Respiratory Research最新文献

{"title":"Correction to: Epidemiology, ventilation management and outcomes of COVID-19 ARDS patients versus patients with ARDS due to pneumonia in the Pre-COVID era.","authors":"Fleur-Stefanie L I M van der Ven, Siebe G Blok, Luciano C Azevedo, Giacomo Bellani, Michela Botta, Elisa Estenssoro, Eddy Fan, Juliana Carvalho Ferreira, John G Laffey, Ignacio Martin-Loeches, Ana Motos, Tai Pham, Oscar Peñuelas, Antonio Pesenti, Luigi Pisani, Ary Serpa Neto, Marcus J Schultz, Antoni Torres, Anissa M Tsonas, Frederique Paulus, David M P van Meenen","doi":"10.1186/s12931-025-03176-y","DOIUrl":"https://doi.org/10.1186/s12931-025-03176-y","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"117"},"PeriodicalIF":5.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744352","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":"Risk of acute exacerbation of chronic obstructive pulmonary disease after COVID-19 recovery: a nationwide population-based cohort study.","authors":"Sang Hyuk Kim, Hyun Lee, Min Ji Kim, Youlim Kim, Kyung Hoon Min, Kwang Ha Yoo, Jong Seung Kim, Ji-Yong Moon","doi":"10.1186/s12931-025-03123-x","DOIUrl":"10.1186/s12931-025-03123-x","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is associated with severe Coronavirus disease 2019 (COVID-19) outcomes. However, it is uncertain whether the risk of acute exacerbation of COPD (AECOPD) increases after recovering from COVID-19.</p><p><strong>Methods: </strong>This study included 2,118 individuals with COPD from the Korea National Health Insurance Service database who were also diagnosed with COVID-19. Matched controls were chosen using 1:1 propensity score (PS) matching. We compared the risk of AECOPD after COVID-19 recovery between the COVID-19 cohort and matched controls between October 8, 2020, and December 31, 2021, using PS-matched Cox proportional hazard regression models.</p><p><strong>Results: </strong>During a median follow-up of 62 days (interquartile range, 29-179 days), including a median of 14 days of recovery time after COVID-19, 68 people (5.6%) in the COVID-19 cohort and 50 (3.9%) in the matched control group experienced AECOPD. Compared to the matched controls, the COVID-19 cohort had a significantly higher risk of overall AECOPD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.09-1.92). This increased risk was particularly evident for severe AECOPD among individuals who had severe COVID-19 within the first 30days post-recovery (aHR = 8.14, 95% CI = 3.32-19.97). When classified by COVID-19 severity, while severe COVID-19 significantly increased this risk (aHR = 2.97, 95% CI = 2.15-4.11), non-severe COVID did not significantly influence the risk of AECOPD, regardless of time duration or exacerbation severity.</p><p><strong>Conclusion: </strong>Individuals with COPD who had severe COVID-19 have increased risk of AECOPD after COVID-19 recovery, especially within the first 30 days after COVID-19 recovery.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"116"},"PeriodicalIF":5.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732633","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":"Molecular mechanisms and therapeutic targets of acute exacerbations of chronic obstructive pulmonary disease with Pseudomonas aeruginosa infection.","authors":"Zhiwei Lin, Shuang Liu, Ke Zhang, Tianyu Feng, Yewei Luo, Yu Liu, Baoqing Sun, Luqian Zhou","doi":"10.1186/s12931-025-03185-x","DOIUrl":"10.1186/s12931-025-03185-x","url":null,"abstract":"<p><strong>Background: </strong>Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of global mortality, with acute exacerbations of COPD (AECOPD) significantly increasing the disease's morbidity and mortality. Among the pathogens implicated in AECOPD, Pseudomonas aeruginosa (P. aeruginosa) is increasingly recognized as a major co-infecting bacterium. Despite its clinical importance, the molecular mechanisms and therapeutic targets underlying AECOPD with P. aeruginosa infection remain inadequately understood.</p><p><strong>Methods: </strong>We employed a multi-omics approach, integrating proteomic analyses of bronchoalveolar lavage fluid (BALF) and plasma with transcriptomic analysis of peripheral blood. A discovery cohort of 40 AECOPD with P. aeruginosa infection patients and 20 healthy controls was analyzed, followed by validation in an independent cohort of 20 patients and 10 controls. Differentially expressed proteins (DEPs) and genes (DEGs) were identified and subjected to protein-protein interaction (PPI) network analysis, weighted gene co-expression network analysis (WGCNA), and immune infiltration analysis. Molecular docking simulations were conducted to explore potential therapeutic agents.