Ozone (O₃) exposure induces acute airway injury characterized by airway hyperresponsiveness (AHR) and airway mucus hypersecretion (AMH). Oxidative stress and mitochondria-derived reactive oxygen species (mtROS) are key contributors. We investigated and compared the protective mechanisms of N-acetylcysteine (NAC) and the mitochondria-targeted antioxidant Elamipretide (SS-31) in O₃-induced airway inflammation, AHR and AMH. Wild-type C57BL/6J mice received intraperitoneal NAC or SS-31 1 h before a single O₃ exposure. AHR, bronchoalveolar lavage (BAL) inflammatory cells, mucus production and mucin expression, inflammatory mediators, oxidative stress indices, and PI3K/AKT and NLRP3/caspase-1/GSDMD pathway activation were assessed in vivo. BEAS-2B cells were pretreated with NAC, SS-31, or the PI3K/AKT inhibitor LY294002 before O₃ exposure, and pathway activation was evaluate d in vitro. NAC and SS-31 comparably attenuated O₃-induced AHR, reduced BAL inflammatory cell influx, and decreased AMH and MUC5B expression. Both treatments improved redox balance by reducing ROS/mtROS, lowering malondialdehyde (MDA), increasing superoxide dismutase (SOD) activity, and improving GSH/GSSG. NAC and SS-31 also suppressed O₃-induced inflammatory gene expression and inhibited activation of PI3K/AKT and NLRP3/caspase-1/GSDMD signaling in mouse lungs and BEAS-2B cells. PI3K inhibition recapitulated these protective effects in vitro, supporting a mechanistic role for PI3K/AKT signaling during acute O₃ exposure. NAC and SS-31 protect against acute O₃-induced AHR and AMH by alleviating oxidative stress and suppressing PI3K/AKT-driven inflammatory and pyroptotic pathways. Targeting oxidative stress, including mitochondrial ROS, may represent a viable strategy to mitigate airway damage caused by acute O₃ exposure.

Background: Idiopathic pulmonary fibrosis (IPF) has a low incidence but high mortality. Simple prognostic tools for elderly IPF patients in primary care are lacking. This study aimed to develop an accessible nomogram for this population. Methods: A retrospective analysis was conducted on elderly IPF patients from the First Affiliated Hospital of Anhui Medical University (January 2016-February 2023). Early mortality was defined as death within 12 months from diagnosis. A nomogram was developed using predictors identified by univariate and multivariate analyses. To minimize overfitting, we limited the number of predictors to four based on the rule of at least 10 events per variable (39 events). Model performance was assessed using the C-index, calibration curves including the Hosmer-Lemeshow goodness-of-fit test, ROC analysis, and decision curve analysis (DCA). Internal validation was performed using bootstrap resampling (1000 iterations). For missing data, variables with >30% missingness were excluded; for variables with ≤30% missingness, multiple imputation was applied. Risk stratification was performed based on nomogram scores, and survival between groups was compared via Kaplan-Meier analysis. Results: Overall, 83 patients were included. Multivariate analysis identified age, monocyte count, globulin, and DLCO%pre as independent predictors of early mortality. The nomogram incorporating these factors achieved a C-index of 0.846 (optimism-corrected C-index: 0.812 after bootstrap). The AUCs for predicting 1-, 2-, and 3-year overall survival were 0.879, 0.896, and 0.854, respectively. The Hosmer-Lemeshow test showed good calibration (p = 0.42, 0.38, and 0.51 for 1, 2, and 3 years). Kaplan-Meier analysis confirmed significantly worse survival in the high-risk group (p < 0.0001). Conclusions: We developed an accurate and practical nomogram to predict prognosis in elderly IPF patients, offering a useful risk-assessment tool for primary care settings. However, external validation in independent multicenter cohorts is required before clinical implementation. At its current stage, the model should be regarded as hypothesis-generating.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder characterized by persistent airflow limitation, and its pathogenesis is closely associated with cigarette smoke (CS) exposure. Neutrophil extracellular trap (NET) formation contributes critically to airway inflammation and tissue damage in COPD. However, the upstream regulators of NETosis remain poorly defined. In this study, a CS-induced mouse model of COPD was established, and transcriptomic sequencing of lung tissues was performed to identify differentially expressed genes. CXCL3 was significantly upregulated in COPD mouse lungs, a finding confirmed by qPCR, Western blot, and immunofluorescence, which localized CXCL3 predominantly to airway epithelial cells. Analysis of a public human single-cell RNA-seq dataset further validated CXCL3 enrichment in both immune and epithelial cells in COPD lungs. In vitro, knockdown of CXCL3 in BEAS-2B epithelial cells stimulated with cigarette smoke extract (CSE) reduced the ability of these cells to promote NETosis in neutrophil-like HL-60 cells. In vivo functional knockdown of CXCL3 attenuated NETs formation, pulmonary inflammation, and emphysema in CS-exposed mice. Mechanistically, Gene Set Enrichment Analysis (GSEA) revealed enrichment of the MAPK pathway, and Western blot analysis showed that CXCL3 knockdown suppressed CSE-induced phosphorylation of p38, ERK, and JNK. Pharmacological inhibition of each MAPK component (SB203580, U0126, SP600125) phenocopied the effect of CXCL3 knockdown, confirming that CXCL3 acts upstream of MAPK signaling to promote NETs formation. Collectively, this study identifies CXCL3 as a critical regulator of CS-induced NETosis and COPD progression through activation of the MAPK pathway, and highlights epithelial-derived CXCL3 as a promising therapeutic target for COPD intervention.

