European Respiratory Journal最新文献

{"title":"Small extracellular vesicles and induction of epithelial to mesenchymal transition in lymphangioleiomyomatosis.","authors":"Amina Jouida,Lucas Souza Dantas,Donal O'Malley,Evelyn Lynn,Marissa O'Callaghan,Minzhe Guo,Patrick McFadden,Grace Buckley,Michael P Keane,Cormac McCarthy","doi":"10.1183/13993003.02455-2024","DOIUrl":"https://doi.org/10.1183/13993003.02455-2024","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"109 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652895","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}

{"title":"Multi-omic spatial profiling reveals the unique SARS-CoV-2 lung microenvironment and collagen VI as a predictive biomarker in severe COVID-19.","authors":"Éanna Fennell, Graham S Taylor, Ciara I Leahy, Aisling M Ross, Gary Reynolds, Tracey Perry, Esther Youd, Jacob Skidmore, Radwan Ramzi, Radwan Darwish, Kelly J Hunter, Benjamin E Willcox, Philip Jermann, Chowdhury Arif Jahangir, Arman Rahman, William M Gallagher, Nadezhda Nikulina, Bassem Ben Cheikh, Oliver Braubach, Aaron T Mayer, Lawrence S Young, Dimitris Grammatopoulos, Sian Faustini, Alex Richter, Alexander C Dowell, Tonny Venith, Onn S Thein, Dhruv Parekh, Kylie B R Belchamber, David R Thickett, Aaron Scott, Richard Attanoos, Lucia Mundo, Stefano Lazzi, Lorenzo Leoncini, Gareth Leopold, Neil Steven, Janine Marie, Bülow Sand, Morten A Karsdal, Diana Julie Leeming, Stefan Dojcinov, Aedin Culhane, Paul G Murray, Matthew R Pugh","doi":"10.1183/13993003.01699-2023","DOIUrl":"10.1183/13993003.01699-2023","url":null,"abstract":"<p><strong>Background: </strong>Whilst COVID-19 is primarily a respiratory infection, few studies have characterized the immune response to COVID-19 in lung tissue. We sought to understand the pathogenic role of microenvironmental interactions and the extracellular matrix in post-mortem COVID-19 lung using an integrative multi-omic approach.</p><p><strong>Methods: </strong>Post-mortem formalin fixed paraffin embedded lung tissue from fatal COVID-19 and non-respiratory death control lung underwent multi-omic evaluation by Quantseq Bulk RNA sequencing, Nanostring GeoMX spatial transcriptomics, RNAscope, multiplex immunofluorescence and immunohistochemistry, to evaluate virus distribution, immune composition and the extracellular matrix. Markers of extracellular synthesis and breakdown were measured in the serum of 215 patients with COVID-19 and 54 healthy volunteer controls by ELISA.</p><p><strong>Results: </strong>We found that SARS-CoV-2 infection was restricted to the pneumocytes and macrophages of early-stage disease. Spatial analyses revealed an immunosuppressive virus microenvironment, enriched for PDL1+IDO1+ macrophages and depleted of T-cells. Oligoclonal T-cells in COVID-19 lung showed no enrichment of SARS-CoV-2 specific T-cell receptors. Collagen VI was upregulated and contributed to alveolar wall thickening and impaired gas exchange in COVID-19 lung. Serum from COVID-19 patients showed increased levels of PRO-C6, a marker of collagen VI synthesis, predicted mortality in hospitalized patients.</p><p><strong>Conclusions: </strong>Our data refine the current model of respiratory COVID-19 with regard to virus distribution, immune niches, and the role of the non-cellular microenvironment in pathogenesis and risk stratification in COVID-19. We show that collagen deposition is an early event in the course of the disease.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233659","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}

{"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":"https://doi.org/10.1183/13993003.02341-2024","url":null,"abstract":"<p><strong>Background: </strong>Chronic dry cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic dry cough representing a substantial health burden, 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-value <5×10^-8 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":16.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated spatial and single-cell transcriptomics reveal PAK kinase as a therapeutic target in fibroblastic foci and dense fibrosis of IPF.","authors":"Naoaki Watanabe,Masahiro Yoshida,Yuta Hirano,Shota Fujimoto,Sachi Matsubayashi,Takashi Ishiguro,Nobumasa Takahashi,Yoshihiko Shimizu,Noboru Takayanagi,Yoshinori Kawabata,Yutaro Mori,Koji Okamoto,Shunsuke Minagawa,Kazuyoshi Kuwano,Jun Araya,Yusuke Yamamoto,Yu Fujita","doi":"10.1183/13993003.00022-2025","DOIUrl":"https://doi.org/10.1183/13993003.00022-2025","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive fibrosis of lung parenchyma. The histopathology of IPF exhibits temporal and spatial heterogeneity, including immature fibroblastic foci (FF) and densely collagenized fibrosis. FF serve as dynamic niches of profibrotic fibroblasts and play a pivotal role in fibrosis progression and transition into dense fibrosis (DF). Here, we integrated single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics to elucidate cellular heterogeneity and the novel cell type involved not only in FF formation but also in DF development. We identified a novel myofibroblast population, WNT5A+ CTHRC1+ myofibroblasts, enriched in both FF and DF regions, underscoring their pivotal role in fibrosis progression. Differential gene expression analysis revealed the activation of p21-activated kinase 2 (PAK2) in these fibrotic areas, including WNT5A+ CTHRC1+ myofibroblasts. PAK inhibition significantly suppressed TGF-β-induced myofibroblast differentiation and collagen production in IPF-derived fibroblasts. Furthermore, in a bleomycin-induced lung fibrosis mouse model, intraperitoneal administration of the PAK inhibitor significantly attenuated fibrotic progression. This study highlights the therapeutic potential of PAK inhibition for IPF, particularly targeting pathogenic fibroblasts within both FF and DF regions. By leveraging spatial transcriptomics and scRNA-seq, we provide a comprehensive molecular and cellular atlas of FF and DF in IPF lung tissue, offering new insights into fibrosis progression and therapeutic intervention.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"677 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652894","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}

