European Respiratory Journal最新文献

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Rbms1 promotes pulmonary fibrosis by stabilising Sumo2 mRNA to facilitate Smad4-SUMOylation and fibroblast activation. Rbms1通过稳定Sumo2 mRNA促进Smad4-SUMOylation和成纤维细胞活化来促进肺纤维化。
IF 21 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 Print Date: 2025-09-01 DOI: 10.1183/13993003.01667-2024
Yingying Guo, Qianqian Wang, Yuhan Zhang, Lingxue Ren, Yuquan Wang, Yang Liu, Miao Liu, Xiaomu Tian, Qiudi Liu, Yi Chen, Jian Sun, Tongzhu Jin, Xinyue Wang, Yanbo Wang, Tianyu Li, Yuhong Zhou, Zhixin Li, Yunyan Gu, Baofeng Yang, Haihai Liang
{"title":"Rbms1 promotes pulmonary fibrosis by stabilising Sumo2 mRNA to facilitate Smad4-SUMOylation and fibroblast activation.","authors":"Yingying Guo, Qianqian Wang, Yuhan Zhang, Lingxue Ren, Yuquan Wang, Yang Liu, Miao Liu, Xiaomu Tian, Qiudi Liu, Yi Chen, Jian Sun, Tongzhu Jin, Xinyue Wang, Yanbo Wang, Tianyu Li, Yuhong Zhou, Zhixin Li, Yunyan Gu, Baofeng Yang, Haihai Liang","doi":"10.1183/13993003.01667-2024","DOIUrl":"10.1183/13993003.01667-2024","url":null,"abstract":"<p><strong>Background: </strong>The formation of myofibroblast foci constitutes a hallmark pathological feature of idiopathic pulmonary fibrosis (IPF), yet the mechanism remains elusive. RNA-binding motif single-stranded interacting protein 1 (RBMS1) is known to be essential for proliferation and cell cycle progression; however, its role in pulmonary fibrosis remains to be clarified.</p><p><strong>Methods: </strong>This study aimed to systematically elucidate the role and underlying mechanism of RBMS1 in pulmonary fibrosis utilising mouse primary lung fibroblasts (mPLFs), fibroblast-specific Rbms1 deletion and overexpression mice models, and lung samples from IPF patients.</p><p><strong>Results: </strong>RBMS1 was highly expressed in both IPF patient lungs and murine bleomycin-induced fibrotic lesions. Notably, elevated RBMS1 expression was observed in the cytoplasm of mPLFs following transforming growth factor (TGF)-β1 stimulation. Rbms1 promoted lung fibroblast activation, while knockdown of Rbms1 mitigated TGF-β1-induced fibrogenesis. <i>In vivo</i>, overexpression of Rbms1 impaired lung function and exacerbated pulmonary fibrosis, whereas fibroblast-specific deletion of Rbms1 exhibited a significant reduction in fibrosis post-bleomycin treatment. Mechanistically, Rbms1 binds to Sumo2 3' untranslated region, enhancing the mRNA stability. Furthermore, Rbms1 induced the SUMOylation of Smad4, with lysine 158 identified as a critical SUMOylation site. Meanwhile, Sumo2 knockdown alleviated the Rbms1-driven exacerbation of pulmonary fibrosis. Importantly, nortriptyline pharmacologically inhibited RBMS1 to ameliorate pulmonary fibrosis in mice.</p><p><strong>Conclusion: </strong>Collectively, our study sheds light on the regulatory role of RBMS1 in pulmonary fibrosis, highlighting its therapeutic potential for targeted antifibrotic strategies.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pulmonary vascular resistance to define severe pulmonary hypertension: cutting the Gordian knot. 肺血管阻力定义重度肺动脉高压:斩断死结。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 DOI: 10.1183/13993003.01418-2025
Gabor Kovacs,Katarina Zeder,Karen M Olsson,Marius M Hoeper,Marc Humbert
{"title":"Pulmonary vascular resistance to define severe pulmonary hypertension: cutting the Gordian knot.","authors":"Gabor Kovacs,Katarina Zeder,Karen M Olsson,Marius M Hoeper,Marc Humbert","doi":"10.1183/13993003.01418-2025","DOIUrl":"https://doi.org/10.1183/13993003.01418-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"1 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genomics of chronic dry cough unravels neurological pathways. 慢性干咳的基因组学揭示了神经通路。
IF 21 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 Print Date: 2025-09-01 DOI: 10.1183/13993003.02341-2024
Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini
{"title":"Genomics of chronic dry cough unravels neurological pathways.","authors":"Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini","doi":"10.1183/13993003.02341-2024","DOIUrl":"10.1183/13993003.02341-2024","url":null,"abstract":"<p><strong>Background: </strong>Chronic dry cough is a symptom of common lung conditions, can occur as a side-effect of angiotensin-converting enzyme inhibitors (ACEis), or may be unexplained. Despite the substantial health burden presented by chronic dry cough, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes.</p><p><strong>Methods: </strong>We performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants, and polygenic scores for ACEi-induced cough, to identify pleiotropic effects.</p><p><strong>Results: </strong>We found seven novel genetic association signals reaching p<5×10<sup>-8</sup> in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicate neurological functions (<i>CTNNA1</i>, <i>KCNA10</i>, <i>MAPKAP1</i>, <i>OR4C12</i>, <i>OR4C13</i>, <i>SIL1</i>). The polygenic-score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain.</p><p><strong>Conclusion: </strong>Our findings provide support for neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough, and identify diseases and traits associated with genetic predisposition to cough that could inform drug target discovery.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dissecting the genetics of chronic cough. 慢性咳嗽的遗传学解剖。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 DOI: 10.1183/13993003.01267-2025
Alyn Hugh Morice
{"title":"Dissecting the genetics of chronic cough.","authors":"Alyn Hugh Morice","doi":"10.1183/13993003.01267-2025","DOIUrl":"https://doi.org/10.1183/13993003.01267-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"73 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ERJ Podcast September 2025: Neutrophil-derived biomarkers in bronchiectasis. ERJ播客2025年9月:中性粒细胞衍生的支气管扩张生物标志物。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 DOI: 10.1183/13993003.e6603-2025
{"title":"ERJ Podcast September 2025: Neutrophil-derived biomarkers in bronchiectasis.","authors":"","doi":"10.1183/13993003.e6603-2025","DOIUrl":"https://doi.org/10.1183/13993003.e6603-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"47 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pulmonary hypertension in COPD exacerbation: a transient storm with long-term consequences? COPD加重期肺动脉高压:具有长期后果的短暂风暴?
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-25 DOI: 10.1183/13993003.01508-2025
Omer Faruk Uysal,John R Hurst
{"title":"Pulmonary hypertension in COPD exacerbation: a transient storm with long-term consequences?","authors":"Omer Faruk Uysal,John R Hurst","doi":"10.1183/13993003.01508-2025","DOIUrl":"https://doi.org/10.1183/13993003.01508-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"64 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A cautionary note on the naive use of general-population biobanks to study pulmonary arterial hypertension, with a focus on Mendelian randomization. 关于幼稚地使用普通人群生物库来研究肺动脉高压的警告,重点是孟德尔随机化。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-18 DOI: 10.1183/13993003.00436-2025
Benjamin Woolf,Eckart De Bie,Vallerie McLaughlin,Stefan Gräf,Mark Toshner,Martin R Wilkins,Christopher J Rhodes,Stephen Burgess
{"title":"A cautionary note on the naive use of general-population biobanks to study pulmonary arterial hypertension, with a focus on Mendelian randomization.","authors":"Benjamin Woolf,Eckart De Bie,Vallerie McLaughlin,Stefan Gräf,Mark Toshner,Martin R Wilkins,Christopher J Rhodes,Stephen Burgess","doi":"10.1183/13993003.00436-2025","DOIUrl":"https://doi.org/10.1183/13993003.00436-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"10 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Placebo effect on brainstem activity associated with capsaicin-evoked urge-to-cough in healthy humans. 安慰剂效应对与辣椒素诱发的健康人咳嗽冲动相关的脑干活动的影响
