Respiratory Research最新文献

{"title":"Causes and MEchanisms foR non-atopic Asthma in Children (CAMERA) study: rationale and protocol.","authors":"Mary Njoroge, Gabriela Pimentel Pinheiro, Cinthia Vila Nova Santana, Hajar Ali, Stephanie Hobbs, Santiago Mena-Bucheli, Natalia Romero-Sandoval, Steven Robertson, Charlotte E Rutter, Donna Davoren, Collin Brooks, Jeroen Douwes, Philip J Cooper, Harriet Mpairwe, Camila A Figueiredo, Alvaro A Cruz, Mauricio L Barreto, Neil Pearce, Lucy Pembrey","doi":"10.1186/s12931-025-03279-6","DOIUrl":"10.1186/s12931-025-03279-6","url":null,"abstract":"<p><strong>Background: </strong>The Causes And MEchanisms foR non-atopic Asthma in children (CAMERA) study was designed to investigate risk factors and mechanisms of non-atopic asthma in children and young adults in Brazil, Ecuador, Uganda, and New Zealand. Initial epidemiological analyses using existing datasets identified and compared risk factors for both atopic and non-atopic asthma. The focus of this paper is the protocol for sample collection and analysis of clinical data on possible non-atopic mechanisms.</p><p><strong>Methods: </strong>In each of the four centres, the CAMERA study will enroll 160 participants aged 10-28 years, equally distributed among atopic asthmatics (AA), non-atopic asthmatics (NAA), atopic non-asthmatics and non-atopic non-asthmatics. Participants will be new recruits or returning World ASthma Phenotypes (WASP) study participants. Phase I consists of skin prick tests to define atopy, a general CAMERA questionnaire that covers respiratory and general health to identify asthma cases, followed by an asthma control questionnaire for asthmatics only. Phase II consists of a stress questionnaire and the following clinical assessments: lung function, nasal cytology, blood sampling, in vitro whole blood stimulation to assess IFN-γ production, hair cortisol concentration, dry air and capsaicin challenges, plus in a subset, cold air challenges. Analyses will compare inflammatory, physiological and clinical parameters across the four groups overall and by country.</p><p><strong>Discussion: </strong>Here, we present the protocol for the CAMERA study, to provide relevant methodological details for CAMERA publications and to allow other centres globally to conduct similar analyses. The findings of this mechanistic multi-centre study will inform new and phenotype-specific prevention and treatment approaches.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"212"},"PeriodicalIF":5.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRANS: a prediction model for EGFR mutation status in NSCLC based on radiomics and clinical features.","authors":"Zhigang Chen, Huiying Lu, Ao Liu, Jia Weng, Lei Gan, Lina Zhou, Xiao Ding, Shicheng Li","doi":"10.1186/s12931-025-03287-6","DOIUrl":"10.1186/s12931-025-03287-6","url":null,"abstract":"<p><strong>Background: </strong>Early detection of epidermal growth factor receptor (EGFR) is critical for guiding therapeutic decisions in non-small-cell lung cancer (NSCLC). The study aims to develop a predictive model for EGFR mutations with multicohort data.</p><p><strong>Methods: </strong>The study enrolled 254 NSCLC patients of four cohorts: the Affiliated Hospital of Qingdao University (AHQU, n = 54), the Second Affiliated Hospital of Soochow University (SAHSU, n = 78), TCGA-NSCLC (n = 91), and CPTAC-NSCLC (n = 31). Radiomic features were extracted using the LIFEx software. The least absolute shrinkage and selection operator (LASSO) algorithm was utilized to select predictive features of CT radiomics, clinical data, and RNA sequencing, which were evaluated using receiver operating characteristic (ROC) curves. A nomogram was developed by integrating predictive features. Biological functions were analyzed utilizing RNA sequencing data.