American Journal of Respiratory Cell and Molecular Biology最新文献

{"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}

{"title":"Not so sweet: Mitochondrial dysfunction in the alveolar niche caused by cinnamon-flavored vaping.","authors":"Alexandra Noël","doi":"10.1093/ajrcmb/aanag204","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag204","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102926","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":"Vehiculation and functional delivery of lipophilic therapeutics and antibiotics via pulmonary surfactant in a lung-on-chip model.","authors":"Cristina Garcia-Mouton, Richa Mishra, Ainhoa Collada, Melanie Hoos, Kunal Sharma, Theo Nass, Michelle Sommer, Jesus Perez-Gil, Vivek V Thacker","doi":"10.1093/ajrcmb/aanag197","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag197","url":null,"abstract":"<p><p>Pulmonary surfactant forms a dynamic proteolipid thin-film at the alveolar air-liquid interface. It is both a barrier to a \"last mile\" carrier for inhaled particulate matter to the distal lung. Its importance in pulmonary delivery of inhaled particles and therapeutics is poorly understood in part because existing vehiculation models are entirely acellular. Here we report methodological innovations that implement vehiculation in a human lung-on-chip (LoC) model by adapting a thin-film bridge (TFB) method used in acellular models to deliver functionally-effective cargo to the epithelial layer. We find that breathing-like stretch is essential for vehiculation. Vehiculated cargos are retained and strongly co-localize with surfactant lipids in the epithelial layer. In LoCs reconstituted with in vitro-differentiated alveolar-like macrophages, both cargo and lipid are predominantly taken up by these cells, mimicking in vivo physiology. In contrast, delivery of cargos in surfactant formulations in liquid (a protocol typically used in vitro) leads to an unphysiological high uptake in alveolar epithelial cells, poor uptake in macrophages even in LoCs with alveolar-like macrophages and rapid separation of lipid and cargo. We demonstrate that surfactant formulations containing bedaquiline can be effectively vehiculated in both acellular and the human LoC models. TFB-vehiculated bedaquiline effectively suppressed subsequent growth of Mycobacterium tuberculosis in a prophylactic manner. Overall, our work demonstrates an approach for studying drug vehiculation in models of the alveolar interface in vitro, and the feasibility of surfactant-containing therapeutic formulations for direct and effective pulmonary delivery.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102932","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":"Impaired Macrophage Lipid Handling Initiates Lung Fibrosis via Lipid-Mediated Fibroblast Activation.","authors":"Elizabeth F Redente, Isaiah Little, Marissa O'Callaghan, Lucas Dantas, Michelle Steel, Angela Cheng, Elinor Lee, Richard L Watson, Kevin J Williams, Michael P Keane, James P Bridges, Alexandra L McCubbrey, Thomas Q de Aguiar Vallim, Cormac McCarthy, Elizabeth J Tarling","doi":"10.1093/ajrcmb/aanag199","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag199","url":null,"abstract":"<p><strong>Rationale: </strong>Macrophages are essential for lung homeostasis and repair after injury, yet they can also promote pathological remodeling. Although mechanisms that sustain fibrosis are increasingly well defined, the endogenous events that initiate fibrotic remodeling remain incompletely understood.</p><p><strong>Objectives: </strong>To determine whether macrophage lipid dysregulation is sufficient to initiate lung fibrosis and define the cellular and lipid-mediated mechanisms linking macrophage dysfunction to fibroblast activation.</p><p><strong>Methods: </strong>We examined mice deficient in the intracellular sterol transporter ABCG1 and assessed the temporal relationship between macrophage lipid accumulation, collagen deposition, and fibrotic remodeling. Lipidomic profiling was performed on Abcg1-deficient macrophages and macrophages isolated during early experimental fibrosis. Candidate lipid species were tested for their ability to activate fibroblasts in vitro, and therapeutic interventions targeting macrophage cholesterol trafficking or fibroblast lipid uptake were evaluated in vivo.</p><p><strong>Measurements and main results: </strong>Loss of ABCG1 caused lipid accumulation in alveolar macrophages early before collagen deposition and lung remodeling. Lipidomic analyses revealed conserved enrichment of polyunsaturated acyl tails within complex lipid species in Abcg1-deficient macrophages and macrophages from early-stage experimental fibrosis. These lipids directly activated fibroblasts and induced fibrotic gene expression in vitro. Restoration of macrophage cholesterol trafficking or inhibition of fibroblast lipid uptake prevented fibrotic remodeling in vivo.</p><p><strong>Conclusions: </strong>Macrophage cholesterol dysregulation is sufficient to initiate spontaneous lung fibrosis. These findings identify a lipid-mediated macrophage-fibroblast axis as an endogenous driver of fibrotic remodeling and suggest that targeting macrophage lipid handling or fibroblast lipid uptake may represent a therapeutic strategy in fibrotic lung disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102928","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":"Aging in a Dish: Pulmonary Organoids as Models of Lung Aging.","authors":"Corina Meid, Amine Chahin, Maja Funk, Mareike Lehmann","doi":"10.1093/ajrcmb/aanag202","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag202","url":null,"abstract":"<p><p>Dissecting Lung Aging Through Organoid Models: From Mechanisms to Therapeutic Targets Aging of the lung is characterized by progressive alterations in epithelial integrity, stem cell renewal, immune surveillance, and tissue repair. These changes compromise pulmonary function and increase susceptibility to chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), as well as respiratory infections that disproportionately affect older individuals. Mechanistically, lung aging arises from cell-intrinsic dysfunction, impaired intercellular communication, and disrupted homeostasis. Understanding mechanisms driving lung aging remains a critical challenge for preserving respiratory health in the elderly. To address this challenge, advanced in vitro models like lung organoids have emerged as powerful tools to study respiratory aging. Organoids are three-dimensional (3D) cultures derived from lung stem or progenitor cells. Lung organoids enable investigation of aging phenotypes, including impaired self-renewal, differentiation, epigenetic alterations, oxidative stress, and senescence. They can model interactions between epithelial, stromal, and immune cells while recapitulating key microenvironmental influences such as inflammation, fibrosis, and toxin exposure. Together, these features position organoids as a versatile platform to dissect cellular crosstalk and signaling pathways driving lung aging and related pathologies. This review highlights the use of lung organoids to investigate age-related lung diseases. We discuss how organoid systems have been used to study epithelial dysfunction, impaired regeneration and immune-epithelial crosstalk in the aging lung. Furthermore, we emphasize how integration with multi-omics approaches can reveal novel mechanisms and targets. Finally, we consider the translational potential of organoid-based models for drug discovery, target validation, and interventions to mitigate age-related decline in lung function.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102968","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 Köker Özer et al.: Clinical Translation of Inhaled Vitamin A in Preterm Infants: Considering Extrapulmonary Safety.","authors":"Craig A Gelfand, Robert Segal, Virender K Rehan","doi":"10.1093/ajrcmb/aanag201","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag201","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102971","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}