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-18 DOI: 10.1183/13993003.00645-2025
Aung Aung Kywe Moe,Tara G Bautista,Jennifer Leech,Stuart B Mazzone,Michael J Farrell
{"title":"Placebo effect on brainstem activity associated with capsaicin-evoked urge-to-cough in healthy humans.","authors":"Aung Aung Kywe Moe,Tara G Bautista,Jennifer Leech,Stuart B Mazzone,Michael J Farrell","doi":"10.1183/13993003.00645-2025","DOIUrl":"https://doi.org/10.1183/13993003.00645-2025","url":null,"abstract":"BACKGROUNDPlacebo effects are common in studies of cough and antitussive medications, suggestive of a profound influence of brain activity over cough neural processing. We previously reported placebo intervention-associated reductions in the urge-to-cough and the associated higher order brain network activity evoked by capsaicin inhalation, an effect involving increased activation of the prefrontal cortex.OBJECTIVEIn this study, we set out to advance the understanding of placebo antitussive brain circuitry by testing the hypothesis that the activity of brainstem nuclei during capsaicin inhalation will similarly be altered by placebo intervention.METHODSUsing an expectation-dependent placebo induction design during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) optimised for quantifying brainstem activity, we compared regional brainstem responses evoked by capsaicin inhalation in sixteen healthy individuals during No Intervention versus Placebo Intervention trials.RESULTSCapsaicin-induced urge-to-cough subjective ratings were significantly lower during the Placebo Intervention trials than No Intervention trials. Placebo Intervention resulted in a significant reduction in capsaicin-induced BOLD signal activation across many brainstem nuclei including the medullary brainstem sites where airway vagal sensory neurons are known to terminate.CONCLUSIONThese data confirm the inhibitory effects of placebo intervention on capsaicin-evoked urge-to-cough and suggest the existence of a \"top-down\" brain circuit controlling cough sensory neural processing at the level of the brainstem during placebo conditions.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"29 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Changes in Sputum Viscoelastic Properties and Airway Inflammation in Primary Ciliary Dyskinesia are Comparable to Cystic Fibrosis on Elexacaftor/Tezacaftor/Ivacaftor Therapy. 原发性纤毛运动障碍患者痰粘弹性和气道炎症的变化与elexaftor /Tezacaftor/Ivacaftor治疗后的囊性纤维化相当。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-18 DOI: 10.1183/13993003.00616-2025
Hannah Nussstein,Ruth M Urbantat,Kerstin Fentker,Aditi Loewe,Julia Duerr,Mohamed Haji,Felix Doellinger,Mirjam Stahl,Simon Y Graeber,Michael Gradzielski,Jobst Röhmel,Philipp Mertins,Laura Schaupp,Marcus A Mall
{"title":"Changes in Sputum Viscoelastic Properties and Airway Inflammation in Primary Ciliary Dyskinesia are Comparable to Cystic Fibrosis on Elexacaftor/Tezacaftor/Ivacaftor Therapy.","authors":"Hannah Nussstein,Ruth M Urbantat,Kerstin Fentker,Aditi Loewe,Julia Duerr,Mohamed Haji,Felix Doellinger,Mirjam Stahl,Simon Y Graeber,Michael Gradzielski,Jobst Röhmel,Philipp Mertins,Laura Schaupp,Marcus A Mall","doi":"10.1183/13993003.00616-2025","DOIUrl":"https://doi.org/10.1183/13993003.00616-2025","url":null,"abstract":"BACKGROUNDPrimary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are muco-obstructive lung diseases that are caused by distinct genetically determined defects in mucociliary clearance, however, knowledge on the relative severity of airway mucus dysfunction and chronic inflammation remains limited. The aim of this study was therefore to compare sputum viscoelastic properties, inflammation markers and