Introduction:The phase angle (PhA), derived from bioelectrical impedance analysis (BIA), serves as an indicator of cellular health and body composition. While associated with muscle strength and exercise capacity in various conditions, its clinical relevance in chronic obstructive pulmonary disease (COPD) requires further characterization. This study aimed to evaluate the relationship between PhA, muscle strength, and physical function among individuals with COPD. Methods:Between June 2024 and August 2025, 112 male patients with COPD and 20 healthy male controls were enrolled in this cross-sectional study. Assessments included pulmonary function, body composition via BIA, handgrip strength, knee extension strength, walking speed, and other clinical indicators. Relationships were analyzed using multivariable linear and least absolute shrinkage and selection operator (LASSO) regression models. Results:PhA values were significantly lower in COPD patients than in healthy controls. Stratification of COPD patients by PhA revealed that a lower PhA was associated with progressively worse muscle strength, exercise capacity, and other clinical markers. Multivariable linear regression analyses demonstrated that a lower PhA was independently associated with slower walking speed (β = 0.061, p < 0.001) and reduced knee extension strength (β = 1.15, p = 0.002). Furthermore, PhA was selected as a key predictor in a prognostic model for severe physical impairment derived from the LASSO regression analysis. Conclusion:In this cross-sectional study, a lower PhA is independently associated with muscle weakness and impaired physical performance in men with COPD. These findings suggest that PhA may serve as a useful biomarker for assessing nutritional and functional status in this population. However, the cross-sectional design precludes causal inference, and the diagnostic utility of PhA for COPD itself is not established.

Ambient ozone (O3), a ubiquitous oxidant gas and key component of photochemical smog, damages the airway epithelium, provokes oxidative stress, and sustains chronic inflammation, which favors the onset and advancement of chronic obstructive pulmonary disease (COPD). Yet the molecular sensors linking long-term ozone exposure to COPD remain incompletely defined. We examined whether the oxidant-sensitive channel Transient receptor potential ankyrin 1 (TRPA1) mediates ozone-driven murine model of COPD through the Wnt5a/GSK3β/β-catenin pathway. C57BL/6J or TRPA1-deficient mice underwent ozone exposure (2.5 ppm, 3 h/session) every 3 days for 2 months, following administration of either the TRPA1 antagonist A967079 or the Wnt5a/GSK3β/β-catenin inhibitor XAV-939. Similarly, BEAS-2B cells treated with A967079 or XAV-939 or TRPA1-silenced cells were subjected to ozone (1 ppm, 3 h/day) for 4 consecutive days. Oxidative stress, inflammatory responses, emphysematous changes, mitochondrial dysfunction, and airway remodeling were assessed. In addition, gene set variation analysis (GSVA) was used to quantify Reactome Wnt5a/GSK3β/β-catenin pathway activity through public COPD transcriptomic cohorts. Pharmacological inhibition or genetic deficiency of TRPA1 significantly attenuated ozone-induced lung function impairment, and ozone-triggered oxidative stress, emphysematous changes, mitochondrial dysfunction, and airway remodeling. Notably, pharmacological suppression of the Wnt5a/GSK3β/β-catenin pathway using XAV-939 produced comparable protective effects to TRPA1 blockade in both ozone-exposed murine models and BEAS-2B cells. GSVA demonstrated tissue-specific associations between TRPA1 and Wnt5a/GSK3β/β-catenin pathway in COPD patients. TRPA1 mediates crucially ozone-induced COPD through modulation of the Wnt5a/GSK-3β/β-catenin signaling. Therapeutic targeting of both TRPA1 and Wnt5a/GSK3β/β-catenin pathway may represent a promising intervention strategy for ozone-associated COPD pathogenesis. This study elucidates the mechanisms through which ambient O3 impairs respiratory health across the general population.

