American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Circular RNAs are differentially expressed in cystic fibrosis bronchial epithelium and regulate ion conductance.","authors":"Chiara De Santi, Joshua E Donovan, Eimear Fay, Ewelina Hejenkowska, Irene K Oglesby, Xi Jing Teoh, Stephen F Madden, Killian Hurley, Agnieszka Swiatecka-Urban, Catherine M Greene","doi":"10.1093/ajrcmb/aanaf003","DOIUrl":"10.1093/ajrcmb/aanaf003","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"706-709"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281745","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":"Pseudomonas hijacks lactate to rewire host defense.","authors":"Elizabeth F Redente, Elizabeth J Tarling","doi":"10.1093/ajrcmb/aanag004","DOIUrl":"10.1093/ajrcmb/aanag004","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"569-571"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281759","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":"Interleukin-7 receptor activation in interstitial macrophages promotes lung fibrosis through secreted phosphoprotein 1.","authors":"Kohsuke Shirakawa, Motoaki Sano, Iwao Sakane, Kazuhiro Yamanoi, Dai Kusumoto, Shinichi Goto, Hidenori Moriyama, Kyohei Daigo, Kazuhisa Sugai, Yoshinori Katsumata, Jin Endo, Koichi Ikuta, Nagahiro Minato, Masaki Ieda","doi":"10.1165/rcmb.2025-0254OC","DOIUrl":"10.1165/rcmb.2025-0254OC","url":null,"abstract":"<p><strong>Rationale: </strong>Osteopontin, also known as secreted phosphoprotein 1 (SPP1), is a critical mediator of lung fibrosis. However, the cellular sources of SPP1 and the mechanisms by which SPP1-producing cells promote fibrotic progression remain poorly defined. Objectives To define the functional roles and regulatory mechanisms of SPP1-producing macrophages in lung fibrosis.</p><p><strong>Methods: </strong>Publicly available single-cell RNA sequencing datasets from patients with idiopathic pulmonary fibrosis were analyzed to investigate macrophage-fibroblast interactions. A bleomycin-induced lung fibrosis model was used in Spp1-enhanced green fluorescent protein (EGFP) knock-in reporter mice to identify Spp1-producing cells in vivo. Multi-omics approaches were applied to characterize profibrotic macrophage populations. The contribution of interleukin-7 receptor (IL7R)signaling in macrophages was evaluated using Il7r fl/fl Csf1r-iCre mice.</p><p><strong>Measurements and main results: </strong>Single-cell transcriptomic analyses revealed fibrogenic interactions between SPP1-expressing macrophages and fibroblasts in human pulmonary fibrosis. In mice, interstitial macrophages (IMs) were identified as the predominant source of Spp1 in fibrotic lungs and promoted fibrosis by enhancing fibroblast activation. Spp1-EGFP + IMs expanded rapidly, peaking 7 days after bleomycin administration, and subsequently engrafted as inflammatory resident macrophages. Multi-omics analyses demonstrated that these cells produced glycoprotein non-metastatic melanoma protein B (Gpnmb), a profibrotic and proinflammatory mediator. SPP1-producing macrophages expressed IL7R in fibrotic lungs of both humans and mice. Macrophage-specific deletion of Il7r reduced Spp1 and Gpnmb expression and significantly attenuated lung fibrosis.</p><p><strong>Conclusions: </strong>SPP1-producing interstitial macrophages are key drivers of lung fibrosis through IL-7R-dependent mechanisms. Targeting the IL-7/macrophage/SPP1 axis may represent a promising therapeutic strategy for lung fibrosis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"644-660"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297872","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":"Ectopic expression of MUC5B in the respiratory bronchiole initiates endoplasmic reticulum stress in the IPF lung.","authors":"Rachel Z Blumhagen, Jonathan S Kurche, Carlyne D Cool, David Heinz, Xiaoqian Ma, Elizabeth J Davidson, Tasha E Fingerlin, Jonathan P Huber, Evgenia Dobrinskikh, David A Schwartz, Ivana V Yang","doi":"10.1165/rcmb.2025-0261OC","DOIUrl":"10.1165/rcmb.2025-0261OC","url":null,"abstract":"<p><strong>Rationale: </strong>IPF is an irreversible and progressive type of lung fibrosis that is pathologically characterized as spatially heterogeneous. Despite the identified dominant risk factor for IPF as the gain-of-function MUC5B promoter variant, little is understood for how MUC5B drives lung fibrosis.</p><p><strong>Objectives: </strong>We used spatial transcriptomics from idiopathic pulmonary fibrosis (IPF) and unaffected control lung tissue to further understand the pathogenesis of MUC5B-driven lung fibrosis.</p><p><strong>Methods: </strong>We captured 43 fields of view in 15 IPF and 13 controls with and without the MUC5B promoter variant using the CosMx® platform and identified 19 cell types via semi-supervised clustering.</p><p><strong>Measurements and main results: </strong> MUC5B was ectopically expressed in AT2 cells in controls with the risk variant. We observed a decreased proportion of AT2 cells in controls and an increased proportion of aberrant basaloid cells in IPF associated with the MUC5B risk variant. We identified co-localized expression of MUC5B in respiratory bronchioles with 13 genes including the endoplasmic reticulum (ER) stress marker XBP1 and distal secretory markers SCGB3A1 and SCGB1A1. Experimentally, we demonstrated a direct relationship between MUC5B expression and ER stress in bronchiolar epithelia in vitro and validated the co-expression of MUC5B and XBP1 in the IPF lung.