American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Associations of Adult Respiratory Lung Function with Diaphragm Transcriptome.","authors":"Santosh K Patnaik, Elizabeth Wendel, Jordan Lane, Jessica Herrington, Kent L Nastiuk, M Jeffery Mador, Sai Yendamuri, Andrew D Ray","doi":"10.1165/rcmb.2025-0462LE","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0462LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129845","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":"CFTR Modulator Therapy Impacts Neutrophil CD39 Expression in Cystic Fibrosis.","authors":"Debananda Gogoi, Claudie Gabillard-Lefort, Rory Baird, Luke Forde, Mengxin Niu, Sara Waqas Ahmed, Cedric Gunaratnam, Michael Williamson, Michelle Casey, Emer P Reeves","doi":"10.1165/rcmb.2025-0262LE","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0262LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129791","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 NADPH Oxidase DUOX1 Contributes to Profibrotic Macrophage Activation and Pulmonary Fibrosis.","authors":"Aida Habibovic, Miao-Chong Lin, Carolyn R Morris, Caspar Schiffers, Litiele C da Cruz, Inayah S van der Ploeg, Florance Steinvoort, Olaf Utermohlen, Martin Krönke, Amit Kumar, Vikas Anathy, Yvonne M W Janssen-Heininger, Albert van der Vliet","doi":"10.1165/rcmb.2024-0602OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0602OC","url":null,"abstract":"<p><p>Fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by various forms of environmental injury and involve reciprocal interactions between activated (myo)fibroblasts and recruited monocyte-derived macrophages (MoMacs), collectively leading to progressive tissue remodeling. Extending previous findings implicating redox-based mechanisms in IPF pathogenesis, we here highlight the involvement of the NADPH oxidase (NOX) homolog DUOX1 in pulmonary fibrosis, based on observed increases in DUOX1 expression within fibrotic regions of IPF lung tissues or lung tissues from mice with experimentally induced pulmonary fibrosis, localized primarily to (myo)fibroblasts and recruited MoMacs. Building on a previous report implicating DUOX1 in myofibroblast activation, conditional DUOX1 ablation from myeloid cells (including macrophages) using LysM-Cre was found to dramatically attenuate fibrosis, highlighted by impaired MoMac recruitment, reduced collagen production, and improved oxygen saturation. A macrophage-intrinsic role of DUOX1 was further supported by its observed contribution to in vitro migration of bone marrow-derived macrophages (BMDM) and to profibrotic BMDM activation, the latter including production of several epidermal growth factor receptor ligands involved in macrophage-fibroblast cross-talk. Finally, these DUOX1-mediated actions were associated with oxidative activation of Src kinase via cysteine oxidation, and were inhibitable by saracatinib, a clinically used Src inhibitor. Collectively, our findings highlight the involvement of DUOX1 in macrophage-(myo)fibroblast crosstalk in the pathogenesis and/or progression of pulmonary fibrosis, implicating it as a putatively novel therapeutically targetable feature of this devastating disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129815","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":"IRAK2 Ubiquitination Mediated by PELI1 Impairs Airway Epithelial Function and Accelerates Pediatric Asthma.","authors":"Sha Wang, Jinping Ruan, Pan Yan, Linyan Ying","doi":"10.1165/rcmb.2024-0573OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0573OC","url":null,"abstract":"<p><p>PELI1, an E3 ubiquitin ligase, has been identified as a controller of the innate immune response. This study was designed to expound the functional role of PELI1 in asthma (AS). Newborn mice were induced with house dust mite (HDM) to establish a mouse model of AS, and overexpression of <i>Peli1</i> was performed specifically in airway epithelial cells by AAV6.2 vector. Human bronchial epithelial cell line 16HBE was induced with HDM, <i>PELI1</i> was overexpressed in 16HBE cells by liposome transfection, and knockout was elicited through CRISPR/Cas9. <i>Peli1</i> expression was reduced in the airway epithelium of newborn mice induced with HDM, and overexpression