American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"MUC5B Overproduction Disrupts Club Cell Mediated Alveolar Repair in COPD.","authors":"Yan Hu, Stephen A Chang, Minh D Le, Rushikesh Shinde, Shah S Hussain, Steven M Rowe, Isabelle Salwig, David A Schwartz, Melanie Koenigshoff, Christopher M Evans","doi":"10.1093/ajrcmb/aanag218","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag218","url":null,"abstract":"<p><strong>Rationale: </strong>Chronic obstructive pulmonary disease (COPD) is characterized by small airway disease (SAD) and emphysema, but mechanisms linking these pathologies remain unclear. SAD arises early and is the primary site of airflow limitation, marked by epithelial injury, mucus obstruction, and bronchiole loss. Excessive production of the mucin MUC5B by bronchiolar club cells is a key feature of SAD and is associated with impaired mucociliary clearance and inflammation. Club cells also function as progenitors for alveolar type II (ATII) cells, yet how their regenerative capacity is altered in COPD is unknown.</p><p><strong>Objectives: </strong>To determine whether MUC5B overproduction in small airway club cells alters their capacity to regenerate ATII cells and contributes to emphysema progression.</p><p><strong>Methods: </strong>We assessed MUC5B expression in human emphysematous lungs and a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Genetic approaches were used to overexpress or conditionally delete Muc5b in club cells to evaluate effects on club-to-ATII differentiation, alveolar structure, and lung function in health and emphysema.</p><p><strong>Results: </strong>MUC5B is overexpressed in small airway club cells in human emphysematous lungs and animal models. Muc5b overexpression impairs differentiation of club cells into ATII cells and worsened lung function decline in emphysema. Importantly, conditional deletion of Muc5b during early disease stages restored club cell-derived alveolar regeneration.</p><p><strong>Conclusions: </strong>MUC5B overproduction links SAD to defective alveolar repair by limiting club cell progenitor function. Targeting MUC5B may restore epithelial regeneration and slow early COPD progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating lung fibrosis by restoring AT2 cell identity: does a S100A2-RAGE pathway really exist?","authors":"Ziru Chen","doi":"10.1093/ajrcmb/aanag216","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag216","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to Chen: Mitigating lung fibrosis by restoring AT2 cell identity: does a S100A2-RAGE pathway really exist?","authors":"Qi Tan","doi":"10.1093/ajrcmb/aanag217","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag217","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling BPD anew: TSP1 at the intersection of mechanical signaling and bronchopulmonary dysplasia.","authors":"Miguel A Alejandre Alcázar","doi":"10.1093/ajrcmb/aanag214","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag214","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining GRAMD2 expression in the alveolar epithelium using organoid and single cell approaches.","authors":"Hua Shen, Weimou Chen, Minxiao Yang, Yixin Liu, Alessandra Castaldi, Jonathan Castillo, Yanbin Ji, Masafumi Horie, Per Flodby, Shivah Sundar, Changgong Li, Parviz Minoo, Crystal N Marconett, Beiyun Zhou, Zea Borok","doi":"10.1093/ajrcmb/aanag167","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag167","url":null,"abstract":"<p><p>Alveolar epithelial regeneration is critical for normal lung function and disrupted in disease. Precise identification of alveolar epithelial cell populations, particularly type I (AT1) cells, remains a barrier to understanding alveolar homeostasis and repair. We previously identified GRAM domain-containing 2 (GRAMD2) as enriched in distal alveolar epithelium, with predominant expression in type I (AT1) cells. However, recent single-cell datasets reveal low level Gramd2 transcripts in other lung epithelial populations raising questions about specificity. To address this, we performed immunofluorescence of whole lung and cytospins of GFPhigh cells from Gramd2CreERT2;mTmG mice. Cre-induced lineage labeling predominantly marked cells expressing established AT1 markers, with minimal labeling of AT2 or club cells. GFPhigh cells were enriched for AT1 cells and formed organoids in culture that over time showed expression of AT2 and airway markers, suggesting plasticity. Despite apparent purity of the GFPhigh population by immunostaining, single-cell RNAseq identified AT2 cells and a small number of club cells in the labeled population, revealing discordance between GRAMD2 transcript and protein expression. Gramd2CreERT2;mTmG mice enable enrichment of AT1 cells but have limitations for definitive lineage tracing.