Respir. Res. [JOURNAL]
Sun
200 papers
Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer.
Lin J, Xia G, Wu Y … +6 more , Chen L, Zhang Y, Ma Y, Yin JC, Zhang Z, Pan X
Respir Res · 2026 May · PMID 42174600 · Full text
BACKGROUND: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC) and can emerge as an acquired drug resistance mechanism to MET, EGFR or ALK inhibitors. The clinical and ge...
BACKGROUND: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC) and can emerge as an acquired drug resistance mechanism to MET, EGFR or ALK inhibitors. The clinical and genomic features of METΔex14 in NSCLC require further characterization. METHODS: Our study included a total of 585 patients with METΔex14 + NSCLC, comprising 556 baseline samples, 53 samples from patients exhibiting resistance to MET inhibitors, and 16 samples from patients resistant to EGFR/ALK inhibitors. Genomic data from targeted next-generation sequencing (NGS) of tissue and/or plasma samples using GeneseeqPrime™ (a 425 pan-cancer gene panel) were analyzed. RESULTS: Overall, METΔex14 exhibited a prevalence of 1.02% (n = 585) in the screened NSCLC population, with a higher incidence in patients with a sarcomatoid histology. METΔex14 was predominantly detected at the splice donor site, though the non-coding region adjacent to the splice acceptor site contributed considerably to the complexity of METΔex14. Common concurrent alterations identified at baseline included those in TP53 (40.8%), CDK4 (16%) and EGFR (12.4%). Concurrent MET amplification and cell cycle pathway mutations were both associated with worse outcomes in patients treated with crizotinib, with significant co-occurrences observed also among these concurrent genomic variations. In addition, increased chromosomal instability and intra-tumoral heterogeneity correlated with a poorer response to crizotinib. Mechanisms of acquired resistance to MET inhibitors were primarily attributed to on-target MET D1228X/Y1230X mutations or off-target alterations within genes in the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways. Intriguingly, our exploratory analysis also identified the FGFR3::TACC3 fusion as a potential resistance mechanism to savolitinib. Moreover, METΔex14 was identified in 16 patients following progression on EGFR and ALK inhibitors, highlighting the need for developing tailored therapeutic strategies to overcome resistance. CONCLUSIONS: This study provides a comprehensive characterization of METΔex14 in NSCLC, revealing its dual role as a primary driver of oncogenesis and a potential resistance mechanism to EGFR/ALK inhibitors. The identification of concurrent genetic alterations and potential resistance mechanisms enhances our molecular understanding of treatment responses. These findings highlight the need for further investigation into targeted therapies that consider the genomic complexity of METΔex14 to improve treatment efficacy and patient outcomes.
Recent advances in pulmonary fibrosis: from lung surfactant to the immune connection.
Losada-Oliva P, Autilio C, Olmeda B … +6 more , Carbone T, Gilio M, Pafundi V, Aloisio E, Panteghini M, Perez-Gil J
Respir Res · 2026 May · PMID 42174593 · Full text
Pulmonary fibrosis (PF) encompasses a heterogeneous group of progressive interstitial lung diseases characterized by aberrant wound healing, extracellular matrix accumulation, and irreversible architectural remodeling of...
Pulmonary fibrosis (PF) encompasses a heterogeneous group of progressive interstitial lung diseases characterized by aberrant wound healing, extracellular matrix accumulation, and irreversible architectural remodeling of the lung. This review provides a comprehensive overview of the clinical spectrum, epidemiology, and genetic predisposition underlying PF, followed by an in-depth analysis of key molecular and cellular mechanisms driving fibrogenesis, including epithelial injury, dysregulated repair, profibrotic signaling pathways, and immune-mediated processes. Particular emphasis is placed on the role of lung surfactant dysfunction in fibrosis development, highlighting alterations in surfactant composition, metabolism, and associated genetic variants that contribute to epithelial stress and disease progression. The review also evaluates established and emerging circulating biomarkers, including serum proteins linked to epithelial damage, extracellular matrix remodeling, and immune activation, with attention to their diagnostic and prognostic utility. Finally, current and evolving therapeutic strategies are discussed in the context of progressive fibrosing phenotypes. Despite significant advances in understanding PF pathobiology, substantial gaps remain in early detection, disease stratification, and targeted treatment, underscoring the urgent need for improved translational approaches and precision medicine strategies.
Qingre Runzao oral liquid and its key compound ophiopogonin D inhibit CXCL9 and block CXCL9/CXCR3 axis to ameliorate asthma by suppressing RAS/ERK pathway.
Jiang L, Li H, Bao W … +5 more , Zhang A, Guo S, Sun J, Li D, Wei D
Respir Res · 2026 May · PMID 42169113 · Full text
BACKGROUND: Qingre Runzao oral liquid (QRRZ) is a Chinese medicine prescription. Previous studies have confirmed its good therapeutic effect on bronchial asthma (BA), but the mechanisms remain unclear. This study aims to...
BACKGROUND: Qingre Runzao oral liquid (QRRZ) is a Chinese medicine prescription. Previous studies have confirmed its good therapeutic effect on bronchial asthma (BA), but the mechanisms remain unclear. This study aims to clarify the anti-BA effect and mechanisms of QRRZ, and further reveal the key compounds of QRRZ that ameliorate BA. METHODS: Firstly, the BA model mice were used to evaluate the therapeutic effect of QRRZ on BA. Then, RNA-seq analysis was performed to reveal the key targets and mechanisms of QRRZ in ameliorating BA, and the results were verified by RT-PCR and Western Blotting. Molecular docking, molecular dynamics simulation, and CETSA were used to screen the key compounds of QRRZ in ameliorating BA. The potential of key compounds on BA was evaluated in vitro. Finally, the mechanisms were verified, and a rescue experiment was conducted. RESULTS: QRRZ can ameliorate bronchial pathological changes and airway hyperresponsiveness, alleviate the progression of BA by reducing inflammatory cell infiltration, especially neutrophils. QRRZ significantly inhibits the expression of MUC5AC and Th2-related cytokines IL-6 and IL-13 in BALF solution and upregulates the Th1-related cytokine IL-2. RNA-seq results showed QRRZ mainly blocks CXCL9/CXCR3 axis and inhibits RAS/ERK pathway activation to ameliorate BA, and CXCL9 is the key protein of QRRZ. Molecular docking and molecular dynamics simulation results showed that Ophiopogonin D (Oph D) can bind to CXCR3 (CXCL9 receptor) tightly. CETSA and CO-IP assays confirm that Oph D can bind stably to CXCR3. Then, Oph D exhibited potent anti-BA efficacy both in vitro and in vivo. Furthermore, results indicated Oph D can down-regulate CXCL9 and block the CXCL9/CXCR3 axis to inhibit RAS/ERK pathway activation in 16HBE cells. CONCLUSION: QRRZ could block the CXCL9/CXCR3 axis to inhibit RAS/ERK pathway activation, reduce neutrophil infiltration in bronchioles, and improve bronchial asthma. Among these, Oph D is the key component of QRRZ in ameliorating BA.
