscape of AS in silicosis, demonstrating that AS constitutes a critical layer of pathological regulation distinct from transcriptional alterations. We identified and validated that the Clec4e-RI splicing isoform may play a key role in the silicosis pathogenesis by modulating macrophage-related inflammatory responses.
Diagnostic yield and safety of needle-based COnfocaL LAser endomicroscopy and ultrasound-guided pleural BiOpsy in diagnosing patients with unknown pleuRAl effusion: a protocol for a mulTIcenter, randomized cONtrolled trial (COLLABORATION-II).
Zheng Z, Ye S, Liu X … +6 more , Xiao K, Deng M, Tong R, Porcel JM, Wang T, Hou G
Respir Res · 2026 Apr · PMID 42026599 · Full text
BACKGROUND: The diagnosis of exudative pleural effusion is challenging. Although ultrasound-guided pleural biopsy (UGBx) is common, its effectiveness varies, especially in the absence of pleural abnormalities. New imagin...
BACKGROUND: The diagnosis of exudative pleural effusion is challenging. Although ultrasound-guided pleural biopsy (UGBx) is common, its effectiveness varies, especially in the absence of pleural abnormalities. New imaging techniques have been explored to improve UGBx outcomes, but the results remain inadequate. Recently, needle-based confocal laser endomicroscopy (nCLE) has been used to improve biopsy targeting and diagnostic yield through real-time cellular-level imaging; however, robust evidence is lacking. This trial aims to assess the diagnostic yield and safety of nCLE-assisted UGBx for unknown exudative pleural effusions. METHODS: COLLABORATION-II is a multicenter randomized controlled study in China involving 324 participants across ten centers. Participants will be divided into two groups based on the ultrasound findings: Group 1 with pleural thickening (> 5 mm) and/or pleural nodularity, and Group 2 with thickness ≤ 5 mm and no nodularity. Each group will be randomly assigned to either the nCLE-assisted UGBx or UGBx arm at a 1:1 ratio, with a 12-month follow-up. The primary outcome is the overall diagnostic yield, while secondary outcomes include the biopsy success rate, diagnostic sensitivity for specific diseases, complication in incidence, and specimen characteristics, such as size, quality, interpretability, and adequacy for achieving molecular diagnosis. DISCUSSION: We hypothesize that the nCLE-assisted UGBx will achieve higher diagnostic yield than conventional UGBx by providing real-time, cellular-level visualization and targeted sampling of pathological areas. If this hypothesis is validated, nCLE-assisted UGBx could emerge as a novel and effective option for diagnosing patients with unknown exudative pleural effusion. TRIAL REGISTRATION: This study has been registered at www.clinicaltrials.gov (Registration number: NCT07040241; Registration Date: 2025-06-26).
A prospective cohort study for characterization and predictive factors of long-term POST-COVID interstitial changes.
Hernandez-Argudo M, Bordas-Martinez J, Vicens-Zygmunt V … +32 more , Bermudo G, Suarez-Cuartin G, Del Rio B, Bolivar S, Jofre-Grimaldo H, Llatjós R, Pijuan L, Climent F, Gutierrez Y, López-Monzoni S, Sabater J, Fuset MP, Perez-Fernandez XL, Planas R, Gasa M, Moreno A, Robles-Perez A, Balcells E, Badenes D, Barril S, Gonzalez J, Portillo K, Millan-Billi P, Menendez R, Valenzuela C, Santos S, Montes-Worboys A, Fuentes M, Peñafiel J, Lagarda A, Luburich P, Molina-Molina M
Respir Res · 2026 Apr · PMID 42021247 · Full text
INTRODUCTION: Chronic interstitial lung changes are potential long-term sequelae of severe COVID-19. This study aims to evaluate the prevalence and type of interstitial changes over time and identify serum biomarkers ass...
INTRODUCTION: Chronic interstitial lung changes are potential long-term sequelae of severe COVID-19. This study aims to evaluate the prevalence and type of interstitial changes over time and identify serum biomarkers associated with persistent lung abnormalities. METHODS: Prospective, multicenter, observational cohort study of patients with severe COVID-19 pneumonia between March 2020 and June 2021. Clinical evaluation, pulmonary function tests (PFTs), and chest high-resolution computed tomography (HRCT) were performed at baseline and up to 24 months. Serum biomarkers were assessed at baseline and at 12 months. RESULTS: Of the 290 patients enrolled, 247 completed the follow-up. Mild dyspnea (mMRC1) was the most common residual symptom. PFTs showed significant improvement: mean FVC increased from 88.8% to 99.5%, and DLCO from 71.6% to 82%. Among patients with baseline DLCO < 80% (n = 67), only 38.8% achieved normalization. Radiological improvement was observed in all patients, though 32% of the 118 patients assessed at 24 months still had residual changes, primarily mild reticulation, ground glass opacities, and lower lobes traction bronchiectasis. Pulmonary functional improvement correlated with radiological resolution, especially during the first year. Elevated baseline levels of MMP-7 and KL6 were associated with persistent interstitial abnormalities at 12 months. CONCLUSION: Severe COVID-19 survivors exhibit progressive functional and radiological improvement, particularly within the first year. However, a subset of patients shows long-term interstitial changes. Elevated MMP-7 and KL-6 levels may help identify individuals at higher risk for persistent interstitial changes.
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