of <i>Peli1</i> alleviated airway inflammation, mitigated airway injury, and inhibited airway remodeling in AS mice. PELI1 induced protein degradation of IRAK2 through K63 ubiquitination modification. Ectopic expression of Irak2 abated the mitigating effect of <i>Peli1</i> overexpression on airway inflammation by activating the Mapk/Nfκb signaling. Blockade of the MAPK/NF-κB signaling mitigated the exacerbation of inflammatory responses and cellular damage in 16HBE cells induced by <i>IRAK2</i> overexpression. Taken together, this research reveals a functional role of PELI1 in IRAK2 degradation and airway inflammation, which provides novel insights into the treatment of pediatric AS.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129827","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":"IGF2BP3-mediated NTSR1 m6A Methylation Enhances Irinotecan Resistance and LUAD Malignant Progression.","authors":"Hao Ding, Xuan Zhu, Yongquan Pan, Qi Zhang, Min Feng, Yi Yu, Yueping Fan, Li Zhu","doi":"10.1165/rcmb.2024-0487OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0487OC","url":null,"abstract":"<p><p>NTSR1 is a high-affinity receptor for neurotensin. Its abnormal expression correlates with cancer development. However, its mechanisms in promoting the malignant progression and Irinotecan resistance in lung adenocarcinoma (LUAD) remain unelucidated. NTSR1 expression in LUAD and its relationship with patients' prognosis were analyzed by bioinformatics analysis. NTSR1 expression in a human normal pulmonary epithelial cell line and LUAD cell lines was detected by quantitative real-time polymerase chain reaction (RT-qPCR) and western blot (WB). Cell proliferation ability was examined using the cell counting kit-8 assay and colony formation assay. Flow cytometry was employed to detect cell cycle and apoptosis. The Transwell assay was undertaken to assess cell migration and invasion ability. DNA damage was detected using the comet assay and γ-H2AX immunofluorescence. Dot-blot and methylated RNA immunoprecipitation (MeRIP)-qPCR were employed to examine m6A methylation levels. The interaction between IGF2BP3 and NTSR1 was verified by RNA immunoprecipitation (RIP) and dual luciferase experiments. Immunohistochemistry (IHC) was applied to analyze protein expression in mouse tumor tissues. NTSR1 was upregulated in LUAD cells, affecting patients' dismal overall survival. NTSR1 knockdown hindered cell proliferation, migration, and invasion, reinforced apoptosis and Irinotecan sensitivity. Mechanistically, IGF2BP3 interacted with NTSR1 and induced m6A methylation modification to enhance transcriptional stability, advancing the malignant progression of LUAD and irinotecan resistance. Additionally, NTSR1 knockdown enhanced the sensitivity of LUAD to Irinotecan in mice and induced DNA damage. Overall, IGF2BP3-mediated NTSR1 m6A methylation expedites LUAD malignant progression and reinforces irinotecan resistance. Targeting this pathway may be an effective method for treating LUAD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129800","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":"Iron Induces <i>Aspergillus</i> Proteases in Cystic Fibrosis Allergic Bronchopulmonary Aspergillosis.","authors":"Paulami Chatterjee, Aijaz Ahmad, Ekroop Dhillon, Efthymia Iliana Matthaiou, Amer Ali Abd El-Hafeez, Wayland Chiu, Beate Illek, David A Stevens, Carlos Milla, Joe L Hsu","doi":"10.1165/rcmb.2025-0077OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0077OC","url":null,"abstract":"<p><p>Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease triggered by inhaled <i>Aspergillus fumigatus (Af)</i> spores (i.e., conidia), in persons with cystic fibrosis (CF). High iron levels have been commonly described in CF respiratory secretions. <i>Af</i> proteases cause a severe allergic immune response, leading to pulmonary exacerbations and progressive lung function decline. The stimuli that promote <i>Af</i> proteases in ABPA are poorly understood. Therefore, we sought to determine if airway iron is a critical factor in CF-ABPA by regulating fungal protease production. We used transcriptomics and proteomics to investigate the role of iron in stimulating the production of <i>Af</i> proteases and evaluated