Prenatal non-infectious mild stressor modulates early-life lung development in a time-specific manner.
Dong Y, Hadzic S, Leidner A … +4 more , Marega M, Rivetti S, Ehrhardt H, Bellusci S
Respir Res · 2026 May · PMID 42169098 · Full text
BACKGROUND: Maternal exposure to various insults during pregnancy can influence early-life organ development. Whether this applies to seemingly mild stressors remains unclearly defined. Better understanding of the nature...
BACKGROUND: Maternal exposure to various insults during pregnancy can influence early-life organ development. Whether this applies to seemingly mild stressors remains unclearly defined. Better understanding of the nature and strength of prenatal exposure factor to trigger fetal programming effect in the lung may help to optimize perinatal-neonatal health care. METHODS: Pregnant wild type C57BL/6J mice were randomized at 15.5 day post coitum (dpc) or 18.5 dpc to intraperitoneal (i.p.) injection of sterile physiological saline. Mice undergoing a natural process of pregnancy without any intervention served as blank controls. Newborn mice were euthanized at postnatal day 1 for lung harvests. Lung tissues were subjected to Weigert staining to visualize elastic fiber distribution and quantify total parenchymal cells. Additionally, qPCR, immunofluorescence staining and western blot were performed to assess the expression of signature markers of the lung epithelium and other compartments. RESULTS: No adverse perinatal outcomes occurred except a non-significant reduction in maternal weight gain after i.p. injection of sterile physiological saline. Pups demonstrated similar birth weights across groups. The total number of lung parenchymal cells increased in exposed pups compared with blank controls, with no significant difference in elastin fiber distribution. Enhanced macrophage infiltration with predominant type 2 cytokine responses was observed in newborn mice lungs following maternal i.p. injection of saline. There was an elevated surfactant protein C (Sftpc) expression in alveolar type 2 (AT2) cells in the 15.5 dpc exposure group compared to blank controls. No sex-dependent difference was demonstrated in Sftpc expression. Correlational analysis of signature gene expression indicated crosstalk between AT2 cells and other lung cellular compartments. The expression of stem cell antigen (Sca1) in lung mesenchymal progenitor cells demonstrated a time-related response without sex differentiation upon prenatal exposure to maternal i.p. injection of sterile physiological saline. CONCLUSIONS: Results of this preclinical study in newborn mice contribute to current understanding of fetal programming by showing that maternal exposure to even non-infectious mild stressors before birth is able to modulate early-life lung development. This underscores an intensified sensibility of unborn fetus to seemingly harmless low-magnitude maternal stressors.
S100A9 deletion ameliorates acute lung injury by attenuating excessive neutrophil activation via activating the NRF2/HO-1 signaling axis.
Yin S, Hu X, Cai H … +3 more , Jiang R, Li J, Cheng Y
Respir Res · 2026 May · PMID 42169076 · Full text
BACKGROUND: Acute lung injury (ALI) is a complex and life-threatening condition. In severe cases, ALI can progress to acute respiratory distress syndrome (ARDS), which is associated with high mortality. It is characteriz...
BACKGROUND: Acute lung injury (ALI) is a complex and life-threatening condition. In severe cases, ALI can progress to acute respiratory distress syndrome (ARDS), which is associated with high mortality. It is characterized by diffuse pulmonary parenchymal inflammation and refractory hypoxemia. Neutrophils, as pivotal immune cells in the lungs, play a critical role in the development and progression of ALI. This study aimed to determine whether S100A9 deletion alleviates LPS-induced ALI by modulating neutrophil activation through the NRF2/HO-1 signaling axis. METHODS: We established an ALI model using LPS in both wild-type (WT) and S100A9 gene knockout (KO) mice to assess pulmonary inflammation and oxidative stress. Lung injury severity, inflammation, oxidative stress status, neutrophil accumulation, and NET formation were evaluated in vivo, and bone marrow-derived primary neutrophils were exposed to LPS in vitro to examine their activation characteristics and antioxidant capacity. RESULTS: S100A9 KO significantly ameliorated lung tissue injury, edema, and inflammatory cell infiltration, and improved mouse survival rates. Mechanistically, S100A9 knockout alleviates acute lung injury by activating the NRF2 signaling pathway, which in turn downregulates neutrophil activation and the production of NETs. CONCLUSION: Our findings indicate that S100A9 deletion attenuates neutrophil activation and oxidative stress and may alleviate LPS-induced ALI through activation of the NRF2/HO-1 signaling pathway.
Single-cell N4-acetylcytidine regulatory landscape identifies ARIH1 as a ferroptosis-suppressive oncogenic driver in lung adenocarcinoma.
Tang M, Li G, Wang L … +3 more , Jian Y, Teng C, Tu J
Respir Res · 2026 May · PMID 42169065 · Full text
BACKGROUND: N4-acetylcytidine (ac4C) is an emerging post-transcriptional RNA modification implicated in cancer biology, yet its cellular distribution, prognostic value, and functional relevance in lung adenocarcinoma (LU...