</p><p><strong>Results: </strong>Our integrative analysis identified key biomarkers, which played critical roles in oxidative stress and neutrophil extracellular trap (NET) formation, both of which were pivotal in the pathogenesis of AECOPD with P. aeruginosa infection. The combined analysis of BALF, plasma, and peripheral blood underscored the interplay between local lung changes and systemic immune responses. Functional enrichment analyses highlighted significant pathways related to bacterial defense, inflammation, and immune activation. Validation in an independent cohort confirmed the diagnostic value of three key proteins (AZU1, MPO, and RETN), with high area under the curve (AUC) values in ROC analyses. Molecular docking indicated strong binding affinities of these proteins with Pioglitazone and Rosiglitazone, suggesting potential therapeutic utility.</p><p><strong>Conclusions: </strong>This study provides a comprehensive understanding of the molecular mechanisms underlying AECOPD with P. aeruginosa infection, highlighting the pivotal roles of oxidative stress and NET formation in disease progression. The identified biomarkers offer promising diagnostic and therapeutic targets. Our findings pave the way for novel strategies to improve outcomes for AECOPD patients with P. aeruginosa infection. While the study design limits our ability to establish causality, these results provide important insights that warrant further investigation, particularly through longitudinal studies, to confirm the specific contributions of P. aeruginosa in exacerbations.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"115"},"PeriodicalIF":5.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721973","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":"Lung IL-13 gene signatures are associated with raised tissue eosinophils in COPD.","authors":"Karl J Staples, Jodie Ackland, Sruthymol Lukose, Bastian Angermann, Graham Belfield, Maria Belvisi, Raghothama Chaerkady, Damla Etal, Ashley Heinson, Sonja Hess, Ventzislava A Hristova, Michael Hühn, Christopher McCrae, Daniel Muthas, Lisa Öberg, Kristoffer Ostridge, Adam Platt, C Mirella Spalluto, Alastair Watson, Tom Wilkinson","doi":"10.1186/s12931-025-03177-x","DOIUrl":"10.1186/s12931-025-03177-x","url":null,"abstract":"<p><strong>Background: </strong>The role of eosinophils in COPD and their utility as biomarkers for cytokine targeting monoclonal therapies remains unclear. We investigated the distribution of eosinophils across different tissue compartments in COPD and analysed gene expression to understand the possible mechanistic drivers of eosinophilic inflammation in COPD.</p><p><strong>Methods: </strong>Blood and BAL from ex-smoking volunteers with mild/moderate COPD (n = 31) and healthy ex-smoking controls (n = 20), and bronchial biopsy tissue in a subcohort (n = 19 and n = 8, respectively) was analysed. Differentially-expressed genes (DEGs) were characterised using RNASeq. Proteomic analysis of BAL was conducted using mass-spectrometry.</p><p><strong>Results: </strong>COPD subjects had more eosinophils in blood and lung tissue compared to controls, with increased eosinophil protein CLC/Galectin-10 in BAL. However, peripheral blood eosinophil counts related poorly to numbers in lung tissue (rho = -0.09192, p = 0.3541) or proportions in BAL (rho = 0.01762, p = 0.4632). Tissue IL-5Rα expression was higher in frequent exacerbators and related to tissue eosinophils, but not peripheral blood eosinophils. Higher blood eosinophils were associated with DEGs that differed with compartment. Higher tissue eosinophil levels were associated with IL-13-induced DEGs including POSTN in bronchial brushes and CCL26 in bronchial biopsies. Gene-set enrichment analysis on data from brushings revealed significant enrichment of IL-4/IL-13, but not IL-5, pathways associated with eosinophil presence.</p><p><strong>Conclusion: </strong>Eosinophilic lung inflammation is related to exacerbation frequency, but lung eosinophils are not predicted by blood eosinophil counts in COPD. Our data suggest IL-13-mediated pathways may be responsible for the presence of tissue eosinophils in COPD. Further work to establish more predictive biomarkers of lung eosinophil biology are required to unlock this axis to optimised treatment.