American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Senescence at the Crossroads of Lung Development and Injury.","authors":"Kent A Willis, Namasivayam Ambalavanan","doi":"10.1165/rcmb.2024-0564ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0564ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735543","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":"Pathogenic Concepts in Pulmonary Arterial Hypertension Revisited - A Multigenerational Perspective.","authors":"Grazyna Kwapiszewska, Christopher Rhodes, Marlene Rabinovitch, Catherine Simpson, Paul Hassoun, Kenzo Ichimura, Marc Humbert, Edda Spiekerkoetter","doi":"10.1165/rcmb.2024-0519PS","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0519PS","url":null,"abstract":"<p><p>The rapid advancement of next-generation omics platforms, bioinformatic data analysis, and novel imaging techniques is transforming biomedical research, especially in pulmonary hypertension. These cutting-edge tools generate vast data, leading to innovative therapeutic and diagnostic possibilities, such as personalized medicine and patient-specific risk stratification. However, while embracing new technologies, it is crucial to integrate decades of hypothesis-driven research with emerging discovery platforms to avoid redundant efforts and enhance scientific progress. At the 2024 American Thoracic Society (ATS) conference, senior and junior investigators in vascular biology, pulmonary hypertension, and right heart failure engaged in pro/con debates on research paradigms. These discussions explored how evolving disease frameworks fit within the context of traditional research, emphasizing the balance between newer multi-omics approaches and classical hypothesis-driven science. Three key objectives were addressed: (1) integrating unbiased analytic methods with traditional frameworks, (2) interpreting new multi-omics findings within known pathobiological pathways, and (3) reviewing modern imaging methods for the right ventricle to improve disease understanding. While omics approaches offer a broad, integrative view and support personalized medicine, they present challenges, such as managing large datasets and ensuring effective clinical translation. Conversely, traditional reductionist approaches, focusing on known genetic alterations and signaling pathways, have led to significant breakthroughs, including the development of current therapies. Combining both approaches holds great potential to drive future discoveries and develop more effective treatments for pulmonary hypertension, a goal that can only be achieved through coordinated, transdisciplinary teams of investigators with diverse skillsets and knowledge working together to advance the field.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735542","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":"Protecting the Future of Medical Innovation: Balancing Fiscal Responsibility with the Need for National Institutes of Health and Federal Health Funding.","authors":"Irina Petrache, Raed A Dweik, Michelle Ng Gong, Jesse Roman, M Patricia Rivera, Karen J Collishaw","doi":"10.1165/rcmb.2025-0167ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0167ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727386","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":"Engineering HMGB1-Derived Peptides to Unravel Sex-Specific Mechanisms in Pulmonary Arterial Hypertension.","authors":"Qi Zheng, Zhiyu Dai","doi":"10.1165/rcmb.2025-0070ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0070ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708232","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":"eNAMPT Is a Novel DAMP and Therapeutic Target in Human and Murine Pulmonary Fibrosis.","authors":"Nancy G Casanova, Jose D Herazo-Maya, Carrie L Kempf, Belinda L Sun, Jin H Song, Annie Hernandez, Jason Canizales Galaviz, Xiaoguang Sun, Sara M Camp, Julie G Ledford, Riley D Hellinger, Marisela Rodriguez, Amy Y Zhao, Avraham Unterman, Ivan Rosas, Steve Duncan, Victor J Thannickal, Matthew K Hufford, Mohamed Ahmed, Nahla Zaghloul, Akash Gupta, Christian Bime, Saad Sammani, Ben N Stansfield, Jinjing Chen, Annadurai Anandhan, Matthew D Disney, Aikseng Ooi, Shaira L Kee, Theodoros Karampitsakos, Panayiotis V Benos, Naftali Kaminski, Donna Zhang, Joe G N Garcia","doi":"10.1165/rcmb.2024-0342OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0342OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutics. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand that contributes to the severity of radiation-induced lung fibrosis and NASH-associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF utilizing the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, PBMCs, and lung tissues from IPF patients and from an experimental bleomycin-induced lung fibrosis model in C57Bl6 mice were analyzed. Biochemical and histologic measurements, as well as gene expression through bulk and single-cell RNA sequencing of human PBMCs and murine lung tissues were performed. Human studies revealed NAMPT expression to be significantly elevated in plasma, lung tissues, and in PBMCs from IPF subjects, correlating with disease severity and inversely associated with IPF survival. Bleomycin-exposed mice exhibited increased inflammatory indices associated with lung fibrosis development (including NAMPT levels), as well as physiologic lung stiffening, and TGFβ pathway-related protein and gene expression with each indice significantly mitigated in mice receiving ALT-100 mAb. scRNAseq studies demonstrated the ALT-100 mAb to reverse bleomycin-induced dramatic expansion of alveolar type 2 epithelium (AT2) and indiction of endothelial- and epithelial cell-to-mesenchymal/myofibroblast transitions (EndMT, EMT). These finding support the fundamental involvement of eNAMPT/TLR4 signaling pathway in lung fibrosis pathobiology with eNAMPT neutralization a viable therapeutic strategy to directly address the unmet need for novel IPF treatments.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690902","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":"scRNAseq Identifies Unique Macrophage Population in Mouse Model of Ozone Induced Asthma Exacerbation.","authors":"Jess L Ray, Joshua Walum, Daria Jelic, Ryelie Barnes, Ian D Bentley, Rodney D Britt, Joshua A Englert, Megan N Ballinger","doi":"10.1165/rcmb.2024-0358OC","DOIUrl":"10.1165/rcmb.2024-0358OC","url":null,"abstract":"<p><p>Ozone (O₃) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms are unknown. Previously, we developed a murine model of dust mite, ragweed, and <i>aspergillus</i> (DRA)-induced allergic lung inflammation followed by O₃ exposure for mechanistic investigation. The present study used single cell RNA-sequencing for unbiased profiling of immune cells within the lungs of mice exposed to DRA, O₃, or DRA+O₃, to identify components of the immune cell niche that contribute to AHR. Alveolar macrophages (AMs) had the greatest number of differentially expressed genes following DRA+O₃, most of which were unique to the 2-hit exposure. Following DRA+O₃, AMs activated transcriptional pathways related to cholesterol biosynthesis, degradation of the extracellular matrix, endosomal TLR processing, and various cytokine signals. We also identified AM and monocyte subset populations that were unique to the DRA+O₃ group. These unique AMs activated gene pathways related to inflammation, sphingolipid metabolism, and bronchial constriction. The unique monocyte population had a gene signature that suggested phospholipase activation and increased degradation of the extracellular matrix. Flow cytometry analysis of BAL immune cells showed recruited monocyte-derived AMs after DRA and DRA+O₃, but not after O₃ exposure alone. O₃ alone increased BAL neutrophils but this response was attenuated in DRA+O₃ mice. DRA-induced changes in the airspace immune cell profile were reflected in elevated BAL cytokine/chemokine levels following DRA+O₃ compared to O₃ alone. The present work highlights the role of monocytes and AMs in the response to O₃ and suggests that the presence of distinct subpopulations following allergic inflammation may contribute to O₃-induced AHR.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661565","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":"Loss of <i>Tbx4</i> Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension.","authors":"Gabriel Maldonado-Velez, Elizabeth A Mickler, Todd G Cook, Micheala A Aldred","doi":"10.1165/rcmb.2024-0459OC","DOIUrl":"10.1165/rcmb.2024-0459OC","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the precapillary pulmonary arteries. Genomic variation within the T-box 4 (TBX4) transcription factor is the second most common genetic cause of PAH, and can also cause severe lung developmental disorders with neonatal PH. Currently, the effect of TBX4 loss-of-function on later stages of lung development and predisposition to lung disease, including PH, is not well understood. Therefore, we have generated <i>Tbx4</i> conditional knockout (<i>Tbx4-CKO</i>) mice in which <i>Cre</i> recombinase deletes exon 5 of <i>Tbx4</i> within the embryonic lung mesenchyme to create a null allele. We harvested lungs from these mice at various timepoints to examine alveologenesis, vascularization, vascular remodeling, lung cellular composition, and disruption of transcriptional activity compared with control lungs. Right ventricular systolic pressure (RVSP) was measured in six-month-old mice to evaluate for PH. <i>Tbx4-CKO</i> lungs show enlargement of airspaces, as confirmed by an increase in mean linear intercept at P14 (24.9%), P36 (31.5%), and P180 (49.6%). These lungs also show a 39.3% decrease in von Willebrand Factor-positive vessels and a 14.2% increase in vessel wall