BACKGROUND: N4-acetylcytidine (ac4C) is an emerging post-transcriptional RNA modification implicated in cancer biology, yet its cellular distribution, prognostic value, and functional relevance in lung adenocarcinoma (LUAD) remain insufficiently characterized. This study aimed to systematically define the ac4C-related regulatory landscape in LUAD and identify functionally and clinically relevant targets. METHODS: A single-cell RNA-sequencing dataset comprising 87,634 cells was reanalyzed to quantify ac4C-related gene (acRG) activity across major cellular compartments using AUCell scoring. Prognostic acRGs were identified through differential expression analysis and univariate Cox regression, followed by integrative machine-learning modeling using LASSO and random survival forest algorithms. The biological function of ARIH1 was examined through cell proliferation assays, ferroptosis-related biochemical measurements, and mechanistic analyses including cycloheximide chase, co-immunoprecipitation, and ubiquitination assays. RESULTS: Epithelial cells displayed the highest acRG activity within the LUAD tumor ecosystem. A prognostic acRG-based signature was established, identifying ARIH1 as a high-risk factor associated with unfavorable survival outcomes. ARIH1 knockdown significantly inhibited LUAD cell growth and tumorigenic potential. Mechanistically, ARIH1 interacted with NCOA4 and promoted its K48-linked ubiquitination and proteasomal degradation, thereby suppressing ferritinophagy and ferroptosis. ARIH1 loss resulted in iron accumulation, lipid peroxidation, glutathione depletion, and ferroptotic cell death. Additionally, ARIH1 depletion markedly enhanced cisplatin-induced ferroptosis. CONCLUSIONS: These findings map the single-cell ac4C regulatory architecture of LUAD and identify ARIH1 as a ferroptosis-suppressive E3 ubiquitin ligase, highlighting a potential therapeutic target to enhance ferroptosis-based and chemotherapy-based interventions.
The role of the RS1-NEDD4-YAP1 axis orchestrates epithelial-macrophage interplay in COPD.
Zhong Z, Cao C, Jia H … +2 more , He W, Xia S
Respir Res · 2026 May · PMID 42169001 · Full text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by persistent airflow limitation and is a leading cause of morbidity and mortality worldwide. While cigarette smoking is...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by persistent airflow limitation and is a leading cause of morbidity and mortality worldwide. While cigarette smoking is the primary environmental risk factor, only a subset of smokers develops clinically significant COPD, indicating roles for genetic susceptibility and dysregulated cellular responses. Although traditionally viewed as an immune-driven inflammatory disease, recent evidence underscores the active contribution of structural cells-particularly alveolar type II epithelial cells (AT2 cells)-to immune regulation and tissue remodeling. METHODS: This study integrated single-cell transcriptomics, conditional gene knockout mouse models, organoid culture, multiplex immunofluorescence validation, and flow cytometry to investigate the role of the RS1 gene in chronic obstructive pulmonary disease (COPD). Single-cell sequencing technology revealed RS1 as a signature gene of AT2 cells. Using cigarette smoke (CS)-exposed AT2 cell-specific RS1 knockout mice and organoids as models, we elucidated the mechanisms by which RS1 regulates AT2 cells and its associated role in COPD pathogenesis through molecular experiments. RESULTS: Single-cell RNA sequencing analysis revealed that RS1 is specifically expressed in AT2 cells in COPD models, and its expression exhibits interactions with immune cells. By constructing a COPD mouse model with AT2 cell-specific RS1 knockout (Sftpc;RS1) and organoid models, we demonstrated that RS1-deficient AT2 cells display enhanced proliferative capacity and suppress macrophage infiltration. Mechanistically, RS1 mediates the interaction between NEDD4 and YAP1 through serine 105, while the RS1-NEDD4 interaction facilitates YAP1 dephosphorylation and nuclear translocation. Treatment with the selective NEDD4 inhibitor I3C further suppressed TGFB1 expression and macrophage infiltration. CONCLUSION: RS1 suppresses AT2 cell proliferative capacity and promotes macrophage infiltration. RS1 interacts with NEDD4 to mediate YAP1 dephosphorylation and nuclear translocation, and treatment with the selective NEDD4 inhibitor I3C further suppresses TGFB1 expression and macrophage infiltration.
Th2 cytokine-induced mucociliary remodeling in chronic rhinosinusitis: implications for antiviral defense and epithelial function.
Theorell J, Drnevich J, Jovanovic Gasovic S … +3 more , Lawate B, Lee VS, Veiga-Lopez A
Respir Res · 2026 May · PMID 42168989 · Full text
Chronic rhinosinusitis (CRS) is a sinonasal inflammatory disease, often complicated by aberrant Th2-driven immunologic responses and increased susceptibility to viral infections. Th2-induced epithelial remodeling has bee...
Chronic rhinosinusitis (CRS) is a sinonasal inflammatory disease, often complicated by aberrant Th2-driven immunologic responses and increased susceptibility to viral infections. Th2-induced epithelial remodeling has been proposed to facilitate viral entry and replication, thereby increasing susceptibility to infection and exacerbating inflammation in CRS. This exploratory study investigated if chronic Th2-mediated remodeling alters the transcriptional response to rhinoviral infection between individuals with and without CRS. We hypothesized that Th2 cytokine exposure of human primary nasal epithelial cells during their differentiation disrupts mucociliary function, impairing the antiviral response to rhinovirus. Primary nasal epithelial cells from patients with and without CRS were differentiated at air-liquid interface while being exposed to Th2 cytokines (IL-4, IL-13, or IL-4/13; 10 ng/mL) followed by a rhinovirus (RV-A16) infection. RNA sequencing and inflammatory cytokine profiling revealed significant downregulation of pathways involved in cilia structure, development, and function, as well as lower rhinovirus reads in Th2 cytokine-exposed cultures, with similar trends observed in CRS and non-CRS samples. Chronic Th2 cytokine exposure also altered cytokine release, shifting toward an anti-inflammatory profile. Notably, sex-specific differences were observed in unexposed cultures, with male-derived cultures exhibiting higher levels of inflammatory cytokines and accompanying more inflammatory transcriptomic profiles, thus highlighting intrinsic sex-specific immune variability. These findings underscore how Th2 cytokine-driven epithelial remodeling may compromise mucociliary function and antiviral defenses across CRS and non-CRS cultures. Understanding these mechanisms may inform therapeutic strategies aimed at restoring epithelial integrity and mitigating chronic inflammation.