</p><p><strong>Results: </strong>Eight radiomic features, four clinical features, and seven genomic features were selected to construct distinct signatures. Through internal 5-fold cross-validation, the first two signatures demonstrated notable discrimination capabilities for distinguishing between mutated and wild-type EGFR, resulting in area under the curve (AUC) values of 0.79 (± 0.08) and 0.74 (± 0.06), respectively. The combination of clinical variables and radiomics signature resulted in an increased AUC of 0.84 (± 0.01). This combined model was named TRANS, representing TTF-1, radiomic signature, AE1/AE3, NapsinA, and stage, which uses radiomics and routine immunohistochemistry markers as inputs. High-risk TRANS was observed to be associated with poor overall survival, and showed relationships with high T cell infiltration and response to PD-1 immunotherapy.</p><p><strong>Conclusions: </strong>The TRANS model demonstrated favorable ability in predicting EGFR mutation status in NSCLC, providing a valuable approach for optimizing therapeutic strategies in clinical practice.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"211"},"PeriodicalIF":5.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: EIT guided evaluation of regional ventilation distributions in neonatal and pediatric ARDS: a prospective feasibility study.","authors":"Leon Soltész, Judith Leyens, Marieke Vogel, Thomas Muders, Christian Putensen, Florian Kipfmueller, Till Dresbach, Andreas Mueller, Lukas Schroeder","doi":"10.1186/s12931-025-03292-9","DOIUrl":"10.1186/s12931-025-03292-9","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"208"},"PeriodicalIF":5.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HNRNPH1 promotes autophagy to inhibit the development of lung adenocarcinoma via the HSP90AB1/MAP1LC3B axis.","authors":"Rong Li, Fen Li, Qian Liu, Xu Wu, Xiaowu Tan","doi":"10.1186/s12931-025-03280-z","DOIUrl":"10.1186/s12931-025-03280-z","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is a prevalent subtype of lung cancer (LC) whose progression is regulated by multiple genes. This study sought to find the impact and mechanism of HNRNPH1 on LUAD.</p><p><strong>Methods: </strong>The expression and role of HSP90AB1, HNRNPH1, and autophagy-related protein MAP1LC3B in LUAD were detected. Additionally, bioinformatics analysis, silencing and overexpression techniques, and in vivo modeling were used to explore the regulatory mechanisms of these proteins in the progression of LUAD.</p><p><strong>Results: </strong>HSP90AB1 showed high expression in LUAD and was linked to a worse prognosis. Overexpression of HSP90AB1 significantly promoted the malignant phenotype of LUAD cells and inhibited MAP1LC3B-mediated autophagy. However, overexpression of HNRNPH1 could reverse the malignant phenotype resulting from HSP90AB1 overexpression and promote MAP1LC3B-mediated autophagy by binding to HSP90AB1 mRNA and inhibiting its protein expression. Animal experiments also revealed that overexpression of HNRNPH1 could inhibit tumor progression by promoting cellular autophagy.</p><p><strong>Conclusions: </strong>We verified the key role of HSP90AB1, HNRNPH1, and MAP1LC3B in LUAD, and revealed a possible regulatory mechanism, namely, HNRNPH1 could inhibit the development of LUAD by promoting autophagy through the HSP90AB1/MAP1LC3B axis. These findings may offer new insights for improving the treatment and prognosis of LUAD.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"206"},"PeriodicalIF":5.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local and systemic effects in e-cigarette users compared to cigarette smokers, dual users, and non-smokers.","authors":"Shanzina Iasmin Sompa, Jie Ji, Mizanur Rahman, Bengt Sjögren, Swapna Upadhyay, Koustav Ganguly, Anna-Carin Olin, Anna Bergström, Lena Palmberg","doi":"10.1186/s12931-025-03289-4","DOIUrl":"10.1186/s12931-025-03289-4","url":null,"abstract":"<p><strong>Background: </strong>The use of electronic (e)-cigarettes in the long term has been associated with an increased risk of respiratory diseases. Dual use of e-cigarettes and traditional cigarettes may increase these risks even more due to the combined exposure effects of these products. The aim of this study was to investigate the local and systemic effects of e-cigarette use for more than one year and compare them with healthy non-smokers, cigarette smokers, and dual users.