American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Blast These Dying Fibroblasts in Asthma.","authors":"Y S Prakash","doi":"10.1093/ajrcmb/aanag160","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag160","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700589","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":"Dual epithelial-mesenchymal induction of Sfrp1/Frzb constrains alveolar epithelial differentiation in neonatal hyperoxia-induced lung injury.","authors":"Ming Xu, Liyan Xiang, Gongxia Ling, Xinyu Chen, Yanqing Hu, Huihong Wang, Chaonan Zhu, Wanqi Miao, Manjun Zhang, Saverio Bellusci, Hailin Zhang, Jin-San Zhang, Lei Chong","doi":"10.1093/ajrcmb/aanag152","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag152","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is a major complication of prematurity, characterized by impaired alveolar epithelium regeneration and long-term respiratory morbidity. The cellular basis of this defect and the underlying epithelial-mesenchymal signals remain unclear. To define alveolar type 2 (AT2) cell heterogeneity and regenerative capacity, we analyzed lineage-traced AT2 cells in neonatal mice exposed to hyperoxia (85% O2, postnatal days 1-14). We assessed cellular states and function by flow cytometry, transcriptomics, and organoid assays. During normal lung development, AT2 cells gradually segregated into two transcriptionally distinct subpopulations, TomHigh and TomLow. TomHigh cells exhibited canonical AT2 identity, lipid metabolism, and enhanced mitochondrial function, showing strong organoid-forming and differentiation potential. TomLow cells displayed metabolic restriction and limited regenerative capacity. Hyperoxia caused alveolar simplification, expanding TomLow cells at the expense of TomHigh cells. AT2 cells entered a proliferative state and became Krt8+ transitional cells, but RNA velocity and lineage analyses showed impaired maturation toward AT1 cells, leading to persistent AT1 deficiency. Hyperoxia induced Sfrp1 and Frzb expression in a rare but detectable Sftpc+Acta2+ AT2 subset, and more prominently in Pdgfra+ fibroblasts, which adopted a myofibroblast-like phenotype. Fibroblast-epithelial co-culture and fibroblast-specific Sfrp1/Frzb overexpression impaired organoid formation and reduced AT2-to-AT1 differentiation. These findings identify a fibroblast-dominated Sfrp1/Frzb-mediated niche that constrains AT2 differentiation into AT1 cells, providing a cellular basis for impaired alveolar regeneration in BPD and suggesting potential therapeutic targets.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668157","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":"Metabolic Control of Alveolar Epithelial Regeneration: Implications for Lung Repair and Pulmonary Fibrosis.","authors":"Morgan A Pantuck, Ying Tian","doi":"10.1093/ajrcmb/aanag155","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag155","url":null,"abstract":"<p><p>Alveolar type 2 (AT2) cells are the resident progenitors of the distal lung. They maintain tissue homeostasis and regenerate the alveolar surface after injury through coordinated self-renewal and differentiation into alveolar type 1 (AT1) cells. When this differentiation program fails, AT2 cells accumulate in aberrant intermediate states, now recognized as the epithelial \"transitional state\" or alveolar differentiating intermediate (ADI), a defining feature of idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases. Although the signaling pathways and transcription factors governing AT2 cell fate have been extensively characterized, the metabolic requirements for successful AT2-to-AT1 differentiation remain poorly understood. Emerging evidence indicates that AT2 cells undergo dynamic metabolic reprogramming during repair, with fatty acid oxidation, glucose metabolism, and glutamine catabolism each playing temporally distinct and mechanistically integrated roles. In IPF, AT2 cells exhibit profound mitochondrial structural abnormalities that compromise oxidative metabolism and likely underlie, at least in part, the broader pattern of metabolic dysregulation observed in diseased epithelium. This mitochondrial dysfunction, together with Warburg-like glycolytic reprogramming and impaired fatty acid oxidation, may function not only as a consequence of epithelial injury but also as a driver of differentiation failure. This review synthesizes current evidence, evaluates causal relationships among metabolic pathways, integrates metabolism with established signaling networks, and proposes a translational framework for metabolism-directed restoration of alveolar repair capacity in fibrotic lung disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663412","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":"Lung