Epithelial CD155-TIGIT/CD226 signaling links CD8⁺ T-cell exhaustion to frequent exacerbations in COPD.
Wang D, Li H, Zhao Z … +8 more , Zhao J, Hai X, Fan Y, Ma W, Chen J, Ge X, Duan X, Hou J
Respir Res · 2026 May · PMID 42168982 · Full text
BACKGROUND: The immune mechanisms underlying chronic obstructive pulmonary disease (COPD) remain incompletely understood, particularly regarding immune checkpoint dysregulation. This cross-sectional observational study a...
BACKGROUND: The immune mechanisms underlying chronic obstructive pulmonary disease (COPD) remain incompletely understood, particularly regarding immune checkpoint dysregulation. This cross-sectional observational study aimed to determine whether activation of the T-cell immunoglobulin and ITIM domain (TIGIT) pathway contributes to CD8-positive T-cell exhaustion and susceptibility to frequent exacerbations in COPD. METHODS: We integrated publicly available single-cell RNA sequencing data from human lung tissue with analyses of peripheral blood, bronchoalveolar lavage fluid, and lung tissue obtained from patients with COPD and healthy controls. Flow cytometry was used to assess CD8-positive T-cell differentiation and expression of TIGIT and its co-stimulatory counterpart CD226, while immunohistochemistry quantified the TIGIT ligand CD155 in airway and alveolar epithelium. Functional assays, including cytokine production, apoptosis, and lentiviral TIGIT knockdown, were conducted to evaluate the reversibility of TIGIT-mediated exhaustion. RESULTS: Single-cell and flow-cytometric analyses revealed an expansion of terminally differentiated effector memory CD8-positive T cells re-expressing CD45RA with high TIGIT expression in COPD, particularly among frequent exacerbators. CD155 was upregulated in airway and alveolar epithelial cells, whereas CD226 expression on CD8-positive T cells was reduced. TIGIT-positive CD8-positive T cells exhibited decreased tumour necrosis factor-alpha and interferon-gamma production and increased apoptosis. TIGIT knockdown restored cytokine secretion and reduced apoptosis, indicating a reversible exhausted phenotype. CONCLUSION: The TIGIT-CD155/CD226 pathway is associated with epithelial stress, CD8⁺ T-cell exhaustion and frequent exacerbations in COPD. Targeting this immune checkpoint may help restore antiviral immunity and reduce airway damage, providing a promising therapeutic avenue for immune modulation in chronic airway disease.
Butyrate attenuates house dust mite-induced activation of 16HBE bronchial epithelial cells in association with modulation of gene expression.
Verstegen REM, Hotie J, Bikineeva M … +4 more , van Brummelen S, Garssen J, Folkerts G, Willemsen LEM
Respir Res · 2026 May · PMID 42157237 · Full text
INTRODUCTION: The airway epithelial barrier is the primary defense line of the lungs against allergens, such as house dust mite (HDM). A disrupted airway epithelial barrier plays a major role in asthma development. Short...
INTRODUCTION: The airway epithelial barrier is the primary defense line of the lungs against allergens, such as house dust mite (HDM). A disrupted airway epithelial barrier plays a major role in asthma development. Short-chain fatty acids (SCFAs) are bacterial fermentation products that are associated with prevention against allergic inflammation. In this study, we aim to elucidate the direct preventative effects of SCFAs, particularly butyrate, on the HDM-induced bronchial epithelial cell (BEC) activation and barrier disruption in-vitro. MATERIALS AND METHODS: Immortalized human 16HBE cells were exposed to HDM to simulate allergen-induced BEC inflammation. Pre-exposure of 1-1000 µM acetate, propionate or butyrate were studied for their ability to prevent epithelial activation. Histone deacetylase activity of cells was measured after pre-incubation with 100 or 200 µM butyrate and combined butyrate and HDM exposure. In a transwell, air-liquid interface (ALI)-culture, the effects of 100 µM butyrate on barrier integrity (transepithelial resistance (TEER) and 4 kDa FITC-dextran permeability) and inflammation were assessed in presence and absence of HDM. To gain broader insight in the effects of butyrate, RNA sequencing (RNAseq) was performed using 16HBE cells exposed to HDM, butyrate or both. RESULTS: Pre-incubation with butyrate protected against the production of HDM-induced IL-8 (1-100 µM), CCL5 (1-100-1000 µM) and CCL20 (1-10-100 µM) by solid phase cultured 16HBE-cells, although 1000 µM butyrate increased IL-8 and CCL20 release. Pre-incubation with acetate and propionate showed similar effects. 100 µM butyrate did not suppress HDAC activity, while a dose of 200 µM butyrate did. In ALI-culture, HDM increased barrier permeability, and pre-incubation with 100 µM butyrate tended to prevent this. Additionally, HDM-induced CCL20 production was significantly decreased by butyrate. RNAseq revealed 100 µM butyrate to significantly affect biological processes of the cells linked to gene expression, mitochondrial function, cell division and cell signaling. These effects were observed both in absence and presence of HDM-exposure. CONCLUSION: Butyrate, at physiologically relevant doses, modulates gene expression of 16HBE cells, affecting amongst others post-transcriptional and mitochondrial pathways. In ALI-cultures, butyrate prevented epithelial activation (CCL20) and tended to prevent HDM-induced barrier defects. These findings highlight the relevance of SCFAs such as butyrate in maintaining bronchial epithelial cell homeostasis relevant for prevention and control of allergic airway disease.
Snhg18 promotes hypoxic pulmonary hypertension by enhancing glycolysis.
Qu T, Ma K, Du Q … +7 more , Zhang C, Shen Z, Wang E, Chen Z, Chen P, Liu Y, Zhang R
Respir Res · 2026 May · PMID 42152052 · Full text
BACKGROUND: Pulmonary hypertension (PH) is a life-threatening vascular disorder characterized by progressive pulmonary vascular remodeling. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) play vital r...
