American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Anchors Astray: An Oxidized tRNA Fragment Drives Pulmonary Fibrosis by Uncoupling cAMP Signaling.","authors":"Sean M Fortier","doi":"10.1093/ajrcmb/aanag213","DOIUrl":"https://doi.org/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}

{"title":"Time is of the Essence: Airway Organoid Maturation Matters for Infection Modeling.","authors":"Kasey Minakin, Matthew E Poynter","doi":"10.1093/ajrcmb/aanag203","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag203","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134771","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 Respiratory Infections Using Patient-Derived Apical-Out Airway Organoids.","authors":"Inbal Shamir, Yael Nevo-Caspi, Eran Bacharach, Rakefet Ben-Yishay, Gil Goldinger, Petro Busko, Igor Grinberg, Sylvie Polak-Charcon, Rachel Zamostiano, Marcelo Ehrlich, Moshe Biton, Iris Barshack, Dana Ishay-Ronen, Sharon Amit","doi":"10.1093/ajrcmb/aanag193","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag193","url":null,"abstract":"<p><p>Airway organoids bridge the gap between conventional epithelial cultures and animal models by combining human tissue architecture, cellular diversity, and experimental accessibility. However, because these systems are dynamic, reproducible infection modeling requires careful definition of parameters influencing infection readouts, including epithelial polarity, maturation, cellular composition, and access to a physiologically relevant apical surface. We established patient-derived apical-out airway organoids and characterized them longitudinally using multiple modalities throughout differentiation, followed by proof-of-concept viral infection and host-response profiling. Organoids generated from resected human lung tissue were converted from an apical-in to an apical-out orientation and maintained in suspension. Over 21 days, they retained outward-facing apical features and matured from basal-cell-enriched structures into airway-like epithelium containing goblet cells, microvilli, ionocytes and ciliated cells, with mucus production and motile surface cilia. This time-resolved characterization demonstrated changes in organoid growth, epithelial organization, and lineage composition, guiding selection of maturation stages for infection experiments. Exposure of the apical surface to GFP-expressing human metapneumovirus (hMPV) enabled infection without disruptive shearing or microinjection. Viral fluorescence and immunostaining confirmed hMPV infection and revealed associated cytopathic changes in infected organoids. Infection efficiency and cellular tropism varied across maturation stages. Bulk RNA sequencing of infected versus mock-infected organoids showed reproducibly distinct transcriptional profiles and enrichment of antiviral and innate immune pathways. These findings demonstrate that the epithelial features shaping infection readouts must be defined empirically within each organoid system through longitudinal, multimodal characterization, thereby supporting rigorous interpretation and reproducible application in mechanistic and translational respiratory infection studies.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134840","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":"T cell hyporesponsiveness to TSC2null cells suggests bidirectional interactions in LAM.","authors":"Chang Xue, Sajad Moshkelgosha, Julio A Castiblanco Guzman, Bingyu B Li, Prodipto Pal, David W Andrews, Adam Pietrobon, Julien Yockell-Lelièvre, William L Stanford, Stephen C Juvet, Molly S Shoichet","doi":"10.1093/ajrcmb/aanag185","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag185","url":null,"abstract":"<p><strong>Rationale: </strong>Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of neoplastic smooth muscle-like cells in women. The role of the immune system in LAM progression is unclear.</p><p><strong>Objectives: </strong>Investigate the influence of T cells on TSC2null smooth muscle cell behaviour at cellular and transcriptome levels.</p><p><strong>Methods: </strong>Archival LAM and control lung tissues were compared by gene profiling with NanoString analyses where elevated CD8 T cell accumulation was observed in LAM vs. control tissues. Acknowledging the limited translational potential of animal models, a human T cell-TSC2null smooth muscle cell co-culture system was established and cell phenotype and proliferation over time using flow cytometry was examined.</p><p><strong>Main results: </strong>TSC2null smooth muscle cells adopt cancer-associated fibroblast (CAF)-like phenotypes, which could be regulated by IFN-γ. TSC2null cells suppressed T cell proliferation and induced T cell anergic phenotypes, which could not be reversed by antigen receptor and co-stimulation. TSC2null cells decreased expression of co-stimulatory molecule, CD40, and increased proliferation in the presence of T cells, yet underwent apoptosis in the presence of activated T cells.