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"114"},"PeriodicalIF":5.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711685","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":"Mediastinal staging lymph node probability map in non-small cell lung cancer.","authors":"J Bordas-Martinez, J L Vercher-Conejero, G Rodriguez-González, P C Notta, C Martin Cabeza, N Cubero, R M Lopez-Lisbona, M Diez-Ferrer, C Tebé, S Santos, M Cortes-Romera, A Rosell","doi":"10.1186/s12931-025-03121-z","DOIUrl":"10.1186/s12931-025-03121-z","url":null,"abstract":"<p><strong>Background: </strong>Mediastinal lymph node (LN) staging is routinely performed using PET/CT and EBUS-TBNA. Promising predictive algorithms for lymph nodes have been reported for each technique, both individually and in combination. This study aims to develop a predictive algorithm that combines EBUS, PET/CT and clinical data to provide a probability of malignancy.</p><p><strong>Methods: </strong>A retrospective study was conducted on consecutive patients with non-small cell lung carcinoma staged using PET/CT and EBUS-TBNA. Lymph nodes were identified by level (N1, N2, and N3) and anatomical region (AR) (subcarinal, paratracheal, and hilar). A Standardized Uptake Value (SUV) was determined for each sampled LN. The ultrasound features collected included diameter in the short axis (DSA), morphology, border, echogenicity and the presence of the vascular hilum. A robust logistic regression model was used to construct an algorithm to estimate the probability of malignancy of the lymph node.</p><p><strong>Results: </strong>A total of 116 patients with a mean age of 66, 93% of whom were men, were included. 358 lymph nodes were evaluated, 51% of which exhibited adenocarcinoma and 35% were squamous, while 14% were classified as non-small-cell lung carcinoma. The model estimated the probability of malignancy for each lymph node using age, DSA, SUVmax, and AR. The Area Under the ROC curve, was 0.89. A user-friendly application was also developed ( https://ubidi.shinyapps.io/lymma/ .) CONCLUSIONS: The integration of patient clinical characteristics, EBUS features, and PET/CT findings may generate a pre-sampling malignancy probability map for each lymph node. The model requires prospective and external validation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"113"},"PeriodicalIF":5.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701793","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":"Aging shapes infection profiles of influenza A virus and SARS-CoV-2 in human precision-cut lung slices.","authors":"Melanie Brügger, Carlos Machahua, Trix Zumkehr, Christiana Cismaru, Damian Jandrasits, Bettina Trüeb, Sara Ezzat, Blandina I Oliveira Esteves, Patrick Dorn, Thomas M Marti, Gert Zimmer, Volker Thiel, Manuela Funke-Chambour, Marco P Alves","doi":"10.1186/s12931-025-03190-0","DOIUrl":"10.1186/s12931-025-03190-0","url":null,"abstract":"<p><strong>Background: </strong>The coronavirus disease 2019 (COVID-19) outbreak revealed the susceptibility of elderly patients to respiratory virus infections, showing cell senescence or subclinical persistent inflammatory profiles and favoring the development of severe pneumonia.</p><p><strong>Methods: </strong>In our study, we evaluated the potential influence of lung aging on the efficiency of replication of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as determining the pro-inflammatory and antiviral responses of the distal lung tissue.</p><p><strong>Results: </strong>Using precision-cut lung slices (PCLS) from donors of different ages, we found that pandemic H1N1 and avian H5N1 IAV replicated in the lung parenchyma with high efficacy. In contrast to these IAV strains, SARS-CoV-2 Early isolate and Delta variant of concern (VOC) replicated less efficiently in PCLS. Interestingly, both viruses showed reduced replication in PCLS from older compared to younger donors, suggesting that aged lung tissue represents a suboptimal environment for viral replication. Regardless of the age-dependent viral loads, PCLS responded to H5N1 IAV infection by an induction of IL-6 and IP10/CXCL10, both at the mRNA and protein levels, and to H1N1 IAV infection by induction of IP10/CXCL10 mRNA. Finally, while SARS-CoV-2 and H1N1 IAV infection were not causing detectable cell death, H5N1 IAV infection led to more cytotoxicity and induced significant early interferon responses.