BACKGROUND: Pulmonary hypertension (PH) is a life-threatening vascular disorder characterized by progressive pulmonary vascular remodeling. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of PH. In this study, we aim to clarify the role of lncRNA small nucleolar RNA host gene 18 (Snhg18) in pulmonary vascular remodeling and investigate its underlying mechanisms. METHODS: Differential gene expression was detected by qRT-PCR and Western blot assays. CCK-8, EdU, transwell assays, and the in vivo pulmonary hypertension model were used to investigate the effect of Snhg18 on pulmonary hypertension. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, RNA pull-down, and transcriptome sequencing were employed to explore the mechanism by which Snhg18 functions in pulmonary hypertension. RESULTS: LncRNA Snhg18 is upregulated in pulmonary artery smooth muscle cells (PASMCs) and lung tissues under hypoxic conditions. Inhibition of Snhg18 attenuates cell proliferation in vitro and in vivo. Mechanistically, copy number amplification promotes the expression of Snhg18 at the genomic level, and the transcription factor Sp1 activates Snhg18 transcription by binding to its promoter. Furthermore, Snhg18 interacts with the m6A "reader" protein heterogeneous nuclear ribonucleoprotein A2/B1 (Hnrnpa2b1), thus increasing the stability of enolase 3 (Eno3) mRNA in an m6A-dependent manner. The elevation of Eno3 augments glycolysis in PASMCs, thus promoting cell proliferation and vascular remodeling. CONCLUSIONS: Our study demonstrates the important role of Snhg18/Hnrnpa2b1/Eno3 axis in pulmonary vascular remodeling, and provides a potential novel therapeutic target for PH.
Inhibition of macrophage migration inhibitory factor attenuates bleomycin-induced murine pulmonary fibrosis via the MAPK pathway.
Wang J, Zhao W, Dilixiati N … +3 more , Wang Y, Song Y, Ye Q
Respir Res · 2026 May · PMID 42143357 · Full text
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease marked by excessive extracellular matrix deposition and deteriorating lung function. Although macrophage migration inhibitory factor (MIF)...
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease marked by excessive extracellular matrix deposition and deteriorating lung function. Although macrophage migration inhibitory factor (MIF) has been implicated in pulmonary fibrosis, the downstream mechanisms-particularly whether MIF drives fibrosis through its receptor CD74-remain insufficiently understood. This study investigated whether MIF/CD74 signaling promotes fibroblast activation through specific downstream pathways that regulate proliferation and matrix production. METHODS: Single-cell RNA sequencing and ELISA were used to characterize MIF-CD74 interactions and circulating MIF levels in IPF patients. Bleomycin-induced fibrosis models were established using C57BL/6J mice, Mif⁻/⁻ mice, and the MIF inhibitor 4-IPP. Macrophage-fibroblast co-culture systems were treated with bleomycin, 4-IPP, or CD74 shRNA. Lung injury, fibrosis, and signaling activation were assessed by histology, qRT-PCR, Western blotting, and functional assays. RESULTS: scRNA-seq identified MIF-CD74 as a dominant macrophage-fibroblast signaling axis in fibrotic lungs, and serum MIF levels were elevated in IPF patients. In mice, bleomycin markedly increased MIF and CD74 expression and activated MAPK signaling. Genetic deletion or pharmacologic inhibition of MIF attenuated collagen deposition, improved lung architecture, and reduced profibrotic and inflammatory signaling. In vitro, MIF promoted fibroblast proliferation, migration, and matrix synthesis, whereas CD74 knockdown or MIF inhibition significantly attenuated fibroblast profibrotic responses. CONCLUSIONS: MIF promotes pulmonary fibrosis by activating CD74-dependent MAPK signaling in fibroblasts, enhancing their proliferation and extracellular matrix production. Targeting the MIF/CD74 axis reduces tissue remodeling and represents a promising therapeutic strategy for IPF.
OGDH primes macrophage for M1-like polarization and ferroptosis in sepsis associated acute lung injury.
Chen L, Li R, Qin H … +5 more , Jiang Y, Jiang Q, Li Y, Li Y, Jiang J
Respir Res · 2026 May · PMID 42143323 · Full text
BACKGROUND: Sepsis-associated acute lung injury (S-ALI) is a clinical syndrome characterized by dysregulated inflammation and overwhelming oxidative stress, and is associated with a poor prognosis. Alpha-ketoglutarate de...
BACKGROUND: Sepsis-associated acute lung injury (S-ALI) is a clinical syndrome characterized by dysregulated inflammation and overwhelming oxidative stress, and is associated with a poor prognosis. Alpha-ketoglutarate dehydrogenase (OGDH) is a key enzyme in the tricarboxylic acid cycle that catalyzes the oxidative decarboxylation of α-ketoglutarate (α-KG) to succinyl-CoA, a critical step linking mitochondrial energy metabolism to immune response. However, the mechanism by which OGDH participates in S-ALI remains unclear. METHODS: The mouse model of sepsis was established via intraperitoneal injection of lipopolysaccharide (LPS), and CPI-613 was administered intraperitoneally prior to LPS challenge. Peripheral blood samples and baseline characteristics were collected from septic patients. In vitro, BMDMs were used to evaluate the therapeutic effects of CPI-613. Using untargeted metabolomics (LC-MS), RNA sequencing transcriptomics (RNA-seq), macrophage-specific small interfering Nrf2 RNA (si-Nrf2), and enzyme-linked immunosorbent assay (ELISA), we assessed lung tissue pathology, inflammatory cytokine levels, ferroptosis markers, OGDH enzyme activity, and clinical correlation. RESULTS: In LPS-induced septic mice, we observed systemic metabolic changes characterized by decreased α-KG levels and increased OGDH enzyme activity. Intraperitoneal administration of the OGDH inhibitor CPI-613 attenuated acute lung injury and systemic inflammation, thereby improving survival. Flow cytometry revealed that CPI-613 suppressed M1-like polarization of alveolar macrophages in septic mice, a finding corroborated in vitro. Transcriptomic profiling indicated that CPI-613 treatment preferentially modulated ferroptosis and glutathione metabolic pathways in LPS-treated bone marrow-derived macrophages (BMDMs). In both LPS-challenged mice and BMDMs, CPI-613 reduced ferroptosis biomarkers and activated the Nrf2-mediated antioxidant axis. Critically, genetic silencing of Nrf2 via siRNA or pharmacological inhibition with ML385 eliminated the anti-ferroptotic effects of CPI-613, positioning Nrf2 as a central mediator of this protection. Serum from patients with sepsis-associated ARDS exhibited significantly elevated OGDH enzyme activity relative to healthy controls. Moreover, OGDH activity correlated strongly with disease severity and clinical outcomes, including septic shock and death. CONCLUSION: Overall, our study reveals that OGDH is a key immunometabolism regulator and a novel biomarker in S-ALI, and its inhibitor CPI-613 may represent a potential therapeutic target for this condition.