the impact of these iron-induced <i>Af</i> proteases on Th2 immune response in CF bronchial epithelial (CFBE) cells and in a CF-ABPA murine model. Transcriptional analysis showed significant upregulation of <i>Af</i> proteases with exposure to iron and a downregulation with iron chelation. This finding was validated in secretome studies showing that <i>Af</i>-culture filtrates (<i>Af</i>-cf) from iron-exposed conidia contained significantly higher levels of 14 proteases compared to controls. Exposure to iron-primed <i>Af</i>-cf increased the production of Th2 promoting cytokines (IL-33, IL-25 and TSLP) in CF bronchial epithelial cells compared to the wild type cells. In vivo, inoculation of CF mice with iron-primed <i>Af</i> conidia led to higher levels of serum IgE and Th2 cytokines (IL-4, IL-5, IL-9, IL-13) in lung tissue. These findings suggest that airway iron is a potent stimulus for <i>Af</i> proteases and represents a modifiable risk factor and potential therapeutic target for CF-ABPA.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079102","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":"Hyperoxia and Surfactant Dysfunction in Critical Illness: Insights and Future Therapeutic Prospects.","authors":"Alastair Watson, Tom Roe, Isis Terrington, Anthony D Postle, Daniel Martin, Michael P W Grocott, Ahilanandan Dushianthan","doi":"10.1165/rcmb.2025-0358TR","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0358TR","url":null,"abstract":"<p><p>Supplemental oxygen is an essential therapy during critical illness. However, patients with severe hypoxemic respiratory failure and/or acute respiratory distress syndrome (ARDS) often require high oxygen concentrations, exposing lungs to alveolar hyperoxia despite systemic hypoxemia, with consequent pulmonary oxygen toxicity. Pulmonary oxygen toxicity causes disruption of surfactant, which is essential for maintenance of alveolar functional anatomy as well as efficient and effective gas exchange and immune regulation. Surfactant dysregulation can increase alveolar surface tension, causing alveolar collapse with atelectasis, resulting in poor lung compliance and impaired gas exchange. Hyperoxia-induced lung injury mechanisms may interact with mechanisms of harm associated with infections and mechanical ventilation. The intricate relationship between these different, inter-related, stressors and altered surfactant metabolism and function has yet to be fully delineated, particularly in humans. This review examines current understanding of hyperoxia-induced surfactant dysregulation. We discuss potential mechanisms, including biochemical/compositional and functional changes to lipids and proteins including surfactant protein A (SP-A) and SP-D, epithelial atrophy, impaired surfactant synthesis/metabolism, redox imbalances, phospholipase-A2, and altered macrophage clearance. Key areas for future research are outlined, emphasising the need for clinically relevant human models that discriminate between the effects of oxygen therapy dose and duration, as well as other iatrogenic effects and underlying disease processes. We propose a roadmap to progress current knowledge and outline opportunities for well-designed human studies, novel surfactant preparations resistant to functional inhibition and breakdown, and technological developments, with the potential for leveraging these to identify innovative biomarkers individualised therapeutic targets and novel therapies in the future.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079552","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":"Sequential Roles of VLA-4/VCAM-1 Interactions and CXCR4/CXCL12 Cues in the Early Phases of Injured Lung Regeneration by Lung Cell Transplantation.","authors":"Xiaohua Su, Sandeep K Yadav, Christa Blagdon, Aloukick Kumar Singh, Irit Milman-Krentsis, Einav Shoshan, Ronen Alon, Yair Reisner","doi":"10.1165/rcmb.2025-0010OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0010OC","url":null,"abstract":"<p><p>Lung cell transplantation has demonstrated remarkable regenerative potential in various mouse models of lung injury, including pulmonary fibrosis. However, early processes governing donor cell lung homing and fate following transplantation remain