American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Beyond the Binary: Why M1/M2 is Holding Lung Immunology Back.","authors":"Eric D Morrell, Kara J Mould, Megan N Ballinger","doi":"10.1093/ajrcmb/aanag181","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag181","url":null,"abstract":"<p><p>Macrophages are the most abundant immune cell in the lung and play essential roles in tissue development, homeostasis, the initiation of immune responses, and the resolution of injury. Historically, macrophage activation has been defined by the in vitro culture conditions used to generate populations such as M1 or M2, or by the expression of individual transcriptional and cell-surface protein markers. In this Lung Science Brief, we review the historical evolution of macrophage classification and highlight key limitations of conceptual frameworks such as the M1/M2 paradigm for the understanding of lung biology and disease. We argue that comprehensive molecular profiling is a necessary, but not sufficient, starting point for defining lung macrophage subset identities. Meaningful classification schemes for lung monocyte and macrophage subsets should incorporate validation based on functional properties and clinical relevance. We provide examples of approaches to assess lung macrophage function that extend beyond traditional marker-based classification frameworks. Greater emphasis on functional validation may help unify experimental approaches, improve reproducibility, and accelerate translation of macrophage biology into clinical practice.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910650","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":"Heterogeneity of Transitional Alveolar Epithelial States.","authors":"Dawei Sun, SeungHye Han","doi":"10.1093/ajrcmb/aanag176","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag176","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910664","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":"Titrating cumulative neonatal hyperoxia in mice to model bronchopulmonary dysplasia severities.","authors":"Brooke Dir, Raveena Mishra, Nicole Hennen, Emily Mooers, Ru-Jeng Teng, Ganesh Konduri, Jeffrey L Segar, Justin Grobe, Matthew R Hodges, Gary C Mouradian","doi":"10.1093/ajrcmb/aanag031","DOIUrl":"10.1093/ajrcmb/aanag031","url":null,"abstract":"<p><p>The severity of bronchopulmonary dysplasia (BPD) is defined by the type or amount of respiratory support needed at 36 weeks' postmenstrual age, reflecting varying degrees of impairment in the supply and demand systems regulating arterial oxygenation. However, existing preclinical BPD models fail to account for the comprehensive nature of arterial oxygen regulation (lungs, control mechanisms, and metabolism). Here, based on the predictive power of cumulative supplemental oxygen and BPD severity, we demonstrate that dose-dependent increases of cumulative supplemental oxygen (CSO) limited to the saccular stage of lung development in neonatal mice underlie distinct pathophysiologic features associated with varying degrees of BPD-like phenotypes. Specifically, greater saccular-stage CSO levels elicited pathological features commonly associated with severe BPD, including worse alveolar simplification, risk for pulmonary hypertension, hypoventilation, changes in body growth, greater work of breathing, and metabolic acidosis. However, low levels of saccular-stage CSO elicited features associated with mild BPD, including mild but significant alveolar simplification and pulmonary vascular medial wall thickening, with a compensatory ventilatory hyperpnea driven by an increased neural drive to breathe. Thus, we show that different levels of CSO can elicit clinically relevant mild or severe BPD-like phenotypes, underscoring the widespread impact of CSO on physiological systems regulating arterial oxygenation. This paradigm enables preclinical testing of therapeutic efficacy across BPD severities, albeit without other common complicating factors. However, this paradigm is amenable to additional insults to align with the more complex clinical course of BPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1160-1169"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13068295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281768","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":"Species-specific iNOS expression distinguishes epithelial and myeloid IFNγ responses in tuberculosis.","authors":"Fabian Stei, Erin F McCaffrey, Björn Zessin, Jonathan Pioch, Stefan Simm, Beate Stubbe, Ralf Ewert, Frank Verreck, Bianca E Schneider, Anca Dorhoi, Bryan D Bryson, Björn Corleis","doi":"10.1093/ajrcmb/aanag166","DOIUrl":"10.1093/ajrcmb/aanag166","url":null,"abstract":"<p><strong>Rationale: </strong>Tuberculosis vaccines aim to elicit protective immunity, with IFNγ-producing CD4⁺ T cells considered central mediators of host defense. In murine models, IFNγ activates macrophages to induce inducible nitric oxide synthase (iNOS), resulting in nitric oxide-dependent control of Mycobacterium tuberculosis (Mtb).