Integrative bioinformatics and machine learning reveal an association of LTF and MMP8 with systemic inflammation and lung injury.
He J, Wei Y, Wu Y … +6 more , Wang W, Xu M, Zhou X, Zhu S, Li X, Tang H
Respir Res · 2026 May · PMID 42141451 · Full text
BACKGROUND: Acute lung injury and its severe form, acute respiratory distress syndrome (ARDS), represent life-threatening conditions with high mortality rates. Since the lung is the primary target organ in systemic infla...
BACKGROUND: Acute lung injury and its severe form, acute respiratory distress syndrome (ARDS), represent life-threatening conditions with high mortality rates. Since the lung is the primary target organ in systemic inflammatory conditions like sepsis, this study aimed to identify key regulatory genes by analyzing systemic inflammation-related transcriptomic data, and to explore their roles in lung injury. METHODS: We performed bioinformatic screening on the GSE32707 dataset (systemic inflammation patients vs. controls) using differential expression analysis, WGCNA, and machine learning. Functional enrichment, PPI network, immune infiltration, ceRNA network, and molecular docking analyses were conducted. Validation was carried out using human samples, cell-based assays, and murine lung injury models. RESULTS: We identified 506 differentially expressed genes, predominantly enriched in immune-related pathways. Machine learning algorithms prioritized lactoferrin (LTF) and matrix metalloproteinase-8 (MMP8) as key genes. Co-IP assays demonstrated a physical association between LTF and MMP8. A predicted ceRNA network suggested post-transcriptional regulation of LTF, while molecular docking indicated binding potential of LTF/MMP8 with methylprednisolone. Experimental validation confirmed that both genes are upregulated during lung injury and can be modulated by anti-inflammatory treatment. CONCLUSION: LTF and MMP8 play critical roles in lung injury, potentially serving as molecular connectors between systemic inflammation and pulmonary damage, and represent promising therapeutic targets for further investigation.
The adult nasal mucosa is defined by distinct immune profiles that modulate in-vitro SARS-CoV-2 infection.
Gowanlock SN, Lam VHK, Tepe ZG … +15 more , Park DE, Tai V, Salazar JE, Pham T, Khan Y, Nelson S, Horn C, Zuanazzi D, Yang D, Price LB, Kaul R, Sowerby L, Troyer RM, Liu CM, Prodger JL
Respir Res · 2026 May · PMID 42135777 · Full text
BACKGROUND: The nasal mucosa is the primary entry site for many respiratory viruses, and immune molecules present at the time of exposure may dictate if infection occurs. However, the baseline immune state in healthy adu...
BACKGROUND: The nasal mucosa is the primary entry site for many respiratory viruses, and immune molecules present at the time of exposure may dictate if infection occurs. However, the baseline immune state in healthy adults - and how it influences susceptibility to viruses - remains poorly defined. METHODS: Levels of 16 immune molecules were measured in nasal secretions from two independent cohorts of healthy adults (total n = 166, Luminex). Participants were clustered based on normalized concentrations of immune analytes to identify profiles. An in vitro organotypic model of the nasal epithelium was used to examine the effect of immune profiles on SARS-CoV-2 infection: primary human nasal epithelial cells (n = 9 donors) were grown at air-liquid interface to induce mucociliary differentiation (42 days), treated with recombinant human cytokines (72 h), and then challenged with wildtype SARS-CoV-2 Omicron BA.1 (24 h). SARS-CoV-2 entry factor expression (post-cytokines, pre-challenge) and viral infection (N gene) were measured by qRT-PCR. RESULTS: In both cohorts, a unique cluster was observed, characterized by distinctly high levels of antiviral interferons - particularly IFN-λ3 - with comparatively low levels of inflammatory chemokines and cytokines. In contrast, individuals with high overall levels of inflammatory mediators had absent IFN-λ3. In vitro, pretreatment with IFN-λ3 and IFN-α2, but not with pro-inflammatory cytokines, significantly reduced SARS-CoV-2 replication in differentiated nasal epithelial cultures, despite upregulating ACE2 expression. CONCLUSIONS: Healthy adults exhibit distinct nasal immune profiles, with an exogenous IFN-λ3-dominant, low-inflammatory state conferring resistance to SARS-CoV-2 in an in vitro primary nasal epithelial model. The nasal immune milieu may influence susceptibility to respiratory viruses and the efficacy of mucosally administered vaccines.
Quantitative label-free multiphoton imaging of collagen features predicts disease severity and progression in idiopathic pulmonary fibrosis.
Liu W, Sun Y, Zhao L … +8 more , Wang S, Zhou G, Wang S, Xie S, Geng J, Xie B, Wang A, Dai H
Respir Res · 2026 May · PMID 42135759 · Full text
OBJECTIVE: The prognostic value of deep-tissue microstructure profiling derived from transbronchial lung cryobiopsy (TBLC) specimens in idiopathic pulmonary fibrosis (IPF) remains poorly explored. This study aims to brid...