the proteome between patients with PCD and patients with CF before and under elexacaftor/tezacaftor/ivacaftor (ETI) therapy.METHODSWe compared sputum rheology, inflammation markers and the proteome in 42 clinically stable adolescent and adult patients with PCD, 40 patients with CF with at least one F508del allele before (baseline) and 3 months after initiation of ETI and 15 age-matched healthy controls.RESULTSThe elastic modulus (G') and viscous modulus (G″) of PCD sputum was increased compared to healthy controls (p<0.001), lower than in CF at baseline (p<0.001) and similar to CF on ETI. Inflammation markers in PCD sputum including neutrophil elastase (NE), free DNA, myeloperoxidase (MPO), interleukin (IL)-1β and IL-8 were also increased compared to healthy controls (all p<0.001), lower than in CF at baseline (p<0.05 to p<0.001) and comparable to CF on ETI. Similar, changes in the sputum proteome were less pronounced in PCD compared to CF at baseline, but comparable between PCD and CF on ETI.CONCLUSIONSClinically stable patients with PCD show changes in sputum viscoelastic properties, inflammation markers and the proteome that are less severe than in patients with CF at baseline, but comparable to CF patients on ETI therapy.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"1 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency. 口服中性粒细胞弹性酶抑制剂alvelestat治疗α -1抗胰蛋白酶缺乏症的两项随机对照2期研究。
IF 24.3 1区 医学
European Respiratory Journal Pub Date : 2025-09-18 DOI: 10.1183/13993003.01019-2025
J Michael Wells,Ingrid L Titlestad,Hanan Tanash,Alice M Turner,Kenneth R Chapman,Umur Ş Hatipoğlu,Monica P Goldklang,Jeanine M D'Armiento,Cheryl S Pirozzi,M Bradley Drummond,Igor Z Barjaktarevic,Wissam M Chatila,Megan S Devine,Charlie Strange,Robert A Sandhaus,Jacqueline M Parkin,Elizabeth Westfall,Vivian Y Lin,Robin Parks,Hui-Chien Kuo,Adzoa Ekue,Kelly L Moffitt,Jamie Inshaw,Inmaculada Aban,Mark T Dransfield,Robert A Stockley
{"title":"Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency.","authors":"J Michael Wells,Ingrid L Titlestad,Hanan Tanash,Alice M Turner,Kenneth R Chapman,Umur Ş Hatipoğlu,Monica P Goldklang,Jeanine M D'Armiento,Cheryl S Pirozzi,M Bradley Drummond,Igor Z Barjaktarevic,Wissam M Chatila,Megan S Devine,Charlie Strange,Robert A Sandhaus,Jacqueline M Parkin,Elizabeth Westfall,Vivian Y Lin,Robin Parks,Hui-Chien Kuo,Adzoa Ekue,Kelly L Moffitt,Jamie Inshaw,Inmaculada Aban,Mark T Dransfield,Robert A Stockley","doi":"10.1183/13993003.01019-2025","DOIUrl":"https://doi.org/10.1183/13993003.01019-2025","url":null,"abstract":"BACKGROUNDAlpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the AAT serpin anti-protease, leading to protease-anti-protease imbalance. Weekly intravenous AAT therapy (augmentation) is the only specific treatment available. Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy. Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD.METHODSWe conducted two complementary, double-blind, randomized, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 mg and 240 mg twice a day without augmentation. Primary and secondary endpoints were the change in blood NE (the putative target) and its activity in AATD (Aα-Val360 and desmosine/isodesmosine) as well as safety and tolerability.RESULTSWe enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS). Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at the 240 mg BID dose. There was no effect of 120 mg on disease activity biomarkers, whilst the 240 mg dose demonstrated significant reduction Aα-Val360 and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected.CONCLUSIONSAlvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice daily dose into a clinical endpoint study.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"56 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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