OBJECTIVES:Perioperative factors can influence planned discharge and survival prediction for lung transplant patients. In this study, we retrospectively analyzed perioperative clinical data of lung transplant recipients and assessed the predictive effects of relevant indexes on timely discharge of patients within 90 days post -transplant. MATERIALS AND METHODS:We conducted a retrospective study on 81 lung transplant patients seen from March 1, 2017, to March 1, 2024, using data from the hospital information system. We used univariate and multi-variate logistic regression, ROC curve analysis, and Kaplan -Meier survival analysis to analyze perioperative indicators. To strengthen the robustness of our findings, we performed external validation. RESULTS:Univariate logistic analysis showed that preoperative hemoglobin, albumin, blood loss, lactic acid, and postoperative hemoglobin were prognostic factors, whereas multivariate logistic analysis showed that postoperative lactic acid was an independent risk factor (P < .05 ). A negative correlation was shown between postoperative hemoglobin and lactate (r = -0.433, P < .001 ). External validation results provided additional confirmation of our study's findings. CONCLUSIONS:Further analysis and exploration with larger cohort studies are needed to enhance the generalizability and reliability of the findings that showed preoperative hemoglobin, albumin levels, blood loss, lactic acid, and postoperative hemoglobin were factors affecting prognosis and that postoperative lactic acid level was an independent risk factor discharge status.

This study aimed to identify the genes associated with the development of lung adenocarcinoma (LUAD) and potential therapeutic targets. Differentially expressed genes (DEGs) were identified by self-transcriptome sequencing of tumor tissues and paracancerous tissues resected during surgery and combined with The Cancer Genome Atlas (TCGA) data to screen for the genes associated with LUAD prognosis. The expression was validated at mRNA and protein levels, and the gene knockdown was used to examine the impact and underlying mechanisms on lung cancer cells. A total of 227 DEGs were identified by transcriptome sequencing, and the 20 DEGs with the most significant differences were used for co-analysis with TCGA data. The findings suggested that KRT16 and ANXA10 might have an important role in the development of LUAD after validating the mRNA and protein expression levels at the cellular level. The knockdown of KRT16 and ANXA10 inhibited the proliferation of lung cancer cells, and the cell cycle was blocked in the G1 phase. The expression of the G1/S–phase cell cycle checkpoint–related proteins cyclin D1 and cyclin E was inhibited by KRT16 and ANXA10 knockdown, respectively. The tumor formation ability decreased after KRT16 or ANXA10 knockdown in vivo. KRT16 and ANXA10 are potential genes regulating the development of LUAD. Also, they may be potential targets for the targeted therapy of LUAD by inhibiting the proliferation of lung cancer cells and blocking the cell cycle by affecting key protein expression levels at cell cycle checkpoints.

Objective Multidrug-resistant tuberculosis (MDR-TB) is a global health threat. Our study aimed to develop and externally validate a nomogram to estimate the probability of MDR-TB in patients with TB. Methods A total of 453 patients with TB in Anhui Chest Hospital between January 2019 and December 2020 were included in the training cohort. In addition, 116 patients with TB from Anhui Provincial Hospital Infection District between January 2015 and November 2023 were included in the validation cohort. Multivariable logistic regression analysis was applied to build a predictive model by combining the feature selected in the least absolute shrinkage and selection operator regression model. The C-index, calibration plot, and decision curve analysis were implemented to evaluate the predictive model’s discrimination, calibration, and clinical practicality. Then, logistic regression and least absolute shrinkage and selection operator (LASSO) models were constructed using R software, and the accuracy, goodness of fit, and stability of the models were verified using the validation cohort. Results Eight variables of patients with TB were selected using the best penalization parameter of the LASSO regression method, and the nomogram was established. The model displayed good discrimination with a C-index of 0.752 and good calibration. A high C-index value of 0.825 could still be reached in the validation cohort. The decision curve analysis demonstrated the clinical value of the model. Conclusion In this study, we constructed the LASSO regression model based on eight clinical traits and outcomes of laboratory tests, providing a novel insight for evaluating MDR-TB.