OBJECTIVE: The prognostic value of deep-tissue microstructure profiling derived from transbronchial lung cryobiopsy (TBLC) specimens in idiopathic pulmonary fibrosis (IPF) remains poorly explored. This study aims to bridge this gap by quantitatively extracting collagen features in heterogeneous pathological regions using multiphoton microscopy (MPM), and providing novel insights into the potential of collagen features as sensitive biomarkers for predicting severity and disease progression in IPF. METHODS: In this prospective and observational study, a total of 82 patients with IPF undergoing TBLC and 22 healthy controls were enrolled. The differences in collagen features between the normal/mild and moderate/severe groups were compared. Multivariate logistic regression was used to identify collagen features associated with disease progression. RESULTS: Histopathologically, 62.2% of the cohort exhibited a probable usual interstitial pneumonia (UIP) pattern. PERMANOVA indicated pronounced divergent collagen topographies among the five pathological regions (F = 14.14, R = 0.233, P = 0.001). Collagen features in histologically appeared normal regions exhibited significant collagen micro-remodeling compared to healthy controls (P = 0.01). Specifically, in advanced regions comprised of destructive regions and honeycombing regions, the anisotropy index (P < 0.001), eccentricity (P = 0.007), and local solidity heterogeneity (P = 0.03) were found to be decreased in comparison to the alveolar preserved fibrotic regions, while the crosslink spacing (P = 0.001) was expanded. In the moderate-to-severe group categorized by FVC% predicted, local orientation heterogeneity was markedly elevated (P = 0.01), and the crosslink spacing expanded (P = 0.008). In the moderate-to-severe group categorized by DLCO% predicted, the collagen fiber complexity network was reduced (P = 0.002). After adjusting for GAP score and antifibrotic therapy, the elevated gabor_l4_th120_mean was independently associated with disease progression (OR = 3.25, P = 0.009). In contrast, increased collagen fiber independent index (OR = 0.27, P = 0.008) and longer collagen fiber length (OR = 0.35, P = 0.03) were identified as protective factors. CONCLUSIONS: MPM imaging successfully mapped the spatial heterogeneity of the fibrotic microenvironment in IPF by quantifying collagen signatures. The morphological and structural features of collagen fibers could serve as promising pathological biomarkers for precisely assessing the severity and progression of IPF.
Nerandomilast attenuates Pantoea agglomerans-induced hypersensitivity pneumonitis by regulating M1 macrophage polarization and fibroblast activation.
Shi Y, Liu Y, Liu Z … +8 more , Chen R, Wang M, Li Z, Chen Q, Shao C, Li X, Zhou H, Huang H
Respir Res · 2026 May · PMID 42135743 · Full text
BACKGROUND: Hypersensitivity pneumonitis (HP) is characterized by bronchiolocentric inflammation and fibrosis. The characteristic pathological features include bronchiolocentric inflammation, peribronchiolar fibrosis, an...
BACKGROUND: Hypersensitivity pneumonitis (HP) is characterized by bronchiolocentric inflammation and fibrosis. The characteristic pathological features include bronchiolocentric inflammation, peribronchiolar fibrosis, and the presence of poorly formed granulomas. Nerandomilast is a novel oral phosphodiesterase 4 (PDE4) inhibitor with good selectivity for PDE4B. PDE4 inhibitors (PDE4i) exhibit anti-inflammatory/antifibrotic properties, the efficacy of nerandomilast remains unexplored in HP. METHODS: We selected macrophages and fibroblasts as effector cells for the inflammatory and fibrotic phases of HP in vitro. And we established in vivo HP models induced by saline extract of the cells of P. agglomerans (SE-PA). RESULTS: The results of the in vitro studies revealed that nerandomilast inhibited the expression of proinflammatory markers (i.e., CD86, iNOS, and IL-1β) of M1 macrophages by increasing CREB phosphorylation and inhibiting the NF-κB signaling pathway. Furthermore, nerandomilast reduced TGFβ1-induced fibroblast activation by inhibiting Smad and non-Smad signaling pathways. In vivo studies confirmed that nerandomilast could reduce the number of inflammatory cells in bronchoalveolar lavage fluid and the secretion of proinflammatory cytokines (such as IL-1β, IL-6, and TNF-α), lower the serum levels of the oxidative stress markers MPO and MDA, and inhibit the transcription of proinflammatory cytokines in lung tissue. Moreover, nerandomilast alleviated pulmonary fibrosis and pulmonary dysfunction in mice with HP induced by SE-PA. CONCLUSION: Our findings indicated that nerandomilast might attenuate inflammation and fibrosis in SE-PA-induced HP mice by regulating macrophage polarization and inhibiting fibroblast activation, which provides new insights for the clinical treatment of HP.
Real-world comparison of shape-sensing robotic-assisted bronchoscopy and virtual bronchoscopic navigation for peripheral pulmonary lesions: a propensity score-matched study.
You M, Li Y, Wang L … +6 more , Li F, Xu S, Xu L, Ren B, Zhang J, Chen E
Respir Res · 2026 May · PMID 42121236 · Full text
BACKGROUND: Robotic-assisted bronchoscopy (RAB) may improve diagnosis of peripheral pulmonary lesions (PPLs), particularly when lesion localization and sampling are technically demanding. However, direct real-world compa...
BACKGROUND: Robotic-assisted bronchoscopy (RAB) may improve diagnosis of peripheral pulmonary lesions (PPLs), particularly when lesion localization and sampling are technically demanding. However, direct real-world comparisons between shape-sensing RAB (ss-RAB) and virtual bronchoscopic navigation (VBN) remain limited. METHODS: We retrospectively reviewed patients who underwent navigational bronchoscopy for PPLs at a single center. Propensity score matching (PSM) was used to balance baseline characteristics between the ss-RAB and VBN groups. Diagnostic yield, tool-in-lesion (TIL) rate, sensitivity for malignancy, adverse events, and learning curves of ss-RAB were evaluated. Learning curves were assessed using cumulative sum analysis based on procedure time and diagnostic success. RESULTS: Following 1:1 PSM, 234 patients were included, with 117 in each group. Final malignancy prevalence was 74.8% overall. Diagnostic yield was higher with ss-RAB than with VBN (85.5% vs. 70.1%; OR 2.39, 95% CI 1.25-4.56). TIL rate was also more frequently achieved with ss-RAB (99.1% vs. 88.9%). Sensitivity for malignancy was 95.6% for ss-RAB compared with 81.2% for VBN. The diagnostic advantage of ss-RAB was most evident in small (< 15 mm), peripheral, bronchus-sign-negative, and upper-lobe lesions, whereas performance was similar in larger or more central nodules. Procedure-related complications were infrequent and comparable between groups. Learning-curve analysis for ss-RAB showed a reduction in procedure time after approximately 23 cases and an earlier improvement in diagnostic success around the 13th case. CONCLUSIONS: In a real-world setting, ss-RAB was associated with higher diagnostic yield and TIL rates compared with the VBN-based comparator arm without compromising safety. The observed benefit of ss-RAB was greater in lesion subgroups with higher procedural difficulty. In experienced centers, procedural performance with ss-RAB improved after a relatively short learning phase.