</p><p><strong>Methods: </strong>The clinical study was conducted among 22 healthy non-smokers, 20 e-cigarette users, 20 cigarette smokers, and 20 dual users. Participants were matched with age and BMI, had normal baseline lung function, and had no allergies. Exhaled FeNO and bronchial responsiveness were assessed along with reactive oxygen species (ROS), toll-like receptor (TLR) expression, and inflammatory cytokines in blood and sputum.</p><p><strong>Results: </strong>Exhaled FeNO was higher in e-cigarette users (14 ppb, p = 0.04) and lower in cigarette smokers (9 ppb, p = 0.04) compared to healthy non-smokers (11 ppb). Bronchial responsiveness was increased in e-cigarette users (1.9 mg, p = 0.01) and cigarette smokers (1.9 mg, p = 0.01) compared to healthy non-smokers (2.9 mg). ROS in blood and sputum in e-cigarette users (p = 0.005 and p = 0.04) and dual users (p = 0.003 and p = 0.04) were increased. Also, TLR2 expression in blood granulocytes in all exposed groups (p = 0.001), TLR2 and TLR4 expression in sputum in e-cigarette users (p = 0.04 and p = 0.03) and dual users (p < 0.0001 and p = 0.004) were increased. Moreover, the percentage of IL13 and IFNγ cytokine-producing T cells in blood were increased in e-cigarette users (p = 0.0001 and p < 0.0001) and dual users (p = 0.001 and p < 0.0001).</p><p><strong>Conclusion: </strong>Our research indicates that both local and systemic inflammatory responses, along with innate immune receptor activity, were significantly altered in e-cigarette users and dual users. Notably, these alterations were detected in e-cigarette users within a short timeframe of just 1 to 3 years of use.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"207"},"PeriodicalIF":5.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sputum sample quality selection in microbiota research; a chance to improve methods??","authors":"Eleanor Kewin, Ross Langley, Alison Jane Dicker","doi":"10.1186/s12931-025-03286-7","DOIUrl":"10.1186/s12931-025-03286-7","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"210"},"PeriodicalIF":5.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sputum quality affects assessment of airway microbiology in childhood asthma.","authors":"Steven L Taylor, Collin R Brooks, Levi Elms, Sarah K Manning, Alyson Richard, Jeroen Burmanje, Jeroen Douwes, Geraint B Rogers","doi":"10.1186/s12931-025-03266-x","DOIUrl":"10.1186/s12931-025-03266-x","url":null,"abstract":"<p><strong>Background: </strong>The analysis of sputum is the principal basis for characterising lower airway microbiology in those with chronic respiratory conditions. For such analysis to be informative, samples that poorly reflect the lower airways must be identified and removed. Our cross-sectional study explored the relationship between the quality of sputum samples and their microbiological content. We further investigated the impact of excluding low quality samples on observed microbiota-disease relationships in childhood asthma.</p><p><strong>Methods: </strong>Induced sputum was collected from children with or without asthma. Sputum quality was assessed according to squamous cell%, cell viability%, detection of sputum plugs, and salivary α-amylase levels. Sputum microbiota was characterised by 16S rRNA amplicon sequencing and qPCR.</p><p><strong>Results: </strong>Of 170 participants, 130 had asthma. Between 19% (32/170) and 29% (53/170) of samples were deemed to be of insufficient quality, depending on the quality criterion applied. Stratification of samples based on any of the sputum quality cut-offs resulted in significant differences in microbiota characteristics (all p < 0.05), with salivary α-amylase the least discriminant between microbiota of acceptable and unacceptable samples. The removal of 53 poor-quality samples based on ≥ 30% squamous cells identified a difference in the sputum microbiota by asthma status (p = 0.017) that was not evident otherwise, including significantly higher levels of Haemophilus and Gemella in asthma samples.</p><p><strong>Conclusions: </strong>Upper airway contamination of induced sputum samples from children is common. Exclusion of samples based on ≥ 30% squamous cells enables identification of asthma-airway microbiology relationships that are otherwise not apparent.