Acute lung injury (ALI) is characterized by excessive inflammation, oxidative stress, and alveolar epithelial damage, often leading to severe pulmonary dysfunction. Astaxanthin (AST), a natural antioxidant, exhibits anti-inflammatory and cytoprotective properties in various disease models. However, its therapeutic potential and underlying molecular mechanisms in ALI remain poorly understood. A murine model of lipopolysaccharide (LPS)-induced ALI was established and treated with two doses of AST (50 mg/kg and 100 mg/kg). Lung histopathology, fibrosis, cytokine levels, oxidative stress markers, and immunohistochemical features were evaluated. In vitro, LPS-stimulated A549 cells were used to mimic ALI, and AST's effects on oxidative stress, inflammation, pyroptosis, and mitochondrial function were investigated. Network pharmacology and molecular docking identified potential AST targets, followed by functional rescue experiments involving NOD-like receptor protein 3 (NLRP3) or calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) overexpression and site-directed mutagenesis in vivo and in vitro. AST administration significantly improved lung histological structure, reduced collagen deposition and inflammatory cell infiltration, and lowered levels of IL-6, IL-1β, and oxidative stress levels in ALI mice. Mechanistically, AST inhibited calcium (Ca2+) influx and suppressed CaMKIIα expression, leading to downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1, thereby mitigating pyroptosis. Moreover, AST suppressed toll-like receptor 2/myeloid differentiation primary response 88 (TLR2/MyD88) signaling both in vivo and in vitro models. Molecular docking and mutational analyses identified Ser257 on CaMKIIα and Glu313 on TLR2 as shared binding sites for AST, critical for its inhibitory effects on inflammasome activation. Notably, the protective effects of AST were abolished in mice injected with Ser257 or Glu313 mutant constructs, highlighting the essential role of these residues in mediating its actions. AST attenuates LPS-induced ALI by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca2+/CaMKIIα and TLR2/MyD88 pathways. These findings identify AST as a promising therapeutic candidate for ALI and provide new insights into targeting pyroptosis-related pathways in inflammatory lung disease.

Objective: Investigate the expression, regulatory network and function of TFF3 in asthma from a multi-omics perspective through bioinformatics and cellular experiments to provide clues for understanding its molecular mechanisms in asthma. Methods: Downloaded two asthma-related datasets (GSE67472 and GSE147878) from GEO. Conducted differential expression analysis and WGCNA to find common genes related to asthma phenotype and TFF3 expression. Constructed a PPI network to identify key genes interacting with TFF3. Performed GO and pathway enrichment analysis using DAVID. Analyzed the relationship between TFF3 and immune cell infiltration with CIBERSORTx. Used molecular docking to validate interactions. In vitro, induced 16HBE cells with HDM to establish asthma model and detected inflammatory indicators and TFF3 by RT-qPCR and western blotting. Results: TFF3 expression was significantly increased in asthma patients in both datasets. ROC analysis showed good diagnostic specificity and sensitivity. 57 co-expressed genes related to asthma and TFF3 were screened, with 11 genes directly interacting with TFF3 and upregulated. Functional enrichment analysis indicated involvement in asthma-related processes. Immune infiltration analysis showed increased M2 macrophages and mast cells, decreased M1 macrophages, and positive correlation with TFF3. Molecular docking confirmed stable binding. In vitro experiments showed increased inflammation index and TFF3 expression after HDM intervention. Conclusion: The study used bioinformatics and cellular experiments to show TFF3's key roles in asthma pathogenesis in aspects like gene expression, protein interaction, and immune microenvironment. TFF3 may regulate genes like AGR2 and AKT1, affect immune cells, and be involved in processes like cell migration and immune response. It provides clues for exploring molecular mechanisms and may offer new directions for asthma diagnosis and treatment. ### Competing Interest Statement The authors have declared no competing interest.

