American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"FTO Alleviates COPD Pathogenesis by Demethylating S100A9 to Suppress ERK1/2-Drp1-Driven Mitophagy.","authors":"Bin Xie, Qiong Chen, Ziyu Dai, Yun Peng, Shaojin You, Chengping Hu, Xi Chen","doi":"10.1093/ajrcmb/aanag094","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag094","url":null,"abstract":"<p><strong>Rationale: </strong>N6-methyladenosine (m6A) modifications are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), yet the precise role of the demethylase fat mass and obesity-associated protein (FTO) remains unclear.</p><p><strong>Objectives: </strong>To identify whether FTO acts as a suppressor of COPD pathogenesis and to elucidate the underlying epitranscriptomic mechanism.</p><p><strong>Methods: </strong>COPD models were established using cigarette smoke-exposed mice and cigarette smoke extract-stimulated BEAS-2B cells. FTO expression was modulated by lentiviral transduction. m6A epitranscriptomic microarray, RNA immunoprecipitation, m6A methylation analysis, and mRNA stability assays were performed. Inflammation, oxidative stress, mitophagy, and ERK1/2-Drp1 signaling were assessed.</p><p><strong>Results: </strong>FTO expression is reduced in COPD patients and murine models, correlating with elevated m6A levels and disease severity. Overexpression of FTO mitigates inflammation, oxidative stress, and mitochondrial dysfunction by destabilizing S100 calcium-binding protein A9 (S100A9) mRNA via m6A demethylation. Mechanistically, FTO inhibits the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)- dynamin-related protein 1 (Drp1), thereby suppressing excessive mitophagy and preserving mitochondrial integrity. Notably, S100A9 overexpression abolishes the protective effects of FTO, establishing the FTO/S100A9 axis as a central regulator.</p><p><strong>Conclusions: </strong>FTO attenuates COPD pathogenesis by demethylating S100A9 mRNA, thereby suppressing ERK1/2-Drp1-driven mitophagy. The FTO/S100A9 axis represents a novel epitranscriptomic mechanism and a potential therapeutic target for COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760144","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 Role of Von Willebrand Factor-αvβ3 Integrin in Human Pulmonary Artery Smooth Muscle Cell.","authors":"Sara Abd Al Rahim, Bruno Ribeiro Baptista, Huguette Louis, Cécile V Denis, Christophe Guignabert, Ly Tu, Véronique Regnault, Patrick Lacolley, Julien Perrin, Ari Chaouat","doi":"10.1093/ajrcmb/aanag083","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag083","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760107","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":"When ZIP code matters: Myeloid-specific role of TLR2 signalling in neonatal influenza.","authors":"Miša Gunjak, Ivana Mižik","doi":"10.1093/ajrcmb/aanag085","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag085","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832587","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":"Retrospective Analysis Reveals the Early Origin and Development of Pulmonary Perivascular Cells.","authors":"Isabel I Sreeram, Beatrice Tan, Ruben G Boers, Joachim B Boers, Anne Boerema-De Munck, Marjon Buscop-Van Kempen, Wilfred F J Van Ijcken, J Marco Schnater, René M H Wijnen, Joost Gribnau, Robbert J Rottier","doi":"10.1093/ajrcmb/aanag088","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag088","url":null,"abstract":"<p><p>The pulmonary vasculature develops in close association with the airways and this network expands through the interactions between endothelial cells and the surrounding mesenchymal cells, the pericytes. Emerging evidence suggests that pericytes play a significant role in various lung diseases, such as congenital diaphragmatic hernia and chronic obstructive pulmonary disease. However, characterizing pericytes remains challenging, impeding our understanding of their exact role in lung development and disease. Therefore, we used a novel cell tracing technology based on a bacterial DNA cytosine methyltransferase (Dcm) fused to RNA polymerase II (DCM-TM) to methylate active genes. The doxycycline inducible Dcm-PolII fusion protein was activated at specific time points during gestation, while the epigenetically labeled genes were analyzed at later time points. This retrospective cell tracing was coupled to single-cell RNA sequencing to track the development of mouse pulmonary pericytes at the single cell level. This revealed the paths to differentiation of perivascular progenitors into pericytes and vascular smooth muscle cells. Temporal analysis uncovered dynamic gene expression profiles during pericyte differentiation, highlighting pathways crucial for pulmonary vascular development. Further analysis showed intricate signaling interactions between pericyte progenitors and mature pericytes, and we validated MCAM as a bona fide pulmonary pericyte marker. Our findings challenge conventional views on pericyte origin and underscore the importance of accurate pericyte identification in developmental and disease contexts. Overall, this study enhances our understanding of pulmonary pericyte ontogeny and differentiation, offering insights into their potential as therapeutic targets in pericyte-associated lung diseases.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832622","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":"Too Much of a Good Thing: Therapeutic Targeting of Type I Interferon in Super-infection.","authors":"Flavia Rago, John F Alcorn","doi":"10.1093/ajrcmb/aanag086","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag086","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832612","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-Protective and Neurotoxic: The Double-Edged Sword of Tau in Respiratory Infections.","authors":"Ajay Keerthy, Joseph A Hippensteel","doi":"10.1093/ajrcmb/aanag084","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag084","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832511","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":"Asthmatic Pulmonary Fibroblasts Aggravate Airway Inflammation Through FKBP5-Dependent Necroptosis.","authors":"Dong Zhang, Wei Liu, Tao Wang, Liang Dong, Wenjun Mao, Qian Qi, Xiaozhi Wang","doi":"10.1093/ajrcmb/aanag080","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag080","url":null,"abstract":"<p><p>Airway inflammation is a hallmark pathological feature of bronchial asthma and is closely associated with airway hyperresponsiveness. Pulmonary fibroblasts are key contributors to asthmatic inflammation, yet the underlying mechanisms remain insufficiently defined. In this study, FK506 binding protein 51 (FKBP5) was significantly upregulated in fibroblasts from individuals with asthma, and its expression was positively correlated with disease severity. Genetic knockout of Fkbp5 reduced HDM-induced airway barrier disruption and inflammatory injury. Single-cell RNA sequencing showed that Fkbp5 knockout suppressed the expression of eosinophil-attracting chemokines and inflammatory cytokines in fibroblasts of asthmatic mice. Fibroblast-specific Fkbp5 knockout further confirmed its essential role in promoting airway inflammation. Mechanistically, FKBP5 facilitated MLKL-dependent necroptosis in fibroblasts, which enhanced the production of proinflammatory cytokines and eosinophil chemokines, disrupted immune homeostasis, and exacerbated airway inflammation. These findings identify FKBP5 in fibroblasts as a potential therapeutic target for asthma prevention and treatment.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832085","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":"Recurrent H1N1 Influenza A virus infections cause airway hyperinnervation and cough hypersensitivity via the IFN-γ-JAK-ERK1/2-CDK5 pathway.","authors":"Zheng Deng, Dongting Xu, Zhengyang Lin, Wenbin Ding, Mengxi Luo, Yun Chen, Kefang Lai","doi":"10.1093/ajrcmb/aanag075","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag075","url":null,"abstract":"<p><strong>Rationale: </strong>Chronic cough patients present with increased airway sensory nerve density-a pathology often initiated by recurrent viral infections, notably H1N1. Infection-induced IFN-γ acts via its highly expressed receptors to promote neurite outgrowth in vitro.</p><p><strong>Objectives: </strong>To investigate the role of IFN-γ as a mediator in the development of airway hyperinnervation and cough hypersensitivity induced by recurrent H1N1 viral infections.</p><p><strong>Methods: </strong>We studied the effects and underlying mechanisms of recurrent H1N1 viral infections on airway hyperinnervation and subsequent cough hypersensitivity.</p><p><strong>Measurements and main results: </strong>Recurrent H1N1 viral infections in mice significantly enhanced cough sensitivity and airway inflammation, accompanied by elevated pulmonary IFN-γ + T cells/IFN-γ levels, vagal CDK5 activity, and airway nerve density. Anti-IFN-γ treatment abrogated these effects-cough hypersensitivity, IFN-γ + T cell infiltration, CDK5 upregulation, and airway hyperinnervation. Roscovitine treatment markedly attenuated viral infection-induced cough hypersensitivity, CDK5 activation in vagal ganglia, and airway hyperinnervation. Viral infections did not change gene expressions of IFN-γ receptors in vagal ganglia. Neither anti-IFN-γ nor roscovitine alleviated viral infection-induced airway inflammation. No evidence of airway hyperinnervation was observed following a single-dose H1N1 infection, either in the short term or long term. IFN-γ sensitized mouse vagal sensory neurons. Pharmacological inhibition of the JAK-ERK1/2-CDK5 pathways decreased IFN-γ-induced neurite outgrowth in mouse vagal sensory neurons.</p><p><strong>Conclusions: </strong>Recurrent H1N1 viral infections may cause airway hyperinnervation and cough hypersensitivity via the IFN-γ-JAK-ERK1/2-CDK5 pathways. Recurrent H1N1 viral infection-induced cough hypersensitivity may be mediated, in part, by IFN-γ-mediated airway hyperinnervation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832614","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":"Immune Regulation by CD55 in Chronic Beryllium Disease.","authors":"Li Li, Sucai Liu, Zhe Lei, Joshua Macaluso, Shujin Guo, Kristyn Macphail, Margaret M Mroz, Clara I Restrepo, Ivana Y Yang, Lisa A Maier","doi":"10.1093/ajrcmb/aanag063","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag063","url":null,"abstract":"<p><p>CD55 is an immune regulator that inhibits T cell activation and also binds to CD97, a molecule involved in immune cell migration and signaling. While CD55 expression is reduced in chronic beryllium disease (CBD), its functional role in disease pathogenesis remains unclear. We hypothesized that CD55 downregulation in peripheral blood mononuclear cells (PBMCs) contributes to heightened beryllium (Be)-specific immune responses in CBD. To test this, we characterized CD55 expression and function in PBMCs from individuals with CBD and beryllium sensitization (BeS), as well as in a human Be-specific T cell model. CD55, sCD55, and CD97 mRNA expression were quantified by qRT-PCR in PBMCs from CBD (n = 25), BeS (n = 36), and control (n = 7) subjects. BeSO4 stimulation was used to assess CD55, STAT1, JAK2, and TNF-α expression over time in CBD PBMCs (n = 8). Serum sCD55 was measured by ELISA in an independent cohort. Functional studies using anti-CD55 neutralizing antibodies and the JAK2 inhibitor TG101348 evaluated effects on TNF-α production and lymphocyte proliferation (BeLPT) in PBMCs, and IL-2 production in a Jurkat-Be cell model. CD55, sCD55, and CD97 were significantly downregulated in CBD PBMCs compared to BeS (P < .001). Serum sCD55 was also reduced in CBD (P < .05). BeSO4 stimulation further downregulated CD55 and upregulated STAT1. CD55 blockade increased TNF-α production and BeLPT responses in CBD (P < .001) and BeS (P < .05); these effects were reversed by JAK2 inhibition. In the Be-cell model, CD55 inhibition enhanced IL-2 production (P < .01), attenuated by JAK2 blockade. These findings suggest that CD55 downregulation amplifies Be-induced immune responses in CBD via JAK2/STAT1 signaling.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832370","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":"Highly Effective Modulator Therapies Restore Neutrophil Dysfunction in People with Cystic Fibrosis.","authors":"Frank H Robledo-Avila, Raul Rascon, Alejandra Montanez-Barragan, Veronica Loyo-Celis, Harpreet Singh, Karen S Mccoy, Benjamin T Kopp, Santiago Partida-Sánchez","doi":"10.1093/ajrcmb/aanag076","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag076","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a common genetic disease caused by a defective CF-transmembrane conductance regulator (CFTR). People with CF (pwCF) are prone to develop infections by opportunistic pathogens, including Burkholderia cenocepacia, leading to chronic inflammation. Neutrophils release granular proteins and oxidative products that contribute to tissue damage. CFTR modulators are a new treatment for pwCF aiming to correct the subcellular location and function of the CFTR ion channel. The triple modulator combination of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) or Trikafta® has significantly improved clinical symptoms and overall provided a better quality of life for pwCF. The mechanism by which CFTR modulators help to restore the antimicrobial functions of neutrophils is unknown. The present study demonstrated that neutrophils functionally express CFTR and revealed how ETI modifies subcellular CFTR trafficking in CF neutrophils. In addition, ETI treatment reduced intracellular chloride levels in human neutrophils, indicating activation of CFTR-dependent chloride efflux. Finally, ETI treatment also re-established the intracellular antimicrobial killing of CF neutrophils by potentiating NADPH oxidase activity and improved trapping microbes by enhancing the production of Neutrophil Extracellular Traps (NETs). Together, our findings suggest that CFTR has an essential role in controlling neutrophil functions and CFTR modulators help restore the antimicrobial functions of neutrophils from pwCF.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832366","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}