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"209"},"PeriodicalIF":5.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics unveils BCAA metabolism markers L-leucine and HMGCS1 as prognostic marker for immunotherapy efficacy in non-small cell lung cancer.","authors":"Liyuan Dai, Xinzheng Wang, Ning Lou, Lin Li, Liling Huang, Le Tang, Jiarui Yao, Yuankai Shi, Xiaohong Han","doi":"10.1186/s12931-025-03277-8","DOIUrl":"10.1186/s12931-025-03277-8","url":null,"abstract":"<p><strong>Background: </strong>This study aims to identify branched-chain amino acid (BCAA) plasma metabolites and gene signatures that enhance prognostic assessments in non-small cell lung cancer (NSCLC) patients receiving immunotherapy.</p><p><strong>Methods: </strong>Plasma metabolites were measured using untargeted UPLC-MS/MS (n = 94 and 40), with lymphocyte subset tests on 72 patients. BCAA-related subtypes were identified in NSCLC datasets (n = 274, 176, and 196). A prognostic risk model was developed and validated in NSCLC (n = 16, 27, 24, and 339), melanoma (n = 25), and pan-cancer ICIs cohorts (n = 330 and 81). Immune cell infiltration and prognostic signatures were validated using mIF (n = 21 in CHCAMS), scRNA-seq (n = 8 and 21), and spatial transcriptomics (n = 2 and 6). Cell and animal experiments involving HMGCS1 were conducted in a lung cancer model. Additionally, based on our previous findings that B cells with higher malignancy exhibited enhanced cholesterol homeostasis pathways in diffuse large B-cell lymphoma (DLBCL), we further analyzed the prognostic value of HMGCS1 using our spatial transcriptomics (n = 10) and immunohistochemistry (IHC, n = 39) in DLBCL.</p><p><strong>Results: </strong>Our plasma metabolite analysis showed higher L-leucine levels were associated with better prognosis and had higher T cell counts and CD4⁺ T cell counts (P < 0.05). In GEO datasets, four NSCLC subtypes were identified, showing distinct prognostic outcomes and tumor microenvironment. Five BCAA-related genes (ACAT2, ALDH2, HMGCS1, MLYCD, and PPM1 K) formed a prognostic risk model for NSCLC, validated through Kaplan-Meier and ROC curve analyses in ICI cohorts (P < 0.05). HMGCS1 was an independent prognostic value in ICI cohorts and was negatively correlated with CD8⁺ T cell infiltration, while positively correlating with tumor severity, cholesterol homeostasis, and BCAA degradation across multiple platforms, including GEO datasets, our mIF cohort, public scRNA-seq, and spatial transcriptomics (P < 0.05). And our cell and animal function experiments found HMGCS1 overexpression promotes metabolic pathways and accelerates tumor growth, whereas HMGCS1 knockdown suppresses tumor progression in a mouse model treated with PD-1 monoclonal antibody (P < 0.05). In DLBCL, high HMGCS1 expression was associated with shorter overall survival, enriched in B cells and relapsed patients, correlated with cholesterol homeostasis and amino acid degradation pathways, and its prognostic value was further validated at the protein level by our IHC cohort (P < 0.05).</p><p><strong>Conclusions: </strong>This study identifies a BCAA-related plasma metabolites and gene signature as effective prognostic markers for NSCLC patients receiving immunotherapy, with HMGCS1 as a key prognostic factor influencing tumor progression and immune response.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"205"},"PeriodicalIF":5.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis.","authors":"Wenxue Bai, Shengding Zhang, Lijuan Hua, Dongyuan Wang, Mengyao Guo, Xuezhao Wang, Ying Zhou, Yong Cao, Qi Wang, Ni Zhang, Bin Xue, Min Xie","doi":"10.1186/s12931-025-03285-8","DOIUrl":"10.1186/s12931-025-03285-8","url":null,"abstract":"<p><strong>Background: </strong>Sirolimus, the therapy choice for lymphangioleiomyomatosis (LAM), displayed cytostatic but not cytocidal action, with disease recurrence after withdrawal. The aim of this study is to identify novel potential biomarkers and therapeutic strategies for LAM patients.