Eosinophils play a featured role among inflammatory cells participating in the onset and development of asthma. Activated eosinophils release several cytotoxic granular proteins, such as major basic protein (MBP), posing a significant threat to airway epithelium. Ferroptosis, a novel form of cell death, is gaining recognition for its involvement in asthma pathogenesis, though the specific mechanisms remain largely unknown. Herein, we revealed that poly-L-arginine (PLA), an MBP mimic, induced ferroptosis in airway epithelium by downregulating gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1). Reduced GABARAPL1 expression was further confirmed in ovalbumin (OVA)-induced asthma mice and PLA-treated human airway organoids (hAOs). Mechanistically, PLA activated mechanistic target of rapamycin complex 1 (mTORC1) signaling, inhibiting preB-cell leukemia transcription factor 1 (PBX1), which in turn leads to transcriptional downregulation of GABARAPL1. Furthermore, MBP extracted from eosinophils, similar to PLA, induced ferroptosis in airway epithelial cells, as well as modulating mTORC1/PBX1/GABARAPL1 pathway. Finally, Ferrostatin-1 treatment or GABARAPL1 overexpression alleviated ferroptosis and airway inflammation in asthmatic mice. Overall, our findings highlight the cell communication between eosinophils and airway epithelial cells. MBP modulates the mTORC1/PBX1/GABARAPL1 axis, thereby serving as a significant contributor to ferroptosis in airway epithelium and airway inflammation. This suggests that suppressing ferroptosis in airway epithelium or targeting eosinophils and MBP could lead to novel therapeutic strategies for asthma management.

Background:Although short-term exposure to air pollutants has been linked to heightened hospital admissions for respiratory diseases (RDs), evidence regarding its association with the risk of mortality from such diseases remains scarce. We aimed to examine the impact of short-term exposure to air pollutants on RD-related mortality. Methods:We employed a time-stratified case-crossover design to explore the impact of short-term exposure to various air pollutants (fine particulate matter (PM2.5), coarse particulate matter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and ozone (O3)) on mortality due to RDs. Our sample comprised 15 878 RD-related deaths that occurred between 2017 and 2020 in Hefei, Anhui province. We delineated daily exposure to air pollutants using raster data corresponding to the residential addresses of the study subjects. We used conditional logistic regression to assess the relationship between pollutant exposure and the risk of mortality. To improve precision in identifying vulnerable populations, we stratified individuals by gender and age. Lastly, we used interrupted time series (ITS) analysis to explore COVID-19's impact on RD mortality. Results:We found that every 10 μg/m3 increase in PM10, PM2.5, and CO at a lag of zero days was associated with the largest significant effect on increased mortality from RDs (excess mortality risks of 0.735%, 1.349%, and 0.160%, respectively). We observed the highest positive associations between NO2 and O3 with delays of one and two days, resulting in excess mortality risks of 1.965% and 0.861%, respectively. We obtained consistent findings through moving average concentration analysis, while our stratified analysis showed that females and the elderly exhibited a heightened susceptibility to mortality from RDs attributable to short-term exposure to pollutants. Additionally, the ITS analysis confirmed that the COVID-19 outbreak did not significantly alter the level and trend of RD deaths. Conclusions:Our findings indicate that short-term exposure to air pollutants, excluding SO2, increases mortality rates from RDs, particularly among women and the elderly. In the context of Hefei, our findings highlight the public health imperative for reducing local residents' exposure to air pollutants, particularly through targeted protection of vulnerable populations, to minimise preventable RD mortality.

Inflammation is a principal mechanism in asthma pathogenesis. Activated eosinophils (EOSs) play an important role in the chronic inflammatory environment of asthma by releasing major basic protein (MBP) and other cationic granule proteins. Pyroptosis has been demonstrated to participate in asthma-related inflammation. Recent studies have reported the involvement of Pyruvate kinase M2 (PKM2) in inflammation development, but its precise mechanism remains elusive. In this study, the levels of PKM2 and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) messenger ribonucleic acids (mRNAs) in peripheral blood were observed to have a positive correlation with the eosinophil count in clinical samples from asthma patients. In addition, pyroptosis was detected in not only a chronic asthma mouse model induced by Ovalbumin (OVA) but also lung epithelial cell lines treated with Poly-L-arginine (PLA), which is a mimic of MBP. Subsequent TEPP-46 (a PKM2 activator) treatment contributed to the alleviation of pyroptosis. PLA up-regulated the expression of PKM2 and promoted the translocation of PKM2 dimers to the nucleus of lung epithelial cells. Therefore, it was hypothesized that targeting the regulation of PKM2 dimer nuclear translocation to reduce pyroptosis may provide innovative therapeutic principles for asthma. After treatment of cells with rapamycin, an inhibitor of mTORC1, inhibition of mTORC1 resulted in a decrease in PLA-induced PKM2 expression. Therefore, we hypothesize that reducing pyrodeath by regulating PKM2 dimer nuclear translocation may provide an innovative therapeutic principle for the treatment of asthma.