endothelial cytopathic tau is sufficient to impair long-term potentiation during infection.","authors":"Mike T Lin, Mikhail Alexeyev, Jakob Körbelin, Chun Zhou, Samantha D Chaney, Chung-Sik Choi, Charu Shastri, Hector D Chavarria-Bernal, Nancy H Chen, Madeline Stone, Allison J Bauman, Linn Ayers, Reece P Stevens, Ji Young Lee, Sarah L Sayner, Ron Balczon, Amy R Nelson, Troy Stevens","doi":"10.1093/ajrcmb/aanag040","DOIUrl":"10.1093/ajrcmb/aanag040","url":null,"abstract":"<p><p>Cytopathic tau variants are recovered from the lung, circulation, and brain following lower respiratory tract infection. Cytopathic tau injures the lung and brain, yet its cellular origin during infection is unknown. Here, we assessed whether lung capillary endothelium is a source of cytopathic tau that contributes to brain injury during infection. Alveolar-capillary permeability was higher in tau knockout than wild-type mice following sublethal Pseudomonas aeruginosa infection, indicating that endogenously expressed tau contributes to integrity of the lung's gas exchange unit. Hippocampal long-term potentiation was inhibited following sublethal infection in wild-type but not tau knockout mice, even though the blood-brain barrier was not overtly disrupted. Tau expression solely in lung capillaries of tau knockout mice was sufficient to restore alveolar-capillary barrier integrity and impair hippocampal long-term potentiation following sublethal infection. Thus, endogenous lung capillary endothelial tau preserves alveolar-capillary integrity, yet it is a source of cytopathic tau that injures the brain during pneumonia.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1125-1141"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832534","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":"TSG-6 promotes fascin-1-mediated microvascular repair in murine airway allografts.","authors":"Mohammad Afzal Khan, Dong Ge Li, Subarna Bhusal, Alexander S Krupnick, Christine L Lau","doi":"10.1093/ajrcmb/aanag032","DOIUrl":"10.1093/ajrcmb/aanag032","url":null,"abstract":"<p><p>Bronchial anastomotic complications, including stenosis, necrosis, and dehiscence, remain major contributors to morbidity and poor graft outcomes following lung transplantation. These complications are primarily driven by microvascular disruption, causing hypoxia, epithelial injury, and impaired wound healing at the anastomosis. Tumor necrosis factor-stimulated gene 6 (TSG-6) protein is a secreted anti-inflammatory mediator with immunomodulatory and tissue-reparative properties; however, its role in transplant-associated vascular and epithelial regeneration remains incompletely defined. In this study, we investigated the therapeutic potential of exogenous TSG-6 in preserving airway microvasculature and promoting immunoregulation in a murine orthotopic tracheal transplant model that mimics the clinical setting of bronchial anastomosis following lung transplantation. BALB/cJ→C57BL/6J allografts were treated intranasally with recombinant TSG-6 (5 µg per transplant) on days -1, 2, 5, and 8 posttransplantation. Exogenous TSG-6 therapy significantly increased the recruitment of M2 macrophages, regulatory T cells, and subsets of regulatory B cells, shifting the graft microenvironment toward an IL-10-dominant anti-inflammatory state. These immunoregulatory effects were accompanied by improved microvascular perfusion, increased Fascin-1 and β-catenin expression in CD31+ endothelial cells, and preserved epithelial architecture with reduced inflammation and airway lumen narrowing, in contrast to untreated allografts that showed epithelial disruption with dense mononuclear infiltration. These findings suggest that TSG-6 coordinates vascular and epithelial repair after transplantation via IL-10-mediated immunoregulation and Fascin-1-dependent endothelial remodeling. These results highlight TSG-6 as a promising immunoregulatory factor with therapeutic potential to mitigate ischemia-related airway injury and offer a novel strategy for preventing bronchial anastomotic complications following lung transplantation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1073-1088"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832647","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":"CircMIRLET7BHG facilitates mast cell degranulation to accelerate allergic rhinitis progression by enhancing IL-33 mRNA stability via interacting with polypyrimidine tract-binding protein 1.","authors":"Jiabin Zhan, Rui Li, Yisen Liang, Dan Luo, Yu Zhou, Xin Wei","doi":"10.1093/ajrcmb/aanag030","DOIUrl":"10.1093/ajrcmb/aanag030","url":null,"abstract":"<p><strong>Background: </strong>Mast cell (MC) degranulation is associated with allergic rhinitis (AR) progression. Although circMIRLET7BHG has been identified as a promoter of AR development, its potential regulatory role in MC degranulation during AR progression has not been clarified.