</p><p><strong>Conclusions: </strong>Based on our results, we conclude that MUC5B injures alveolar and bronchiolar epithelia that results in loss of AT2 cells and an increase in aberrant basaloid cells which initiates ER stress and a secretory phenotype in the terminal respiratory bronchiole, establishing a persistently injured distal airspace.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"632-643"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290760","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":"Sex-based immune and genetic mechanisms in asthma: a shift toward precision medicine?","authors":"Pawan Sharma","doi":"10.1165/rcmb.2025-0423LE","DOIUrl":"10.1165/rcmb.2025-0423LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"704-705"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342716","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 lactylation-YTHDF1 axis promotes DNAH5-dependent ciliary defense in Pseudomonas aeruginosa infection.","authors":"Jing Wang, Xiang Shen, Yanan Li, Zhenwei Xia, Tong Yin, Jing Qiao, Yangyang Deng, Runying He, Yu Guo, Yuxuan Zhang, Guoliang Zhang, Jieming Qu","doi":"10.1093/ajrcmb/aanaf010","DOIUrl":"10.1093/ajrcmb/aanaf010","url":null,"abstract":"<p><p>Pseudomonas aeruginosa infection poses a significant clinical challenge in respiratory diseases by subverting host defense mechanisms. While inflammatory responses in airway epithelial cells (AECs) during infection have been extensively studied, the interplay between epitranscriptomic regulation and metabolic reprogramming remains poorly understood. Here, we identify a lactylation-N6-methyladenosine (m6A) axis that orchestrates ciliary function and antibacterial defense through dual-layer metabolic-epigenetic coordination. Using integrated in vivo and in vitro models, we demonstrate that P aeruginosa infection depletes host lactic acid through direct consumption via lactate dehydrogenase and virulence factor-mediated glycolytic suppression. This metabolic perturbation reduces histone H3K18 lactylation, diminishing m6A methylation by directly downregulating YTHDF1; m6A sequencing analysis reveals preferential hypomethylation of dynein axonemal heavy chain 5 (DNAH5) mRNA, a critical regulator of ciliary motility. Mechanistically, YTHDF1 recognizes m6A-modified DNAH5 transcripts to stabilize translation. The lactylation-YTHDF1-DNAH5 axis proves essential for maintaining ciliary beat frequency and mucociliary clearance capacity. This metabolic-epitranscriptomic circuitry significantly impacts host defense, as evidenced by increased bacterial burden in conditional YTHDF1 knockout mice. Our findings extend the paradigm of lactylation-mediated gene regulation to airway pathophysiology, revealing a novel mechanism where microbial-induced metabolic perturbations reprogram RNA modification landscapes to disable ciliary defenses. This study establishes a conceptual framework for understanding how opportunistic pathogens exploit host metabolic-epigenetic networks to establish persistent infections, suggesting therapeutic potential for targeting the lactate-YTHDF1 axis in P aeruginosa-associated pulmonary disorders.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"590-603"},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281812","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":"Lytic Cell Death in Chronic Lung Diseases.","authors":"Ioannis Siokas, Morgan Heileman, Lawrence C Fritz, Alexei Degterev","doi":"10.1093/ajrcmb/aanag092","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag092","url":null,"abstract":"<p><p>Regulated cell death is critical in maintaining tissue homeostasis and immune functions. The most common form of physiologic cell death is the highly precise, regulated, and relatively inflammation-free pathway of apoptosis. In contrast, necrotic or lytic cell death, which involves rapid cell lysis and release of pro-inflammatory mediators, is more often associated with human pathologies. Pyroptosis and necroptosis are two regulated forms of lytic cell death and are increasingly recognized as important mediators of tissue damage in many diseases, including lung diseases. The death of lung cells is a key contributor to disease in multiple respiratory disorders. However, current interventions are limited to targeting downstream effects to help relieve symptoms without addressing the root cause driving tissue damage. Therefore, new strategies directed towards preventing tissue damage caused by detrimental cell death are desperately needed. Emerging evidence strongly implicates regulated necrosis in many acute and chronic lung diseases, but the specific form(s) of cell death driving pathology and cell types involved require nuanced evaluation. Here, we summarize current literature suggesting that pyroptosis and necroptosis facilitate lung injury and inflammation in Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) by inducing the death of airway and alveolar epithelial cells and resident immune cells, which leads to alveolar barrier disruption, release of inflammatory mediators, excessive immune cell recruitment, and ultimate lung function decline.