thickness. Consistent with these results, <i>Tbx4-CKO</i> mice show a statistically significant increase of 15.7% in RVSP and 16.3% in the Fulton index. Bulk-RNA sequencing analysis revealed enrichment of pathways and genes relevant to lung alveologenesis, angiogenesis, and PH. Our results show that disruption of <i>Tbx4</i> expression during early lung development is sufficient to disrupt postnatal lung development and circulation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662081","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":"Nasal Epithelial Extracellular Vesicles Correlate with Type 2 Inflammation During Aspirin-induced Respiratory Reactions.","authors":"Kaitlyn E Bunn, Zachary J Bressman, Grant K Nation, Pingsheng Wu, Taneem Amin, Courtney Lehman, Anabel Lin, Carleigh J Gray, Tanya M Laidlaw, Katherine N Cahill, Heather H Pua","doi":"10.1165/rcmb.2024-0414OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0414OC","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are membrane-bound particles secreted by cells with emerging roles in intercellular communication during tissue homeostasis and disease. Although EVs are abundant in respiratory biofluids, their cellular sources, critical cargos, and functions in the airway remain poorly understood. To determine how EV populations are changed in respiratory fluids during a chronic tissue inflammatory response, nasal EVs were assayed in 23 control participants and 22 participants with Aspirin-Exacerbated Respiratory Disease (AERD). Nasal lining fluid from participants was found to contain abundant EVs by electron microscopy and tunable resistive pulse sensing. Subset-specific EV subpopulations defined by the monocyte/macrophage marker CD14 or the epithelial marker CD133/1 were increased in participants with AERD. To test how EVs change during an acute exacerbation, nasal lining fluid EVs were assessed in participants with AERD who were repeatedly sampled during an aspirin-induced respiratory reaction. The abundance of several EV subpopulations dynamically correlated with levels of cysteinyl leukotrienes and tryptase in AERD nasal lining fluid. Together, these data implicate EVs in a dynamic signaling network that drives tissue inflammation during aspirin-induced type 2 immune activation in AERD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630008","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 Critical Role of HMGB1Cys106 in Regulating Sex-specific p53 Signaling in Pulmonary Arterial Hypertension.","authors":"Odunayo Susan Lawal, Maki Niihori, Joel James, A J Hinkle, Takanori Sano, Nolan McClain, Ruslan Rafikov, Olga Rafikova","doi":"10.1165/rcmb.2024-0296OC","DOIUrl":"10.1165/rcmb.2024-0296OC","url":null,"abstract":"<p><p>High Mobility Group Box 1 (HMGB1) is a nuclear protein released from damaged cells and implicated in the pathogenesis of Pulmonary Arterial Hypertension (PAH) through activation of pro-inflammatory and pro-survival responses. However, the role of intracellular HMGB1 signaling, particularly its interactions with DNA and transcriptional regulation, remains underexplored. In this study, we investigated the role of intracellular HMGB1 and its critical residue Cys106 by engineering cell-penetrating peptide (αHMGB1Cys106) that mimics part of the HMGB1 dimeric interface surrounding Cys106. The peptide's effects on HMGB1 intracellular distribution, DNA-binding affinity, and p53 expression and signaling were assessed in cell culture and in vivo using the Sugen/Hypoxia rat model of severe PAH. Our findings demonstrate that αHMGB1Cys106 significantly altered HMGB1 intracellular dynamics, prompting its nuclear exit and subsequent degradation. This effect was associated with a decreased HMGB1-DNA binding and reduced p53 expression both in vitro and in vivo. Remarkably, preventive and therapeutic administration of αHMGB1Cys106 mitigated Sugen/Hypoxia-induced PAH development and progression in a sex-specific manner. In females, the peptide therapy reduced pulmonary apoptosis, senescence, and genotoxic stress, providing significant protection in earlier PAH and effectively reversing PAH phenotype at advanced stages. Conversely, in males, the treatment yielded only partial benefits, primarily through attenuated genotoxic signaling. These results establish Cys106 as a critical regulator of intracellular HMGB1 signaling, which mediates p53-mediated downstream effects and PAH progression in a sex-specific manner.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630011","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":"A Mighty Mitochondrial Microprotein: The Protective Role of MOTS-C in Acute Lung Injury.","authors":"Corrine Kliment","doi":"10.1165/rcmb.2025-0062ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0062ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603538","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}