</p><p><strong>Methods: </strong>MCs (LAD2) were co-cultured with ovalbumin (OVA)-induced human nasal mucosa epithelial cells (HNEpC), and an AR mouse model was generated through OVA stimulation. Nasal mucosal tissues were collected from 22 AR patients and 22 normal controls to detect the expression of circMIRLET7BHG and interleukin-33 (IL-33). The expression levels of circMIRLET7BHG and IL-33 were assessed by qRT-PCR, while cytokine production in MCs was quantified using ELISA. MCs degranulation was evaluated by toluidine blue staining, and western blotting was employed to detect the expression of polypyrimidine tract-binding protein 1 (PTBP1) and proteins related to mitochondrial fusion and fission. The interactions of PTBP1 with circMIRLET7BHG and IL-33 were verified by RNA immunoprecipitation and RNA pull-down assays, and IL-33 mRNA stability was determined using the actinomycin D assay.</p><p><strong>Results: </strong>Co-culture of LAD2 cells with OVA-induced HNEpC demonstrated that circMIRLET7BHG knockdown inhibited MC degranulation by suppressing mitochondrial fission. circMIRLET7BHG and IL-33 levels were significantly increased in nasal tissues of AR patients compared with normal controls, showing a positive correlation between their expression levels. Mechanistically, circMIRLET7BHG enhanced IL-33 mRNA stability through its interaction with PTBP1. IL-33 overexpression promoted mitochondrial fission and accelerated MC degranulation, whereas this effect was reversed upon circMIRLET7BHG knockdown. In OVA-induced AR mouse models, circMIRLET7BHG overexpression increased epithelial thickness, eosinophil infiltration, and apoptosis, thereby aggravating allergic symptoms by enhancing mitochondrial fission and MC degranulation via upregulation of IL-33 expression.</p><p><strong>Conclusion: </strong>These findings demonstrate that circMIRLET7BHG promotes AR progression by enhancing mitochondrial fission and MC degranulation through regulation of the PTBP1/IL-33 axis, suggesting a potential novel therapeutic target for AR treatment.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1032-1043"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832113","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":"Lentiviral-mediated gene complementation to rescue pathogenic ABCA3 variants.","authors":"Ashley L Cooney, Shakayla Lamer, Ping Yang, Daniel J Wegner, Frances V White, F Sessions Cole, Chris Wohlford-Lenane, Erin Hennessey, Pushpinder Bawa, Darrell N Kotton, Patrick L Sinn, Jennifer A Wambach, Paul B McCray","doi":"10.1093/ajrcmb/aanag043","DOIUrl":"10.1093/ajrcmb/aanag043","url":null,"abstract":"<p><p>The ATP-binding cassette subfamily A member 3 (ABCA3) protein in the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease. Palliative care or lung transplantation are the only current definitive treatments for progressive respiratory failure due to ABCA3 deficiency. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here, we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3KO). Using this line, we generated additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type (WT) ABCA3. Lentiviral-mediated delivery of WT ABCA3 to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-κB signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene complementation as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1089-1102"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832508","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":"Scarred and esterified: diverse roles of cholesterol esters in pulmonary fibrosis.","authors":"Michael T Forrester, Robert M Tighe","doi":"10.1093/ajrcmb/aanag038","DOIUrl":"10.1093/ajrcmb/aanag038","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"991-993"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832633","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":"Expression of Concern: MGST2hi PMNs mediate NETs and drive pericyte-to-myofibroblast transition in RA-ILD.","authors":"","doi":"10.1093/ajrcmb/aanag099","DOIUrl":"10.1093/ajrcmb/aanag099","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1149"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969596","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":"Rescue of ABCA3 deficiency needs to consider variant-specific epithelial cell dysfunction beyond surfactant production.","authors":"Florian Gothe, Matthias Griese","doi":"10.1093/ajrcmb/aanag059","DOIUrl":"10.1093/ajrcmb/aanag059","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"986-987"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832553","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}