</p><p><strong>Conclusions: </strong>In summary, our findings suggest that aged lung tissue might not favor viral dissemination, pointing to a determinant role of dysregulated immune mechanisms in the development of severe disease.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"112"},"PeriodicalIF":5.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701792","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":"Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19.","authors":"Valentina Pujadas, Chiahsuan Chin, Narendra V Sankpal, James Buhrmaster, Ashwini Arjuna, Rajat Walia, Michael A Smith, Oliver Eickelberg, Ross M Bremner, Thalachallour Mohanakumar, Angara Sureshbabu","doi":"10.1186/s12931-025-03187-9","DOIUrl":"10.1186/s12931-025-03187-9","url":null,"abstract":"<p><p>The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"111"},"PeriodicalIF":5.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694200","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":"Increased circulating Endothelin-1 is a risk factor for ECMO use and mortality in neonates with congenital diaphragmatic hernia: a prospective observational study.","authors":"Lotte Lemloh, Aster de Vadder, Tamene Melaku, Bartolomeo Bo, Neil Patel, Stefan Holdenrieder, Andreas Mueller, Florian Kipfmueller","doi":"10.1186/s12931-025-03188-8","DOIUrl":"10.1186/s12931-025-03188-8","url":null,"abstract":"<p><strong>Background: </strong>Elevated levels of Endothelin-1 (ET-1), a vasoactive peptide, have been associated with adverse outcomes in neonates with congenital diaphragmatic hernia (CDH). However, the relationship between ET-1 levels and clinical outcomes remains poorly understood. This study aimed to investigate the kinetics of ET-1 levels in CDH neonates from birth to 48 h postnatally and assess its association with clinical comorbidities, the need for extracorporeal membrane oxygenation (ECMO), and mortality.</p><p><strong>Methods: </strong>A prospective single-center study was conducted, including 107 newborns with CDH from 2014 to 2022. Blood samples for ET-1 measurement were collected at birth, 6 h, and 48 h postnatally. The need for ECMO and mortality served as primary and secondary clinical endpoints. Based on the ET-1 values patients were assigned to ET-1 high, intermediate, and low groups. Statistical analyses, including ROC curve analysis and multivariate logistic regression, were performed to determine the predictive value of ET-1 levels.</p><p><strong>Results: </strong>Among the 107 CDH neonates 41 (38.3%) required ECMO and the overall mortality rate was 19.6%. Higher ET-1 levels at 0 and 48 h correlated significantly with the need for ECMO (p = 0.028 and p < 0.001) and mortality (p = 0.016 and p < 0.001). The high ET-1 group had a significantly higher rate of ECMO use (63.2%) and higher mortality (42.1%) compared to the ET-1 low group (15.4% and 0%). Furthermore, elevated ET-1 levels were associated with more severe disease characteristics including severe PH and biventricular dysfunction.</p><p><strong>Conclusions: </strong>Elevated ET-1 levels during the first 48 h of life in CDH neonates are significantly associated with increased rates of ECMO and mortality. These findings underline the potential of ET-1 as a predictive biomarker for poor outcomes in CDH and highlight its relevance in guiding therapeutic interventions.</p><p><strong>Trial registration: </strong>DKRS00034329.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"110"},"PeriodicalIF":5.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677395","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":"NLRP3 deficiency abrogates silica-induced neutrophil infiltration, pulmonary damage and fibrosis.","authors":"Maggie Lam, Kristian T Barry, Christopher J Hodges, Christopher M Harpur, James D H Ong, Sarah Rosli, Alison C West, Lovisa Dousha, Paul J Hertzog, Ashley Mansell, Michelle D Tate","doi":"10.1186/s12931-025-03192-y","DOIUrl":"10.1186/s12931-025-03192-y","url":null,"abstract":"<p><strong>Background: </strong>Silicosis is a progressive and often fatal occupational lung disease. The NLRP3 inflammasome is an innate immune sensor that is activated by silica. Accumulating evidence has implicated a role for NLRP3 in silicosis pathogenesis. In this study, we mechanistically elucidated the contribution of NLRP3 to silica-induced pulmonary disease.</p><p><strong>Methods: </strong>The in vivo role of NLRP3 was investigated following intranasal delivery of 2 mg of silica or diluent alone to wildtype, NLRP3 reporter, and NLRP3-deficient mice. Protein expression, inflammation, and histopathology were analyzed in the lung.