Increased potential for atherogenic changes in asthma: evidence from transcriptomic studies of arterial endothelial cells.
Johansson MW, Esnault S, Floerke HL … +8 more , Zhang J, Lee KE, Steffan BN, Denlinger LC, Stein JH, Stewart R, Jarjour NN, Tattersall MC
Respir Res · 2026 May · PMID 42121203 · Full text
BACKGROUND: Asthma is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), yet the mechanistic pathways underlying this relationship remain poorly defined. Clinical ASCVD is initiated by a...
BACKGROUND: Asthma is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), yet the mechanistic pathways underlying this relationship remain poorly defined. Clinical ASCVD is initiated by arterial injury, with endothelial dysfunction representing the earliest detectable stage. We aimed to characterize the differential transcriptomic response of naïve arterial endothelial cells (AECs) exposed to serum from individuals with and without asthma, using a novel stem cell-derived AEC model. METHODS: Pluripotent-derived naïve AECs were incubated with serum from individuals with asthma or healthy controls for 6 and 24 h. RNA sequencing was performed on AEC lysates, genes were compared between asthma and healthy control serum treatments, and differentially expressed genes were identified. Functional enrichment and pathway analyses were conducted using DAVID, ShinyGO, and STRING. Statistical significance was determined using false discovery rate (FDR)-adjusted p values to account for multiple comparisons. RESULTS: After 6 h of exposure to asthma serum, genes associated with biological processes of endothelial cell proliferation, angiogenesis, migration, and focal adhesion assembly (FDR-adjusted p = 0.04) were significantly enriched among upregulated genes (compared to among all genes, p = 0.0002, 0.004, and 0.04, respectively). Enriched pathways included adhesion junction, mitogen-activated protein kinase, neurotrophin, hypoxia-inducible factor-1, and Wnt signaling (p = 0.00001, 0.00004, 0.002, 0.002, 0.00001, and 0.01). At both 6 and 24 h, pathways related to lipid and atherosclerosis (p = 0.02), epidermal growth factor (EGF) receptor (p = 0.03 and 0.02 at 6 and 24 h), advanced glycation end products (AGE)-receptor for AGEs (RAGE) (p = 0.03 and 0.001), and Ras (p = 0.04 and 0.03) and Rap1 (p = 0.04 and 0.046) signaling were upregulated. Fibronectin (FN1), a central hub in the STRING network, was the highest expressed among upregulated genes at 6 h. Other central genes included EGF, vascular endothelial growth factor A and fibroblast growth factor receptor 1. CONCLUSIONS: Serum from individuals with asthma, compared to serum from healthy donors, induced gene expression alterations in a novel model of naïve AECs. These transcriptional changes are consistent with early cellular injury, including pathways of lipid-atherosclerosis, endothelial cell activation, adhesion, and AGE-RAGE signaling. These findings indicate that circulating factors in asthma activate arterial endothelial cells to promote early vascular injury.
Wildfire smoke exposure and persistent respiratory symptoms and illness: a retrospective cohort study.
Liu GY, Raffuse S, Miles M … +5 more , Alaniz M, Gigoyan L, Kenyon NJ, Kalhan R, Hertz-Picciotto I
Respir Res · 2026 May · PMID 42121185 · Full text
BACKGROUND: Wildfire smoke is a growing public health hazard yet there is limited evidence on its intermediate or long-term respiratory health effects. Studying the association between wildfire smoke exposure and indicat...
BACKGROUND: Wildfire smoke is a growing public health hazard yet there is limited evidence on its intermediate or long-term respiratory health effects. Studying the association between wildfire smoke exposure and indicators of impaired respiratory health such as persistent respiratory illness and respiratory symptoms can help elucidate the associated risk of developing chronic lung disease. We sought to determine whether wildfire smoke exposure is associated with medically-attended respiratory illness (MARI) and respiratory symptoms persisting beyond the acute wildfire period. METHODS: This was a population-based retrospective cohort study of adults without chronic lung disease aside from self-reported asthma, who reported living in a Northern California community affected by a wildfire in 2018. The primary predictor was mean daily wildfire-dominated fine particulate matter (PM) exposure during a wildfire, estimated based on home and evacuation locations. The primary outcomes were respiratory illness requiring medical attention (MARI) at least one month after the wildfire and any respiratory symptom ("asthma attack," bronchitis, cough, respiratory infection, or wheezing) that persisted to the time of the survey (mean 8.5 months after wildfire). RESULTS: Among 1,381 adults in the study, the mean daily PM exposure during a wildfire was 87.2 μg/m (SD 44.3). After adjustment for demographic covariates, smoking status, asthma, and allergies, one standard deviation higher wildfire-dominated PM2.5 exposure was associated with greater risk of MARI (RR 1.18, 95% CI 1.06 - 1.31, p=0.002) and persistent self-reported asthma attacks (RR 1.28, 95% CI 1.03 - 1.59, p=0.026), but not associated with other persistent respiratory symptoms. Each additional day exposed to PM >125 μg/m (EPA threshold for very unhealthy or hazardous air quality) was associated with an 11% increased risk of future severe MARI leading to emergency room visit or hospitalization (RR 1.11, 95% CI 1.02 - 1. 20, p=0.018). CONCLUSIONS: Exposure to wildfire-dominated PM is associated with increased risk of respiratory illness and symptoms which persist for months beyond the acute wildfire period and may indicate risk of future chronic lung disease. Additional days of exposure to very unhealthy or hazardous range PM levels are associated with increased risk of ongoing respiratory morbidity and emergency healthcare utilization in the adult general population.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe