American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Reply to Chen et al.: Defining the Translational Validity of CTPA-Derived Pulmonary Blood Volume in CTEPH.","authors":"Hakim Ghani, Muhunthan Thillai, Simon Walsh, Joanna Pepke-Zaba","doi":"10.1093/ajrcmb/aanag091","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag091","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832586","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 the Translational Validity of CTPA-Derived Pulmonary Blood Volume in CTEPH.","authors":"Man Sun, Dan Zang, Jun Chen","doi":"10.1093/ajrcmb/aanag090","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag090","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832392","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":"Long isoforms of the COPD risk gene FAM13A orchestrate human lung epithelial development.","authors":"Rhiannon B Werder, Méline Homps-Legrand, Rebecca Hyatt, Jonathan Lindstrom-Vautrin, Carlos Villacorta-Martin, Pushpinder Bawa, Michael H Cho, Xiaobo Zhou, Andrew A Wilson","doi":"10.1093/ajrcmb/aanag078","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag078","url":null,"abstract":"<p><p>Impaired lung development and lung function can lead to the development of chronic obstructive pulmonary disease (COPD). Genome wide association studies (GWAS) have identified associations between variants in the gene FAM13A with both lung function and COPD. Of the major FAM13A isoforms expressed in humans, only the shorter isoforms are expressed in mice. This species difference has hindered investigations into whether full-length, human-specific isoforms contribute to human lung development, a question that remains unstudied to date. To functionally address this question, we disrupted the long isoform of FAM13A in human induced pluripotent stem cells (iPSCs). Specific loss of this isoform prevented the emergence in culture of mature airway or alveolar epithelial lineages in directed differentiation protocols. We demonstrate that the FAM13A long isoform is critical to patterning NKX2-1 + lung progenitor cells through dysregulating Wnt/β-catenin signaling during early stages of development in vitro. These findings provide the first evidence that the COPD risk gene FAM13A may be vital in the developing human lung epithelium.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832452","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":"α5 Nicotinic Receptor Polymorphism affects cigarette smoke-induced inflammation and COPD development.","authors":"Layal Massara, Lynda Saber Cherif, Anais Ollivier, Gwenola Kervoaze, Muriel Pichavant, Clara Dufossez, Amira Fawaz, Elise Leprêtre, Olivier Le Rouzic, Gaëtan Deslée, Stephanie Pons, Uwe Maskos, Valérian Dormoy, Philippe Gosset","doi":"10.1093/ajrcmb/aanag093","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag093","url":null,"abstract":"<p><strong>Rationale: </strong>COPD is the third leading cause of death globally. Although cigarette smoke is the dominant risk factor, only a subset of smokers develop COPD, pointing to a significant role for genetic susceptibility. The α5 nicotinic acetylcholine receptor polymorphism (α5SNP; rs16969968), is expressed in the majority of COPD patients and may modulate immune responses to cigarette smoke.</p><p><strong>Objectives: </strong>To determine how α5SNP influences CS-induced inflammation and COPD pathogenesis in both experimental and clinical settings.</p><p><strong>Methods: </strong>A murine knock-in model expressing wild-type (WT), heterozygous (HE), or homozygous (HO) α5SNP alleles was exposed to cigarette smoke or ambient air for one or three months. Lung function, histopathology, immune cell profiling, and cytokine expression were evaluated. In a human COPD cohort, we assessed α5SNP prevalence and the cytokine concentrations.</p><p><strong>Measurements and main results: </strong>Cigarette smoke impaired lung function across all genotypes, but HE mice developed the most severe airflow limitation, inflammation, and airway remodeling. This phenotype was linked to heightened γδ T cell activation and increased TNF-α, associated with altered nAChR signaling in macrophages. Alteration of nicotine-induced cell signaling including adenylate cyclase and protein kinase-C is involved in modulation of cytokine production by macrophages. In humans, α5SNP was highly prevalent among COPD patients and strongly correlated with elevated systemic inflammation.</p><p><strong>Conclusions: </strong>α5SNP enhances susceptibility to cigarette smoke-driven lung injury and is present in the majority of COPD patients. These findings support α5SNP as a key genetic marker of susceptibility for COPD and its presence should be associated with precise follow-up in smokers.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832596","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":"Urokinase plasminogen activator receptor attenuates allergen-induced eosinophil migration and airway hyperresponsiveness.","authors":"Gregory S Whitehead, Keiko Nakano, Christina L Wilkinson, Antonio M Patterson, Sandeep Upadhyay, Abdull J Massri, Brian N Papas, Artiom Gruzdev, Manas Ray, Hideki Nakano, Donald N Cook","doi":"10.1165/rcmb.2025-0308OC","DOIUrl":"10.1165/rcmb.2025-0308OC","url":null,"abstract":"<p><strong>Rationale: </strong>The urokinase plasminogen activator receptor (uPAR) is a membrane-bound protein that can contribute to the activation and mobilization of leukocytes and is present at increased levels in asthmatics. However, its role in allergic asthma remains poorly understood.</p><p><strong>Methods: </strong>We used multiple mouse strains and different models of allergic airway disease to study the function of uPAR in the pathogenesis of this disease.</p><p><strong>Measurements and main results: </strong>Plaur, the gene encoding uPAR, was rapidly induced following allergic sensitization through the airway and again following subsequent allergen challenge. Plaur-deficient mice displayed both increased numbers of eosinophils and heightened airway hyperresponsiveness (AHR) in multiple models of allergic asthma. Mice selectively lacking Plaur in eosinophils also had more robust eosinophilia than did wild-type (WT) mice, and eosinophils lacking Plaur displayed increased activity in an ex vivo assay of chemokine-dependent migration. However, those mice did not have increased AHR compared with WT mice. Conversely, although mice selectively lacking Plaur in lung epithelial cells did not have increased inflammation compared with WT mice, they displayed heightened AHR.</p><p><strong>Conclusions: </strong>These findings suggest that uPAR controls both airway inflammation and AHR, but through distinct mechanisms. Targeting uPAR might have therapeutic potential for treating inflammation and AHR in asthma.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"690-703"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367299","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":"Specialized proresolving mediator-loaded extracellular vesicles mitigate pulmonary inflammation.","authors":"Manjula Karpurapu, Jiasheng Yan, Sangwoon Chung, Lalithya Posham, Jonathan R Fritz, Joshua A Englert, Sonal R Pannu, Narasimham Parinandi, Evgeny Berdyshev, Liwen Zhang, John W Christman","doi":"10.1165/rcmb.2025-0398OC","DOIUrl":"10.1165/rcmb.2025-0398OC","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) have emerged as versatile carriers of therapeutic cargo, including nucleic acids, proteins, and small molecules. However, their potential to deliver bioactive lipid mediators remains largely unexplored. Here, we present a novel synthetic biology-based strategy to selectively load EVs with proresolving lipid mediators of the resolvin D- and E-series by coexpressing the resolvin biosynthetic enzymes cyclooxygenase 2, 5-lipoxygenase, and 15-lipoxygenase using a custom-designed multigene expression vector. Human embryonic kidney 293 T cells transfected with the multigene expression vector and cultured in the presence of fatty acid free bovine serum albumen-complexed docosahexaenoic acid, eicosapentaenoic acid, and aspirin produced multiple members of the resolvin D, aspirin-triggered resolvin D-series, and resolvin E1 and E2, along with their biosynthetic precursors, which were subsequently packaged into EVs (referred to as resolvin EVs). Resolvin EVs attenuated neutrophil adhesion to endothelial cells both under static and flow conditions and preserved endothelial barrier integrity by upregulating VE-cadherin. In macrophages, resolvin EVs suppressed nuclear factor κB reporter activity and the release of IL6 and TNFα. Effects of resolvin EVs on endothelial permeability and macrophage activation were abrogated by pharmacologic inhibition of EV uptake using nystatin and cytochalasin D. Furthermore, resolvin EVs enhanced efferocytosis in THP-1-derived macrophages compared to control EVs. Notably, postinjury administration of resolvin EVs attenuated pulmonary inflammation in lipopolysaccharide-treated mice without inducing systemic or pulmonary toxicity. Together, these findings establish a novel, scalable platform for generating resolvin-loaded EVs and highlight their therapeutic potential for acute lung injury and other chronic inflammatory disorders.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"661-674"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342809","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":"Palmitoleic acid loss links pulmonary dysbiosis to lung injury after single-lung ventilation.","authors":"Hadis Najibi, Keyi Li, Changfu Yao","doi":"10.1093/ajrcmb/aanag005","DOIUrl":"10.1093/ajrcmb/aanag005","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"572-574"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281746","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":"Sexually distinct multi-omic responses to progressive endurance exercise training in the rat lung.","authors":"Gina M Many, Tyler J Sagendorf, Hugh Mitchell, James A Sanford, Samuel E Cohen, Ravi S Misra, Igor Estevao, Ivo Díaz Ludovico, David A Gaul, Malene E Lindholm, Mereena George Ushakumary, James C Pino, Nicolas Musi, Jia Nie, Facundo M Fernández, Eric A Ortlund, Karyn A Esser, Sue C Bodine, Simon Schenk, Geremy Clair, Joshua N Adkins","doi":"10.1165/rcmb.2025-0249OC","DOIUrl":"10.1165/rcmb.2025-0249OC","url":null,"abstract":"<p><p>Endurance exercise is broadly beneficial to cardiopulmonary function, with these benefits thought to be driven by extrapulmonary factors rather than direct structural changes in the lungs. Thus, to address how endurance exercise training and sex impact molecular responses in the lungs, we used a multi-omics approach to study 6-month-old Fischer 344 rats that undertook a progressive endurance treadmill training protocol for 1 to 8 weeks. Specifically, we reannotated publicly accessible transcriptomics, metabolomics, proteomics and phosphoproteomics data from the Molecular Transducers of Physical Activity Consortium and integrated newly analyzed acetylproteomics data to assess multi-omic sex differences in sedentary and treadmill trained rats. Female rats displayed enrichment in immune-related features and pathways at the transcriptome and proteome level that were largely maintained with training. However, both sexes exhibited decreases in immune pathway activity following 8 weeks of training, although the effect was more pronounced in males. Shared responses to training included increased enrichment in transcriptomic pathways related to type I alveoli, proteomic pathways related to cilia, and decreased acetylation of pathways linked to mitochondrial function. Furthermore, features known to be enriched in lung diseases were attenuated with training in both sexes. Together, our findings provide novel insight into responses to endurance exercise training in the healthy rat lung and may offer translational insight into sex-specific differences in lung disease pathogenesis and treatment.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"675-689"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367359","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":"C-type lectin-like receptor 2 in lung epithelium protects against acute lung injury.","authors":"Tian Jiang, Linfeng Wu, Ying Wang, Xu Yang, Renhui Huang, Changhao Ren, Qi Zhang, Yunfan Hu, Shaoyuan Zhang, Xinyu Yang, Jun Yin, Lan Wang, Lijie Tan","doi":"10.1093/ajrcmb/aanaf001","DOIUrl":"10.1093/ajrcmb/aanaf001","url":null,"abstract":"<p><p>C-type lectin-like receptor 2 (CLEC2) is a transmembrane receptor highly expressed on platelets, which regulates platelet aggregation and immune response. Yet, the function of CLEC2 in lung epithelium and its contribution to acute lung injury (ALI) is unclear. In this study, a lung epithelial-specific CLEC2 knockout mouse (Clec1bAT2-KO) was generated and performed for ALI models. In both LPS- and acid-induced lung injury models, the ALI signs of Clec1bAT2-KO mice were further exacerbated. The therapeutic application of epithelial-restricted CLEC2 overexpression using adeno-associated virus (AAV) or CLEC2 activation using its endogenous ligand podoplanin serves as a lung epithelial protective agent in the setting of ALI. Transcriptomic analyses reveal that CLEC2-regulated genes are highly enriched in chemotaxis, cytokine, and extracellular matrix (ECM) components. Lung injury was partially attenuated in Ccl5-/-, Csf3-/-, and Cxcl1-/- mice pretreated with AAV-si-CLEC2, followed by LPS challenge. Loss of CLEC2 leads to ECM degradation, which could be reversed by exogenous transforming growth factor beta (TGF-β). Furthermore, interferon regulatory factor 1 (IRF1) was identified as the key molecule that regulates CLEC2-related cytokine/chemokine production and ECM degradation. These findings suggest that epithelial CLEC2 protects against ALI by modulating spleen tyrosine kinase/IRF1-mediated cytokine/chemokine production and TGF-β-mediated ECM remodeling.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"617-631"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281764","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":"Regulation of endothelial cell death in inflammatory lung injury.","authors":"Mansi Upadhyay, Destini Nelson, Mollie Phillips, Seth Gould, Jonathan Davis, Rana Dhar, E Angela Murphy, Colin E Evans","doi":"10.1165/rcmb.2025-0443TR","DOIUrl":"10.1165/rcmb.2025-0443TR","url":null,"abstract":"<p><p>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are heterogeneous and potentially fatal consequences of serious conditions such as trauma and sepsis, an exacerbated inflammatory response to infection. There are no effective treatments for ALI/ARDS, partly due to an incomplete understanding of its pathogenesis across different patient subpopulations, contributing to mortality rates of 25%-40%. ALI/ARDS is characterized by lung hypoxia, inflammatory cell infiltration, edema, and endothelial cell injury and death. Lung endothelial viability is essential for gas exchange, nutrient delivery, and immune cell migration, as well as the prevention of proteinaceous fluid accumulation. Given that lung endothelial death is a predominant feature of ALI/ARDS, its inhibition could represent a novel therapeutic strategy. In this article, we review studies examining pulmonary endothelium death during sepsis-induced ALI/ARDS, including studies of lung endothelium apoptosis, pyroptosis, necroptosis, and ferroptosis. We also highlight gaps in current knowledge that, if addressed, could facilitate the development of effective treatments for sepsis-induced ALI/ARDS. Future studies of the mechanisms regulating lung endothelial death may uncover novel therapeutic targets for ALI/ARDS. These targets could be leveraged in precision medicine approaches to treat patient subpopulations most likely to benefit from inhibiting specific forms of lung endothelial death.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"575-589"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273621","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}