poorly understood. This study interrogates mechanisms underlying donor cell homing, extravasation, and formation of regenerative patches inside recipient lungs after i.v. infusion of CD45- lung cells. Naphthalene (NA) and total body irradiation (TBI) were used to induce lung injury. Donor derived lung cell suspensions were infused intravenously, and donor cell localization were analyzed at various time points using flow cytometry and immuno-fluorescence. The functional roles of VCAM-1/VLA-4 and CXCL12/CXCR4 interactions in early donor cell homing to injured lungs were assessed by incubating donor cells with anti-VLA-4 or anti-CXCR4 blocking antibodies or by pre-treatment of recipient mice with anti-VCAM-1 antibody. At 24 hours post-infusion, only 0.8% of infused cells accumulated inside the lungs, with approximately a third of the cells within the pulmonary vasculature. By day seven, 97% of donor cells were found in the lung parenchyma. These donor cells were highly proliferative and formed regenerative patches by day 21. Blocking VLA-4 or CXCR4 inhibited adhesion of infused cells to blood vessels early after infusion and interfered with subsequent formation of regenerative donor-derived lung patches at 6 weeks post-infusion. This study highlights the sequential roles of VLA-4/VCAM-1 and CXCR4/CXCL12 interactions in facilitating donor lung cell homing and regenerative patch formation in injured lungs.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038873","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":"Extracellular Matrix and Fibroblast Activation in Lymphangioleiomyomatosis.","authors":"Alexander R Mukhitov, Jilly F Evans, Tiegang Han, Owen A Ledwell, Ryan Rue, Kseniya Obraztsova, Susan M Lin, Maria C Basil, Edward Cantu, Yan Tang, Elizabeth P Henske, Vera P Krymskaya","doi":"10.1165/rcmb.2025-0237OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0237OC","url":null,"abstract":"<p><p>Lymphangioleiomyomatosis (LAM) is a rare lung disease caused by hyperactivation of the mechanistic/mammalian target of rapamycin 1 (mTORC1) growth pathway in a subset of mesenchymal lung cells. Histopathologically, LAM lesions have been described as immature smooth muscle-like cells positive for the immature melanocytic marker HMB45/PMEL/gp100 and phosphorylated ribosomal protein S6 (pS6). Advances in single cell sequencing (scRNA-seq) technology allowed us to group LAM cells according to their expression of cancer stem cell (CSC) genes and identify three clusters: a high CSC-like state (SLS), an intermediate state, and a low CSC-like inflammatory state (IS). We show here that in unique LAM cells many extracellular matrix (ECM) genes, including collagens and collagen triple helix repeat-containing 1 (CTHRC1), are expressed in the high and intermediate CSC-like LAM clusters and suggest that as is observed in CSCs, the ECM may provide a shield for LAM lesions against immunosurveillance. In LAM-associated fibroblasts (LAFs), the bi-steric mTORC1-selective inhibitor RMC-5552 blocked translation of TGF-β-induced COL1A1, COL6A1 and phosphorylation of the mTORC1 substrates ribosomal protein S6K1/ribosomal protein S6 (S6K1/S6) and eukaryotic initiation factor 4E-binding protein/translation initiation factor 4E (4E-BP1/eIF4E), whereas rapamycin, the Food and Drug Administration (FDA)-approved therapy for LAM disease, only inhibited the S6K1/S6 axis. C82, a Wnt/-catenin transcription inhibitor, prevented TGF-β-induced collagens but not pS6 or p4E-BP1. This demonstrates that mTORC1-driven 4E-BP1/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM patients.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022706","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":"Non-Canonical HIPPO-MST1/2 Promotes Hyper-Proliferation of Pulmonary Vascular Cells through CDC20.","authors":"Tapan Dey, Iryna Zhyvylo, Lifeng Jiang, Samuel O Olapoju, Andressa Pena, Theodore Avolio, Derek Lin, Dmitry Goncharov, John R Greenland, Paul J Wolters, Horace DeLisser, Soni Savai Pullamsetti, Tatiana V Kudryashova, Elena A Goncharova","doi":"10.1165/rcmb.2025-0238LE","DOIUrl":"10.1165/rcmb.2025-0238LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022680","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}