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809520","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":"Bile Acid Alteration and Alveolar Dysfunction in Cirrhosis: An Aggravating Factor or a New Piece in the Pathogenesis of Hepatopulmonary Syndrome?","authors":"Laurent Savale, Christophe Guignabert","doi":"10.1093/ajrcmb/aanag087","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag087","url":null,"abstract":"","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":"147760013","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":"CCR5+ NK cells drive hypoxemia in endotoxin-induced acute lung injury.","authors":"Reena Bharti, Nancy Greenland, Simon J Cleary, John R Greenland, Daniel R Calabrese","doi":"10.1093/ajrcmb/aanag095","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag095","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a life-threatening clinical syndrome characterized by intense inflammation and pulmonary physiologic dysfunction. While innate immune cells dominate early ALI pathology, lymphocytes are increasingly recognized as important contributors. Prior work demonstrated that natural killer (NK) cells are recruited through CCR5 leading to damage following ischemic lung injury. As endotoxin-induced ALI is an important pre-clinical model for acute respiratory distress syndrome (ARDS), here we asked whether NK cells recruited through CCR5 mediated injury in this clinically relevant model. We examined CCR5 and NK cells in a C57BL/6 mouse model of endotoxin-induced ALI using spectral flow cytometry and genetic knockout animals. We found that CCR5 ligands and CCR5 NK cells were increased during ALI relative to no-injury control mice. CCR5-positive NK cells had markers of tissue residence and CCR5 inhibition reduced NK cell trafficking as measured in the bronchoalveolar lavage. Further, CCR5 inhibition ameliorated lung injury across all domains. CCR5 inhibition had less of an impact on T cell trafficking, and these cells had relatively less CCR5 expression. Adoptive transfer of Ccr5-null NK cells preceding ALI resulted in reduced trafficking and injury compared to wildtype transfers. NK cell depletion and CCR5 inhibition were effective even when administered 2 hours after LPS administration. indicating potential relevance for clinical translation. In summary, this study cements CCR5-positive NK cells as mechanistically important in a clinically relevant acute lung injury model. Inhibition of CCR5-positive NK cells may have translational application for some ARDS endotypes.</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":"147760082","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":"Alveolar Type 2 Cell Dysfunction Is Associated with Bile Acid Alterations in Experimental Hepatopulmonary Syndrome.","authors":"Hyo-Jin Park, Hyung Joon Cho, Peng Chen, William P Pederson, Bin Liu, Dan Yi, Esther Juarez, Nickolaus Lorson, Amaya Bruner, Xiaomei Xia, Qi Zheng, Nabia Kheshtchin-Kamel, Tara Liu, Sarah Raevens, Michael F Beers, Feng Li, Ruud A W Veldhuizen, Huiping Zhou, Julie G Ledford, Steven M Kawut, Zhiyu Dai, Michael B Fallon","doi":"10.1093/ajrcmb/aanag067","DOIUrl":"10.1093/ajrcmb/aanag067","url":null,"abstract":"<p><p>Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis characterized by pulmonary microvascular dilation, hypoxemia, and increased mortality. Patients often exhibit unexplained restrictive ventilatory defects that correlate with circulating bile acids, suggesting superimposed alveolar dysfunction. To investigate this, we evaluated alveolar function, cell types, and the potential role of altered bile acids in the experimental HPS. Common bile duct ligation (CBDL) mice were assessed for pulmonary and surfactant function. AT2 cell-specific RiboTag RNA sequencing, single-cell RNA sequencing (scRNA-seq), and mass spectrometry-based bile acid profiling were performed. MLE12 cells were treated with bile acids in vitro, and an FXR agonist was administered in vivo to test effects on AT2 cell. CBDL mice developed HPS with restrictive defects due to reduced AT2 cell-derived surfactant-protein-C (SP-C), increased alveolar surface tension, and elevated plasma and bronchoalveolar bile acid levels. ScRNA-seq demonstrated a decrease in AT2 cells and an increase in AT2-to-AT1 transitional cells. AT2-specific RNA-seq revealed upregulated bile acid and cholesterol metabolism and downregulated proliferative pathways. In vitro, bile acids mimicking FXR antagonists reduced SP-C in MLE12 cells, while in vivo FXR agonist decreased circulating bile acids and restored SP-C-producing AT2 cells in CBDL mice. Our data demonstrates alterations in AT2 cell biology, including reduced surfactant expression, in the setting of elevated bile acids. These finding indicate an association between bile acid levels and AT2 cell alterations in cirrhosis and identify bile acid signaling and AT2 cell integrity as areas for future mechanistic investigation.</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":"147760005","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}