</p><p><strong>Results: </strong>Intranasal administration of silica recapitulated the key pathological features of human silicosis, including nonresolving inflammation, the formation of silicotic nodules, and diffuse lung fibrosis. A reporter mouse placed under the native NLRP3 promoter revealed silica rapidly upregulated NLRP3 expression throughout the lung. NLRP3-deficient mice displayed marked early reductions in silica-induced IL-1β and IL-18 levels in the airways. Additionally, NLRP3 deficiency impaired the rapid infiltration of conventional Siglec-F^- and fibrotic Siglec-F⁺ neutrophils, which correlated with reduced levels of neutrophil elastase. Deficiency in acute NLRP3-mediated inflammation correlated with significantly reduced pulmonary transforming growth factor beta and alpha smooth muscle actin expression, tissue damage, and fibrosis in the chronic phase of disease progression. Importantly, this included reduced silicotic nodule size and cellularity.</p><p><strong>Conclusions: </strong>These findings highlight a major detrimental role for the NLRP3 inflammasome in driving silica-induced pulmonary neutrophil infiltration, TGFβ-mediated myofibroblast activation, tissue damage, and fibrosis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"109"},"PeriodicalIF":5.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677396","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":"Two novel genetic variants in the WFDC2 gene from patients with bronchiectasis.","authors":"Jeong-Min Kim, Soojin Hwang, Hye-Won Cho, Youngjun Kim, Dong Mun Shin, Eun Lee, Myungshin Kim, Cheonghwa Lee, Jong-Won Kim, Hyun-Young Park, Beom Hee Lee, Mi-Hyun Park","doi":"10.1186/s12931-025-03183-z","DOIUrl":"10.1186/s12931-025-03183-z","url":null,"abstract":"<p><strong>Background: </strong>Bronchiectasis is a chronic respiratory condition characterized by irreversible dilation and damage of the bronchial walls, leading to impaired mucociliary clearance and recurrent infections. Its etiology is diverse; however, genetic factors are critical in its congenital and severe forms. Therefore, we aimed to identify two novel variants of the WFDC2 gene, known as antiprotease, from patients with bronchiectasis and/or related phenotypes using trio-based whole-genome sequencing analysis.</p><p><strong>Methods: </strong>Patients with bronchiectasis were recruited as trio or quad, and their genomic DNA was isolated. The whole genome sequence was produced and analyzed to find causative genetic variants through an internal pipeline using GATK-DRAGEN-Hail. Variant interpretation and pathogenicity assessment using various in-silico tools were performed to identify causative variants. Clinical characteristics were collected from the patients with identified variants.</p><p><strong>Results: </strong>In this discovery study involving four patients from three families, two novel variants in the WFDC2 gene were identified and suggested as causative pathogenic variants for bronchiectasis. The first variant (c.291 C > G, p.(Cys97Trp)) is a homozygous variant that was not found in the population genome data. However, the second variant (c.278G > C, p.(Cys93Ser)) was identified in another patient as a heterozygous variant, forming a compound heterozygous state with the first variant. Notably, both variants, located at cysteine residues that are conserved across many species, are crucial in forming disulfide bonds essential for protein structure and function. In-silico analyses classified both variants as pathogenic; they were also identified as likely pathogenic according to the American College of Medical Genetics and Genomic guidelines. Furthermore, in an expansion study, the homozygous variant was also found in two unrelated patients.</p><p><strong>Conclusion: </strong>We identified two novel bi-allelic variants located at cysteine residues in the WFDC2 gene from patients with bronchiectasis who had previously not received a genetic diagnosis. Therefore, considering prior research on the pivotal role of the WFDC2 protein in the respiratory system, these two novel variants may serve as potential diagnostic markers and therapeutic targets for bronchiectasis.</p><p><strong>Clinical trial number: </strong>Not Applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"108"},"PeriodicalIF":5.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671689","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}