</p><p><strong>Methods: </strong>TMT-labeling proteomics was utilized for screening the differentially expressed proteins (DEPs) in the plasma of 10 LAM patients and 6 controls. Plasma levels of transferrin (TRF), ferritin (FRT) and beta2-microglobulin (B2M) were validated in a cohort of 30 LAM patients and 20 controls. The diagnostic efficacy of TRF with/without VEGF-D was assessed using ROC curve analysis. The therapeutic effects of a ferroptosis inducer artesunate (ART) were evaluated both in vitro Tsc2 - / - MEFs cells and in xenograft LAM models.</p><p><strong>Results: </strong>Proteomics analysis revealed 132 DEPs between LAM patients and controls, which primarily enriched in the regulation of iron ion transport. LAM patients had decreased TRF, elevated FRT and B2M levels compared with controls in the confirmation cohort (p = 0.0386, p = 0.0327 and p = 0.0155, respectively) which independent with VEGF-D level or rapamycin therapy. TRF positively correlated with both FEV₁% predicted (r = 0.4486, p = 0.0251) and DLCO% predicted (r = 0.4018, p = 0.0516) of LAM patients. The combination of TRF and VEGF-D showed superior diagnostic value compared to individual indicator. ART induced the ferroptosis and inhibited the growth in Tsc2 - / - MEFs cells. In LAM animal models, ART exerted anti-tumor effects without obvious adverse effect.</p><p><strong>Conclusions: </strong>LAM patients exhibit abnormal iron metabolism independent of VEGF-D level. Ferroptosis inducer ART holds promise as a therapeutic novel approach for treating LAM.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"204"},"PeriodicalIF":5.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCF7 enhances pulmonary hypertension by boosting stressed natural killer cells and their interaction with pulmonary arterial smooth muscle cells.","authors":"Li-Wei Wu, Min Chen, Dai-Ji Jiang, Chen-Yu Jiang, Yi-Wei Liu, Bei Feng, Chen-Fei Shi, Xu Huang, Xu Zhang, Xiao-He Xu, Xing-Liang Zhou, Yi Shen, Tian-Yu Liu, Lin-Cai Ye, Yang-Yang He, Hao Zhang, Yi Yan","doi":"10.1186/s12931-025-03276-9","DOIUrl":"10.1186/s12931-025-03276-9","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a life-threatening cardio-pulmonary disorder. Whether natural killer (NK) cells could act as participants in PH and the mechanism by which NK cells moderate pulmonary vascular remodeling has not been fully elucidated.</p><p><strong>Methods: </strong>Single-cell RNA sequencing data from lungs of human pulmonary arterial hypertension (PAH) patients and monocrotaline (MCT)-induced PH rat model were retrieved from GEO database or UCSC Cell Browser. Tcf7 conditional knockout mice and TCF7 overexpression following adeno-associated virus 6 (AAV6) intratracheal delivery in rats were generated. The NK92 cell line and primary human pulmonary artery smooth muscle cells (hPASMCs) were used for in vitro experiments.</p><p><strong>Results: </strong>Stressed NK cells were much higher in lungs from human PAH and MCT-induced PH compared to corresponding controls. Of note, TCF7 topped the list differentiating high-stressed from low-stressed human NK cells. TCF7-expressing NK cells displayed higher stress profile than TCF7-deficient cells. Tcf7-deficient NK cells exhibited lower Hsp90aa1 and Hsp90ab1 at transcriptional level and Hsp90 at protein level than Tcf7-expressing cells 24 h post-hypoxia. Mechanistically, TCF7-overexpressing NK cells secrete more SPP1 compared to control NK cells, thus promoting the proliferation and migration of hPASMCs 48 h post-hypoxia. TCF7 overexpression in rats aggravated PH features, while Tcf7 deficiency in mice alleviated pulmonary remodeling possibly due to the manipulation of HSP90 level in NK cells and SPP1 in the microenvironment.</p><p><strong>Conclusions: </strong>TCF7 contributes to the immunopathology of PH possibly through upregulation of stressed NK cells. Under stress conditions, NK cells promote the proliferation and migration of hPASMC through paracrine effects, thereby further promoting vascular remodeling.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"202"},"PeriodicalIF":5.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}