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anchors Astray: An Oxidized tRNA Fragment Drives Pulmonary Fibrosis by Uncoupling cAMP Signaling.","authors":"Sean M Fortier","doi":"10.1093/ajrcmb/aanag213","DOIUrl":"10.1093/ajrcmb/aanag213","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histo-blood group secretor status does not influence mucus plugging or asthma exacerbation outcomes.","authors":"Kritika Khanna, Annabelle R Charbit, Monica Tang, Eugene R Bleecker, Deborah A Meyers, Mario Castro, Suzy A Comhair, Serpil C Erzurum, Loren C Denlinger, Nizar N Jarjour, Mats W Johansson, Elliot Israel, Bruce D Levy, Wendy Moore, David T Mauger, Mark L Schiebler, Kaharu Sumino, Sally E Wenzel, Erin D Gordon, Prescott G Woodruff, Max A Seibold, John V Fahy","doi":"10.1093/ajrcmb/aanag158","DOIUrl":"10.1093/ajrcmb/aanag158","url":null,"abstract":"<p><strong>Rationale: </strong>Fucosyltransferase2 (FUT2) activity in airway epithelial cells (AECs) determines if histo-blood group antigens (HBGAs) are components of mucin glycans. \"Secretors\" (with at least one functioning copy of FUT2) have HBGA-decorated mucins, whereas \"non-secretors\" (homozygous for null mutations in FUT2) do not. Prior research in animal models of asthma and in human asthma suggests that non-secretor status protects against mucus plugging and that type O secretors are prone to exacerbations.</p><p><strong>Methods: </strong>Secretor status was determined in 507 participants in the Severe Asthma Research Program-3 (SARP-3) using a fucose lectin binding assay in sputum and FUT2 genotyping. Blood group was determined using ABO genotyping. Mucus plugging was assessed using the computed tomography (CT)-derived mucus plug segment score, and exacerbation frequency was determined prospectively. We also explored the functional effects of secretor status on mucin outcomes in AECs in culture.</p><p><strong>Results: </strong>Secretor status determined by lectin binding in sputum was strongly concordant with FUT2 genotype. Among the SARP-3 participants, 26.2% were non-secretors, 32.3% were type O secretors, and 41.4% were non-type O secretors. Mucus plug segment scores were similar in secretor and non-secretor subgroups, and exacerbation rates were similar in type O secretors and other secretor subgroups. Mucin gene expression in AECs from secretors and non-secretor donors was similar, as were measures of mucociliary clearance and mucus gel viscosity and elasticity.</p><p><strong>Conclusion: </strong>Secretor status does not influence mucus plugging or exacerbation outcomes in the SARP-3 cohort, and it does not have significant effects on mucin expression or biophysical properties of airway mucus.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The FAulT in our Phagocytes: Dysregulated macrophage lipid handling is sufficient to induce pulmonary fibrosis.","authors":"Sarah E Holton, Elie El Agha","doi":"10.1093/ajrcmb/aanag209","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag209","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary ILC2 Priming as a Link Between Severe Early-Life RSV Bronchiolitis and Asthma.","authors":"An V Q Pham, Afia Kwayie, Anh T Q Phan, Kent A Willis, Diego R Hijano, Emma Jurkovac, Stephania A Cormier, Luan D Vu","doi":"10.1093/ajrcmb/aanag207","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag207","url":null,"abstract":"<p><p>Severe respiratory syncytial virus (RSV) bronchiolitis in infancy is associated with increased childhood asthma risk, but the mechanisms that sustain airway vulnerability remain unresolved. Airway samples from infants with severe RSV disease and experimental models show robust IL-33 responses and pulmonary group 2 innate lymphoid cell (ILC2) activation during acute infection. Additionally, neonatal IL-33 and allergen-rechallenge studies demonstrate that ILC2s can persist and acquire memory-like properties. These observations support, but do not establish, a model in which severe lower-airway RSV disease primes ILC2s or their tissue niche for exaggerated responses to later allergens. Beyond limited interferon control and prolonged epithelial injury, which may amplify IL-33/ST2 signaling during a developmental window when long-lived lung ILC2 populations are established, we focus on additional candidate mechanisms that could sustain this priming. These include metabolic pathways governing glycolysis, lipid utilization, iron uptake, and mitochondrial function; epigenetic mechanisms involving chromatin remodeling and histone or DNA modifications; and neuroimmune signals that regulate ILC2 activation and recall. Direct evidence that RSV induces durable, cell-intrinsic metabolic, epigenetic, or neuroimmune reprogramming of infant pulmonary ILC2s is currently lacking. Longitudinal ILC2 profiling and adoptive transfer of RSV-experienced versus control ILC2s are needed to test this model. Maternal vaccination and long-acting monoclonal antibodies now provide an opportunity to determine whether preventing severe early-life RSV disease alters airway immune programming and subsequent asthma risk.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hidden in Plain Sight: New Respiratory Discoveries from Existing Public Datasets.","authors":"Ilona Jaspers, Benjamin D Singer, Megan N Ballinger, Andrew J Halayko","doi":"10.1093/ajrcmb/aanag205","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag205","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}