</p><p><strong>Objective: </strong>To define the relevance of IFNγ-induced iNOS activity in humans and other natural host of virulent mycobacterial species.</p><p><strong>Methods: </strong>We systematically compared IFNγ-induced effector responses in Mtb-infected myeloid cells across species. Using bulk RNA sequencing, functional infection assays, and nitric oxide measurements, we assessed IFNγ responsiveness in human and mouse macrophages. These analyses were extended to monocytes from seven mammalian species and complemented by reanalysis of publicly available single-cell RNA-sequencing datasets and spatial proteomic imaging of tuberculous granulomas.</p><p><strong>Measurements and main results: </strong>Single-cell transcriptomic reanalysis revealed minimal NOS2 expression in myeloid cells from human and non-human primate granulomas. In vitro, IFNγ pretreatment failed to induce NOS2 transcription, iNOS activity, or Mtb growth restriction in human macrophages, in stark contrast to murine cells. Across species, iNOS activity was largely restricted to mice, with limited induction in cattle monocytes. Instead, human respiratory epithelial cells consistently expressed NOS2, and multiplexed ion beam imaging localized iNOS protein to epithelial compartments adjacent to granulomatous lesions.</p><p><strong>Conclusion: </strong>IFNγ signaling is uncoupled from iNOS induction in primate myeloid cells and epithelial compartments represent dominant sources of iNOS in human tuberculosis. These findings, challenge murine macrophage-centric paradigms and IFNγ-based correlates used in tuberculosis vaccine development and central to pathophysiology of tuberculosis and other pneumonias.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863502","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":"Novel netrin-1-Unc5b-Klf4 axis balances AT2 survival in experimental bronchopulmonary dysplasia.","authors":"Oleksiy Klymenko, Jasmine Mohr, Soula Danopoulos, Ivana Mižík, Celien Kuiper-Makris, Stephanie Stephan, Mohammad A Mahjoub, Cristina M Alvira, Daniela Rheindorf, Thomas Imhof, Serife Akgül, Michele Donato, Lena K Ebert, Stefan Müller, Christina Vohlen, Dharmesh Hirani, Christoph Bartenhagen, Marek Bartkuhn, Tara Procida, Bernhard Schermer, Purvesh Khatri, Saverio Bellusci, Kerstin Goth, Ioannis Alexopoulos, Theodoros Georgomanolis, Gloria S Pryhuber, Soni S Pullamsetti, Werner Seeger, Denise Al Alam, Jörg Dötsch, Manuel Koch, Miguel A Alejandre Alcazar","doi":"10.1093/ajrcmb/aanag061","DOIUrl":"10.1093/ajrcmb/aanag061","url":null,"abstract":"<p><p>Alveolar growth and repair are central processes in development and chronic lung disease, such as bronchopulmonary dysplasia (BPD), a neonatal lung disease without curative therapy. Alveolar epithelial type 2 (AT2) cells are the endogenous progenitor pool giving rise to alveolar epithelial type 1 cells and promoting alveolar repair. Since netrin-1, a regulator of cell homeostasis and stemness, has been linked to lung diseases, we now investigated its signaling and function in AT2 cells in a hyperoxia-based model of BPD and in lungs of infants with BPD. First, we demonstrated that prolonged hyperoxia reduced both netrin-1 and its receptor Unc5b in neonatal mouse lungs and in primary AT2 cells. Second, ex vivo studies using precision-cut lung slices (PCLS) and primary murine AT2 cell culture showed that netrin-1 regulates AT2 cell survival and the expression of Krüppel-like factor 4 (Klf4) through Unc5b, a transcription factor regulating cell survival. Third, single-cell and bulk transcriptomic analysis, as well as proximity-dependent biotin identification assay, showed Klf4 to be upregulated in AT2 cells during alveolarization, downstream of netrin-1, and to regulate AT2 cell survival. In vivo, Klf4 gene expression and protein abundance was significantly reduced in total lung homogenates and in AT2 cells of neonatal mice exposed to hyperoxia. Finally, KLF4+ cells, KLF4+ epithelial, and specifically KLF4+ AT2 cells were reduced in clinical BPD. In summary, our data identify a novel netrin-1-Unc5b-Klf4 axis in AT2 cells that is disrupted in BPD and could offer a novel target for endogenous alveolar repair.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1219-1236"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832542","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":"Gene editing of alveolar organoids reveals AT2 dysfunction due to endosomal SFTPC accumulation.","authors":"Eimear N Rutherford, Dawei Sun, Kyungtae Lim, Christopher S Godbehere, James R Edgar, Lydia E Matesic, Stefan J Marciniak, Emma L Rawlins, Jennifer A Dickens","doi":"10.1093/ajrcmb/aanag163","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag163","url":null,"abstract":"<p><p>Alveolar type 2 (AT2) cell dysfunction is key to the development of many lung diseases including pulmonary fibrosis (PF). The underlying mechanisms often remain poorly understood due to a paucity of manipulable primary human models and lack of defined triggers. Monogenic forms of familial pulmonary fibrosis combined with recent advances in