</p><p><strong>Conclusions: </strong>Our findings suggest a contact-dependent feedback loop between TSC2null smooth muscle cells and T cells, which may both promote immune dysregulation in LAM and explain the invasive behavior and tissue remodeling observed clinically.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134825","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":"Nerandomilast's Antifibrotic Effects Are Modulated by the tRF-AKAP12-PKA Axis in Pulmonary Fibrosis.","authors":"Zhen Chen, Lixin Huang, Fanhao Kong, Junting Zhang, Wenze Wu, Zixin Liu, Jin-Song Bian, Xiaowei Nie","doi":"10.1093/ajrcmb/aanag188","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag188","url":null,"abstract":"<p><strong>Rationale: </strong>Pulmonary fibrosis (PF) involves persistent fibroblast activation, extracellular matrix deposition, and tissue stiffening. The role of oxidatively modified tRNA-derived small RNAs (tsRNAs) in linking fibroblast activation to mechanotransduction remains unclear.</p><p><strong>Methods: </strong>5o8G tRF-1-AspGTC (tRF) expression was analyzed in lung tissues from patients with PF and experimental mouse models. Gain- and loss-of-function approaches were used to define its role in fibroblast activation and PF progression. Mechanistic studies examined the tRF-AKAP12-PKA-YAP pathway, and therapeutic relevance was evaluated by assessing the antifibrotic efficacy of Nerandomilast under AKAP12-deficient or AKAP12-restored conditions.</p><p><strong>Results: </strong>tRF was markedly upregulated in fibrotic lung tissues from PF patients and experimental mice. Myofibroblast-specific inhibition of this tRF significantly attenuated PF in mice. Consistently, tRF accumulation promoted fibroblast activation, cytoskeletal remodeling, and profibrotic phenotypes in human pulmonary fibroblasts (HPFs). Mechanistically, tRF directly targeted and suppressed AKAP12 expression, thereby disrupting the AKAP12-PKA signaling complex. Loss of AKAP12 disrupted AKAP12-dependent PKA compartmentalization, altered PKA substrate phosphorylation, and promoted cytoskeletal reorganization and YAP-dependent mechanotransduction. Importantly, AKAP12 deficiency impaired Nerandomilast-mediated restoration of PKA-YAP signaling and limited its antifibrotic efficacy, whereas AKAP12 restoration re-established this signaling axis and synergistically enhanced Nerandomilast therapeutic effects in PF mice.</p><p><strong>Conclusion: </strong>tRF promotes PF by disrupting AKAP12-dependent spatial PKA signaling and activating YAP-dependent mechanotransduction. Targeting the tRF-AKAP12 axis, particularly through AKAP12 restoration, may improve Nerandomilast-based therapy.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126495","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":"Dissecting PHOX2B-Dependent Mechanisms in CCHS Across Experimental Models.","authors":"Daniel Falik, Yuval Shoam, Avital Adato, Avraham Ashkenazi, Gad David Vatine","doi":"10.1093/ajrcmb/aanag198","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag198","url":null,"abstract":"<p><p>Congenital central hypoventilation syndrome (CCHS) is a rare autonomic nervous system disorder characterized by defective autonomic control of breathing resulting in life-threatening hypoventilation, particularly during sleep. CCHS is most commonly caused by pathogenic mutations in the transcription factor PHOX2B, broadly classified into polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat mutations (NPARMs). These differ in prevalence, clinical severity, and associated comorbidities. Here, we integrate and review evidence from studies in vivo models, immortalized in vitro cell lines, and patient-derived cellular models to elucidate how PHOX2B mutations drive CCHS pathology. Mouse models have revealed lineage-specific vulnerabilities across central, peripheral, and enteric autonomic circuits, with pronounced defects in the retrotrapezoid nucleus. Immortalized cell models have enabled mechanistic dissection of mutation-specific effects on PHOX2B localization, dimerization, transcriptional regulation, and protein homeostasis. At the same time, patient-derived cellular systems recapitulate key aspects of human disease, including altered differentiation trajectories and respiratory-relevant neuronal dysfunction. Collectively, these complementary experimental systems demonstrate that PHOX2B mutations disrupt both developmental and post-developmental mechanisms underlying autonomic dysfunction. Importantly, no single model fully recapitulates human CCHS, highlighting the need for integrated model systems to accelerate mechanistic discovery and therapeutic development.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103012","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}