{"title":"Optimal dosing and duration of linezolid for the treatment of multidrug-resistant and rifampicin-resistant tuberculosis: An individual patient data meta-analysis.","authors":"Nakwon Kwak,Joong-Yub Kim,Areum Han,Catherine Berry,Maria Beumont,Tweed Conor,Angela Crook,Keertan Dheda,Stella Fabiane,Muse O Fadeyi,Salah Foraida,Tinne Gils,Thi Thanh,Thuy Hoang,Menal A Jham,Richard A Murphy,Binh Hoa Nguyen,Thi Mai,Phuong Nguyen,Bern Thomas Nyang'wa,Suzette Oelofse,Seokyung Hahn,Jae-Joon Yim","doi":"10.1183/13993003.00315-2025","DOIUrl":"https://doi.org/10.1183/13993003.00315-2025","url":null,"abstract":"BACKGROUNDThe optimal dosing strategy of linezolid for treating multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) remains unclear. We conducted an individual patient data (IPD) meta-analysis to determine the optimal linezolid dosing strategy.METHODSWe searched PubMed, Embase, and Scopus for randomised controlled trials (RCTs) and prospective cohort studies on short-course, all-oral regimens containing linezolid for treating MDR/RR-TB through 31 August 2023. Patients were grouped according to linezolid dosing patterns. Time to treatment success and adverse events≥grade 3 were analysed using the Fine-Gray sub-distribution hazard model.RESULTSOf 12 eligible studies, 8 (4 RCTs, 4 prospective) were included. Overall, 945 patients were grouped as follows: group 1 (600 mg linezolid for 8 weeks), group 2 (600 mg for 16 weeks, then 300 mg for 8 weeks), group 3 (600 mg for 39 weeks), and group 4 (1200 mg for 25 weeks). Proportions of patients achieving treatment success were 59·1%, 90·4%, 91·3%, and 96·0%, respectively. Compared with group 2, groups 1 (adjusted sub-distribution hazard ratio [aSHR], 0·24, 95% confidence interval [CI], 0·08-0·71) and 3 (aSHR, 0·36, 95% CI, 0·16-0·81) had lower success rates. While group 4 showed no significant difference in treatment success versus group 2 (aSHR, 0·57, 95% CI, 0·23-1·43), it had a higher rate of adverse events≥grade 3 (aSHR, 2·29, 95% CI, 1·37-3·83).CONCLUSIONA dosing strategy of 600 mg linezolid daily for 16 weeks, then 300 mg for 8 weeks, could be optimal for treating MDR/RR-TB when considering effectiveness and safety.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"29 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652896","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}

{"title":"Reply: Tofacitinib is a step forward for management of patients with interstitial lung disease associated with anti-MDA5-positive dermatomyositis.","authors":"Wanlong Wu,Shuang Ye","doi":"10.1183/13993003.00699-2025","DOIUrl":"https://doi.org/10.1183/13993003.00699-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"9 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629968","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}

{"title":"How to treat patients with MDA5-associated rapidly progressive interstitial lung disease? Which immunosuppressive therapy for which patients?","authors":"Yurdagül Uzunhan,Baptiste Hervier","doi":"10.1183/13993003.00446-2025","DOIUrl":"https://doi.org/10.1183/13993003.00446-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"37 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629988","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}

{"title":"A reason to celebrate: multimodal treatments and recent improvements in the long-term outcomes of patients with chronic thromboembolic pulmonary hypertension.","authors":"Irene M Lang","doi":"10.1183/13993003.00562-2025","DOIUrl":"https://doi.org/10.1183/13993003.00562-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"15 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629969","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}

{"title":"Neutrophils in pleural infection: untapped potential for targeted therapeutics.","authors":"Amy Gilmour,James D Chalmers","doi":"10.1183/13993003.00861-2025","DOIUrl":"https://doi.org/10.1183/13993003.00861-2025","url":null,"abstract":"","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"16 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630500","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}

{"title":"A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4.","authors":"Dave Singh, Patricia Guller, Fred Reid, Sarah Doffman, Ulla Seppälä, Ioannis Psallidas, Rachel Moate, Rebecca Smith, Joanna Kiraga, Eulalia Jimenez, Dennis Brooks, Aoife Kelly, Lars H Nordenmark, Muhammad Waqas Sadiq, Luis Mateos Caballero, Chris Kell, Maria G Belvisi, Hitesh Pandya","doi":"10.1183/13993003.02231-2024","DOIUrl":"10.1183/13993003.02231-2024","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.</p><p><strong>Methods: </strong>FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV₁) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV₁, time-to-first COPD composite exacerbation event and safety.</p><p><strong>Results: </strong>The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV₁ (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV₁ (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements <i>versus</i> placebo in change from baseline in pre-bronchodilator FEV₁ (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV₁ (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.</p><p><strong>Conclusion: </strong>Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals <i>versus</i> placebo in a subgroup of patients with COPD with a high risk of exacerbations.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742697","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}