Respiratory Research最新文献

{"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}

{"title":"Deciphering the transcriptomic landscape of systemic lupus erythematosus-associated pulmonary arterial hypertension.","authors":"Yutong Li, Junyan Qian, Xiaoyue Deng, Leyao Ma, Qizhi Yuan, Qian Wang, Zhuang Tian, Xiaofeng Zeng, Xinzhuang Yang, Jiuliang Zhao, Mengtao Li","doi":"10.1186/s12931-025-03169-x","DOIUrl":"10.1186/s12931-025-03169-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multi-organ damage. Pulmonary arterial hypertension (PAH) is one of the life-threatening complications of SLE. The underlying cause of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been fully comprehended. Besides the mechanisms implicated in the development of PAH, such as damage to the endothelial cells, the aberrant activation of the immune system also plays a substantial role in the pathogenesis of SLE-PAH.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this study, peripheral blood samples from 100 patients with SLE-PAH and 95 patients of SLE without PAH (SLE-nonPAH) were obtained for RNA sequencing and comprehensive transcriptomic analysis. Pathway enrichment analysis was performed based on differentially expressed genes (DEGs) between SLE-PAH and SLE-nonPAH to elucidate the mechanisms potentially driving the development of PAH in SLE patients. Utilizing consensus non-negative matrix factorization (cNMF), we also conducted a detailed analysis to identify distinct subgroups within the SLE-PAH population. Meanwhile, the protein-protein interaction (PPI) analysis was performed and hub genes among the SLE-PAH subgroups were detected. Common transcription factors (TFs) of detected hub genes were also discovered to serve as potential therapeutic targets.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Inflammatory signaling pathways, notably those involving interferon and TNFα, were found to play an important role in the SLE-PAH. Utilizing cNMF method, three unique subgroups of SLE-PAH patients were delineated, each characterized by a distinct level of inflammatory activity. Specifically, the high inflammation subgroup, marked by the activity of Interleukin-6 (IL-6), exhibited a milder form of PAH. In contrast, the subgroup with moderate inflammation displayed the most pronounced PAH symptoms. Further disease enrichment analysis revealed that, beyond the dysregulated inflammatory pathways, patients with the most severe PAH exhibited distinct pathogenic transcriptomic profiles that disrupted vascular smooth muscle homeostasis, a critical component of vascular health. In the most severely affected subgroup, 13 hub genes were identified. Additionally, two transcription factors commonly associated with these genes, KLF1 and GATA1, were discovered, which may serve as potential therapeutic targets.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our investigation establishes inflammation as a key driver in the development of SLE-PAH. Patients who presented with concurrent dysregulations in inflammatory responses along with PAH-specific pathogenic markers exhibited a marked increase in the severity of their PAH. The insights gleaned from our transcriptomic analysis reveal the intricate interplay between inflammatory mechanisms and the molecular substrates of PAH. This nuanced understanding paves the way for more targeted and effective therapeutic approaches","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"106"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658975","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":"Perspective and update: intrapleural fibrinolytic therapy for pleural infections and other forms of pleural organization.","authors":"Torry A Tucker, Andrey A Komissarov, Steven Idell","doi":"10.1186/s12931-025-03184-y","DOIUrl":"10.1186/s12931-025-03184-y","url":null,"abstract":"<p><p>Intrapleural fibrinolytic therapy (IPFT), also known as intrapleural enzymatic therapy (IET), has been utilized for decades to treat pleural infections by expediting drainage in patients with pleural organization. The successful MIST2 trial demonstrated that IPFT improves pleural opacification, reduces hospital stays, and decreases short-term surgical referrals. Despite significant progress, gaps remain in identification of the optimal fibrinolytic agents, dosing, and safety improvements. IPFT is generally recommended for patients with loculation and failed pleural drainage, with a consensus panel advocating for combined tissue plasminogen activator (tPA) and DNase therapy. How each agent may affect the activity or function of the other in the combination remains unclear. While IPFT can reduce the need for surgical intervention, there are relatively few comparative clinical trials to guide initial therapy. Emerging low-dose IPFT treatment approaches may benefit patients who are poor surgical candidates. Personalized IPFT candidate approaches, such as the Fibrinolytic Potential Assay (FPA), could refine dosing and improve outcomes. Additionally, biomarkers like pleural fluid PAI-1 and suPAR concentrations may predict clinical outcomes and guide treatment. New therapeutic agents, including PAI-1 inhibiting peptides and mesothelial profibrogenic targets, are under investigation to enhance IPFT efficacy. These advances hold promise for improving the management of pleural infections and other forms of pleural organization.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"105"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659030","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":"Extracellular vesicle-bound S100A8/A9 is differentially expressed in septic shock and prompts acute lung injury.","authors":"Jiangmei Wang, Weiliang Wu, Tingting Wen, Guoping Zheng, Guanguan Qiu, Huifeng Qian, Ruoyang Zhang, Jie Xia, Yaoqin Hu, Ruoqiong Huang, Ruoxi Zang, Zhenkai Le, Qiang Shu, Jianguo Xu","doi":"10.1186/s12931-025-03181-1","DOIUrl":"10.1186/s12931-025-03181-1","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported to participate in the pathogenesis of sepsis. However, the alteration of EV-bound S100A8/A9 during septic shock, along with the role of S100A8/A9 in driving acute lung injury, remains unexplored.</p><p><strong>Methods: </strong>EVs were isolated from the plasma of patients upon admission with sepsis or septic shock, as well as from healthy controls. Levels of EV S100A8/A9 were assayed via ELISA. To examine the effects and underlying mechanisms of septic shock EVs in acute lung injury, these EVs were administered intratracheally into wild-type C57BL/6 mice or mice with a deficiency of advanced glycation end-products (RAGE). In addition, a mouse model of polymicrobial sepsis was introduced using cecal ligation and puncture (CLP).</p><p><strong>Results: </strong>Levels of EV S100A8/A9 were significantly elevated in patients with sepsis or septic shock compared to healthy controls. Receiver operating characteristic (ROC) analysis demonstrated that EV S100A8/A9 effectively distinguished between septic shock and sepsis and had predictive potential for the development of ARDS. Notably, the levels of S100A8/A9 in EVs and alveolar macrophages from CLP mice were significantly higher than those in sham mice. Intratracheal administration of septic shock EVs directly induced acute lung injury and M1 macrophage polarization in a lipopolysaccharide-independent manner. Septic shock EVs were efficiently taken up by alveolar macrophages in vivo, leading to a significant increase in S100A8/A9 levels, which was inhibited by preincubating the EVs with an S100A8/A9 neutralizing antibody. Additionally, mice with deficiency in RAGE, a receptor for S100A8/A9, were partially protected from acute lung injury induced by septic shock EVs. In vitro, septic shock EVs prompted a proinflammatory response in bone marrow-derived macrophages. This response was blocked by preincubating the EVs with the S100A8/A9 neutralizing antibody.</p><p><strong>Conclusions: </strong>Our results suggested that EV S100A8/A9 has potential value in distinguishing septic shock from sepsis and predicting the development of ARDS. Septic shock EVs-induced lung injury is at least partially mediated through S100A8/A9-RAGE pathway, involving the activation of alveolar macrophages.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"107"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658943","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}