Background Type 2 inflammation is a key inflammatory endotype of chronic obstructive pulmonary disease (COPD). The precise identification and targeted intervention of treatable traits related to type 2 inflammation are crucial directions in the current management of COPD. Recently, a growing body of evidence-based medical data has accumulated regarding the clinical characteristics, biomarkers, therapeutic agents, and efficacy evaluation of type 2 inflammation in COPD, providing strong support for clinical diagnosis and treatment. This clinical practice recommendation systematically reviewed the evidence-based medical literature and integrated clinical experience to present expert opinions, aiming to standardize and improve the management of type 2 inflammation in COPD. Methods This clinical practice recommendation followed Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in HealThcare (RIGHT) statement to ensure the thoroughness and transparency. Clinical questions were primarily derived from surveys among experts in the field and thorough discussion at meetings. The evidence grading levels and recommendation grades adopted in the clinical practice recommendation follow the evidence grading levels and recommendation grades established by the Oxford Centre for Evidence-Based Medicine. The expert opinions were formulated through open discussion and expert voting. Expert opinions with an agreement rate of 80 % or higher among the experts are incorporated in the clinical practice recommendation. Results Eight clinical questions concerning diagnosis and treatment were proposed after expert discussion. In addition, fifteen specific major points of expert opinions about type 2 inflammation in COPD, involving clinical features, biomarkers, correlation with clinical outcomes, inhaled corticosteroid (ICS) treatment, biologic treatment and treatment response, were determined. Conclusions A set of comprehensive clinical practice recommendations focusing on the treatable trait of type 2 inflammation in COPD was established, which may provide potential guidance for the precision management of COPD.

Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.

The aim of this study is to assess the impact of serum magnesium (Mg) levels on prognostic outcomes in patients with non-small cell lung cancer (NSCLC) undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). A cohort comprising 91 patients with NSCLC with epidermal growth factor receptor mutations received EGFR-TKI therapy. Assessments of liver and kidney function and electrolyte levels were conducted before treatment initiation and after completing two cycles of EGFR-TKI therapy. Data on variables such as age, gender, presence of distant metastasis, smoking history, other therapeutic interventions, and the specific TKI used were collected for analysis. Cox regression analysis revealed that patients with higher Mg levels prior to EGFR-TKI therapy had significantly longer progression-free survival (PFS) and overall survival (OS). Elevated Mg levels remained predictive of PFS and OS after two cycles of EGFR-TKI therapy. Multiple regression analysis confirmed these findings. Additionally, it was observed that smokers might represent a unique population, demonstrating a correlation between OS and Mg levels. Our findings indicate that serum Mg level is a prognostic factor in patients with NSCLC undergoing EGFR-TKI therapy. This may provide new insights into the underlying mechanisms of EGFR-TKI therapy related to electrolyte balance.

The presence of bone metastases (BM) in patients with lung cancer is indicative of a worse prognosis. The present study aims to investigate the risk factors associated with BM in patients with lung cancer. Patients with lung cancer admitted to the First Affiliated Hospital of Anhui Medical University between June 2019 and September 2021 were enrolled in this study. A nomogram was constructed based on the outcomes derived from univariate and multivariate analyses. Concordance index, calibration plots, receiver operating characteristic curves, and decision curve analysis were used to evaluate the nomogram. To substantiate the influence of monocytes on lung cancer BM, various assays, including cell co-culture, Transwell, wound-healing assays, and immunohistochemistry and immunofluorescence staining, were conducted. Statistical analyses were performed using SPSS 22.0 software and GraphPad Prism 7.0. A total of 462 eligible patients were enrolled, comprising 220 with BM and 242 without. Multivariate analysis revealed that histological type, medical history, monocyte percentage, and LDH (Lactate Dehydrogenase) and ALP (Alkaline Phosphatase) levels were independent risk factors for BM in lung cancer. Transwell and wound-healing assays indicated that co-culture with monocytes significantly enhanced the migration and invasion capabilities of A549 cells in vitro. Immunohistochemistry and immunofluorescence analyses demonstrated a noteworthy increase in monocyte infiltration in the primary lesions of patients with lung cancer with BM. In conclusion, this study successfully constructed and validated a precise, straightforward, and cost-effective prognostic nomogram for patients with lung cancer with BM.