in vitro culture techniques offer a unique opportunity to interrogate early pathogenic events in PF. To model toxic gain-of-function disease caused by the SFTPC variant I73T, we employed a base editing strategy in human lung-derived AT2 (fdAT2) organoids to edit the endogenous SFTPC locus and generate a heterozygous SFTPC-I73T-expressing disease model which we interrogated when grown in standard 3D culture, monolayer culture, and at air-liquid interface. SFTPC-I73T expressing organoids failed to form lumens and displayed disrupted epithelial polarity. This was due to SFTPC accumulation in enlarged early endosomes resulting in impaired apico-basal trafficking of polarity and adhesion proteins. Air exposure exacerbated these defects, causing epithelial barrier breakdown and impaired wound healing. Together, we demonstrate the ability to edit endogenous loci in differentiated alveolar organoids to generate disease models that provide mechanistic insights into disease. We establish endosomal dysfunction and polarity loss as drivers of SFTPC-I73T-mediated epithelial injury and highlight mechanisms that may underlie AT2 dysfunction in disease more broadly.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823470","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":"Building Better Airways: The Promise and Challenge of Engineered Bronchial Epithelium.","authors":"Sandra L Leibel","doi":"10.1093/ajrcmb/aanag174","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag174","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807910","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":"Genetic Variants at Immunoglobulin and Mitochondrial Loci Associated with Chronic Hypercapnia in COPD.","authors":"Renzo Boersma, Alen Faiz, Rachael Rowntree, Tim Raveling, Victor Guryev, Murat Türk, Reinoud Gosens, Maarten van den Berge, Peter J Wijkstra, Marieke L Duiverman","doi":"10.1093/ajrcmb/aanag170","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag170","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787180","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":"Airway smooth muscle relaxation is HETE(ing) up.","authors":"James V Michael, Steve S An, Ajay P Nayak","doi":"10.1093/ajrcmb/aanag173","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag173","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787199","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":"Haptoglobin Protects Against Increased Chlorine Inhalation Vulnerability in Sickle Cell Trait Mice.","authors":"Ammar Saadoon Alishlash, Changchun Ren, Zhihong Yu, Brian A Halloran, Shubham Dubey, Junaid Khan, Malgorzata Kasztan, Vinitha Uppalapati, Subhashini Bolisetty, Brianna Pittman, Sura Ahmed, James Mobley, Tamas Jilling, Sadis Matalon","doi":"10.1093/ajrcmb/aanag165","DOIUrl":"10.1093/ajrcmb/aanag165","url":null,"abstract":"<p><strong>Rationale: </strong>Sickle cell trait (SCT), carried by millions worldwide, is generally considered benign. However, SCT is increasingly linked to life‑threatening complications under environmental stress.</p><p><strong>Objectives: </strong>We tested whether sickle cell trait confers heightened vulnerability to oxidant inhalation injury and whether post-exposure haptoglobin mitigates injury.</p><p><strong>Methods: </strong>Using humanized SCT (AS) and control hemoglobin (AA) mice carrying human hemoglobin knock‑in genes, we examined physiologic, biochemical, histologic, mitochondrial, and proteomic responses to chlorine (Cl₂) inhalation at concentrations encountered near chemical accidents. Pulmonary and kidney injury were assessed 24 h post‑exposure.</p><p><strong>Measurements and main results: </strong>Compared with AA controls, SCT mice exhibited markedly increased mortality, severe acute lung and kidney injury, hypoxemia, and exaggerated hemolysis/rhabdomyolysis following Cl2 exposure. Global lung proteomics revealed widespread remodeling, with modifications to lung proteins. Systems biology analysis revealed that neutrophil degranulation, acute‑phase, and oxidative/mitochondrial injury pathways were uniquely intensified in SCT. To test whether scavenging extracellular hemoglobin mitigates injury, mice received haptoglobin 30 min after Cl2 exposure. Post‑exposure haptoglobin significantly improved survival, oxygenation, renal function, and epithelial barrier integrity, while reversing key inflammatory and mitochondrial injury signatures and restoring proteomic architecture to near-baseline levels.</p><p><strong>Conclusions: </strong>Our data showed that Cl2 inhalation triggers hemolysis-driven multiorgan injury in SCT, establishing SCT as a previously unrecognized high-risk phenotype for toxic environmental exposures. Haptoglobin administered after exposure provides robust protection across physiologic, molecular, and mitochondrial endpoints, supporting hemoglobin scavenging as a practical, rapidly deployable countermeasure for chemical inhalational injury in individuals with SCT.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787220","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}