Abstract Background Patients infected with Acinetobacter baumannii (AB) bacteremia in hospital have high morbidity and mortality. We analyzed the clinical characteristics of pneumonia and nonpneumonia-related AB bloodstream infections (AB BSIs) and explored the possible independent risk factors for the incidence and prognosis of pneumonia-related AB BSIs. Methods A retrospective monocentric observational study was performed. All 117 episodes of hospital-acquired AB bacteremia sorted into groups of pneumonia-related AB BSIs (n = 45) and nonpneumonia-related AB BSIs (n = 72) were eligible. Univariate/multivariate logistic regression analysis was used to explore the independent risk factors. The primary outcome was the antibiotic susceptibility in vitro of pneumonia-related AB BSIs group. The secondary outcome was the independent risk factor for the pneumonia-related AB BSIs group. Results Among 117 patients with AB BSIs, the pneumonia-related group had a greater risk of multidrug resistant A. baumannii (MDRAB) infection (84.44%) and carbapenem-resistant A. baumannii (CRAB) infection (80%). Polymyxin, minocycline and amikacin had relatively high susceptibility rates (> 80%) in the nonpneumonia-related group. However, in the pneumonia-related group, only polymyxin had a drug susceptibility rate of over 80%. Univariate analysis showed that survival time (day), CRAB, MDRAB, length of hospital stay prior to culture, length of ICU stay prior to culture, immunocompromised status, antibiotics used prior to culture (n > = 3 types), endotracheal tube, fiberoptic bronchoscopy, PITT, SOFA and invasive interventions (n > = 3 types) were associated with pneumonia-related AB bacteremia. The multivariate logistic regression analysis revealed that recent surgery (within 1 mo) [P = 0.043; 0.306 (0.098–0.962)] and invasive interventions (n > = 3 types) [P = 0.021; 0.072 (0.008–0.671)] were independent risk factors related to pneumonia-related AB bacteremia. Multivariate logistic regression analysis revealed that length of ICU stay prior to culture [P = 0.009; 0.959 (0.930–0.990)] and recent surgery (within 1 mo) [P = 0.004; 0.260 (0.105–0.646)] were independent risk factors for mortality in patients with pneumonia-related AB bacteremia. The Kaplan‒Meier curve and the timing test showed that patients with pneumonia-related AB bacteremia had shorter survival time compared to those with nonpneumonia-related AB bacteremia. Conclusions Our study found that A. baumannii had a high rate of antibiotic resistance in vitro in the pneumonia-related bacteremia group, and was only sensitive to polymyxin. Recent surgery was a significantly independent predictor in patients with pneumonia-related AB bacteremia.

Rationale: Ferroptosis in lung epithelium and endothelium contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), a critical and often fatal condition marked by acute inflammation and elevated pulmonary vascular permeability. Despite this, there are currently no FDA-approved therapeutics specifically targeting ferroptosis for ARDS management. Methods: A screening of 259 FDA-approved drugs was conducted to identify an effective ferroptosis inhibitor in pulmonary epithelial and endothelial cells. The anti-ferroptotic and therapeutic efficacy of this screened drug was rigorously evaluated using two distinct ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). The regulatory mechanism of this drug on ferroptosis inhibition was investigated via RNA-sequencing, qRT-PCR, western blotting, IF, luciferase reporter assay, chromatin immunoprecipitation assay, limited proteolysis-mass spectrometry assay, cellular thermal shift assay, and drug affinity responsive target stability assay. Furthermore, a proof-of-concept clinical trial was conducted, wherein ARDS patients were administered with the drug as adjunctive therapy. Results: Dipyridamole (DIPY) was identified as a potent inhibitor of ferroptosis in pulmonary epithelial and endothelial cells. DIPY effectively mitigated ferroptosis and pulmonary damage in both mouse models and hAOs, primarily by downregulating heme oxygenase 1 (HMOX1). The transcription factor cAMP responsive element binding protein 1 (CREB1) was identified as a key transactivator of HMOX1, which DIPY effectively downregulated. Mechanistically, DIPY binds to and activates superoxide dismutase 1 (SOD1), which in turn inhibits the CREB1/HMOX1 pathway, thereby suppressing ferroptosis. Notably, the clinical trial further corroborated the therapeutic potential of DIPY in ARDS patients, demonstrating improved outcomes with DIPY adjunctive therapy. Conclusions: These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.