American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"A Pilot Study on the Impact of Vaping on Adolescent Lung Function and Nasal Epithelial Gene Expression.","authors":"Sarah Commodore, Jonathan Hawkins, Cheyret Wood, Cuining Liu, Russell P Bowler, Laura Crotty Alexander, Peter Castaldi, Fernando Holguin, Katerina Kechris, Sunita Sharma","doi":"10.1165/rcmb.2024-0332LE","DOIUrl":"10.1165/rcmb.2024-0332LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 5","pages":"594-597"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967571","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":"Enhanced Gαq Signaling in <i>TSC2</i>-Deficient Cells Is Required for Their Neoplastic Behavior.","authors":"Aurélie Tréfier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof","doi":"10.1165/rcmb.2024-0111OC","DOIUrl":"10.1165/rcmb.2024-0111OC","url":null,"abstract":"<p><p>Inherited or sporadic loss of the <i>TSC2</i> gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage (LAM cells). Their aberrant growth is attributed to increased activity of mechanistic target of rapamycin complex 1 (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G protein-coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in <i>TSC2</i>-deficient cells remained unknown. Using a human pluripotent stem cell-derived <i>in vitro</i> model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and proneoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking <i>TSC2</i> demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared with wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in <i>TSC2</i>-deleted cells was independent of mTOR activity and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent proneoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"578-590"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602776","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 Porcine Model Reveals Two Distinct LGR5 Cell Types during Lung Development and Homeostasis.","authors":"Kathryn M Polkoff, Ross Lampe, Nithin K Gupta, Yanet Murphy, Jaewook Chung, Amber Carter, Jeremy M Simon, Katherine Gleason, Adele Moatti, Preetish K Murthy, Laura Edwards, Alon Greenbaum, Aleksandra Tata, Purushothama Rao Tata, Jorge A Piedrahita","doi":"10.1165/rcmb.2024-0040OC","DOIUrl":"10.1165/rcmb.2024-0040OC","url":null,"abstract":"<p><p>Cells expressing leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) play a pivotal role in homeostasis, repair, and regeneration in multiple organs, including skin and gastrointestinal tract, but little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5⁺ cells in the lung that are conserved in human but not mouse lungs. Using RNA sequencing, three-dimensional imaging, and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9⁺/ETV5⁺/SFTPC⁺ progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5⁺ cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5⁺ cells include a subset of peribronchial fibroblasts that express unique patterns of <i>SHH</i>, <i>FGF</i>, <i>WNT</i>, and <i>TGF-β</i> signaling pathway genes. These results support distinct roles for LGR5⁺ cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"496-509"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581619","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":"TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma.","authors":"Amy Wu, Aisha Kuforiji, Yi Zhang, Dingbang Xu, Jose Perez-Zoghbi, Charles Emala, Jennifer Danielsson","doi":"10.1165/rcmb.2024-0231OC","DOIUrl":"10.1165/rcmb.2024-0231OC","url":null,"abstract":"<p><p>The efficacy of β-agonists in asthma is severely limited by β-adrenoceptor desensitization, which results in poorly managed symptoms and refractory bronchoconstriction. Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional β-adrenoceptor responsiveness. We have previously demonstrated that acute antagonism of the calcium-activated chloride channel, transmembrane member 16A (TMEM16A), relaxes airway smooth muscle (ASM). We sought to determine the efficacy and role of TMEM16A antagonism in the context of desensitization β-adrenoceptor responsiveness. For these studies, we exposed murine tracheal rings on wire myography and precision-cut lung slices to contractile mediators in the presence or absence of TMEM16A antagonists and β-agonists with or without prior β-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of β₂-adrenoceptor-induced cAMP synthesis was measured in human ASM cells. From these studies, we demonstrate that acute TMEM16A antagonism is effective in relaxing β-agonist-desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of β-agonist responsiveness in mouse and human upper airways and prevents desensitization of β-agonist-mediated cAMP production in human ASM cells. Taken together, the present study demonstrates a favorable therapeutic profile of TMEM16A antagonism for ASM relaxation despite functional desensitization of β-agonist responsiveness, which may be a novel therapeutic approach in the face of β-adrenoceptor tachyphylaxis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"510-519"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666795","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":"A Murine Model of <i>Mycobacterium abscessus</i> Infection Mimics Pathology of Chronic Human Lung Disease.","authors":"Kenneth C Malcolm, Alma E Ochoa, Jack H Congel, Patrick S Hume, Jodi M Corley, Emily A Wheeler, Xiyuan Bai, Jerry A Nick, William J Janssen, Edward D Chan, Carlyne D Cool, Katherine B Hisert","doi":"10.1165/rcmb.2024-0376LE","DOIUrl":"10.1165/rcmb.2024-0376LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"591-594"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715025","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":"Cell Population-resolved Multiomics Atlas of the Developing Lung.","authors":"Mereena G Ushakumary, Song Feng, Gautam Bandyopadhyay, Heather Olson, Karl K Weitz, Heidi L Huyck, Cory Poole, Jeffrey M Purkerson, Soumyaroop Bhattacharya, M Cecilia Ljungberg, Thomas J Mariani, Gail H Deutsch, Ravi S Misra, James P Carson, Joshua N Adkins, Gloria S Pryhuber, Geremy Clair","doi":"10.1165/rcmb.2024-0105OC","DOIUrl":"10.1165/rcmb.2024-0105OC","url":null,"abstract":"<p><p>The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects 0-8 years of age with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during postnatal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA <i>in situ</i> hybridization and immunofluorescence imaging. We validated the spatial distribution of alveolar type 1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole-tissue proteome studies. Finally, the proteome was compared with a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"484-495"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493006","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":"Spatiotemporal Clusters of Extracellular Signal-Regulated Kinase Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.","authors":"Nicholaus L DeCuzzi, Daniel Oberbauer, Kenneth J Chmiel, Michael Pargett, Justa M Ferguson, Devan Murphy, Marion Hardy, Abhineet Ram, Amir A Zeki, John G Albeck","doi":"10.1165/rcmb.2024-0256OC","DOIUrl":"10.1165/rcmb.2024-0256OC","url":null,"abstract":"<p><p>Spatially coordinated extracellular signal-regulated kinase (ERK) signaling events (SPREADs) transmit radially from a central point to adjacent cells via secreted ligands for EGFR (epidermal growth factor receptor) and other receptors. SPREADs maintain homeostasis in nonpulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. To address these questions, we measured SPREAD activity with live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial cells, in both submerged and biphasic air-liquid interface culture conditions (i.e., differentiated cells). Airway epithelial cells were exposed to proinflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease. Type 1 proinflammatory cytokines significantly increased the frequency of SPREADs, which coincided with epithelial barrier breakdown in differentiated primary human bronchial epithelial cells. Furthermore, SPREADs correlated with IL-6 peptide secretion and the appearance of localized clusters of phospho-STAT3 immunofluorescence. To probe the mechanism of SPREADs, cells were cotreated with pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) or metabolic modulators (insulin, 2-deoxyglucose). Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence, implying that proinflammatory cytokines and glucose metabolism modulate SPREADs in human airway epithelial cells via secreted EGFR and IL6R ligands. We conclude that spatiotemporal ERK signaling plays a role in barrier homeostasis and dysfunction during inflammation of the airway epithelium. This novel signaling mechanism could be exploited clinically to supplement corticosteroid treatment for asthma and chronic obstructive pulmonary disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"520-532"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646692","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":"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":"10.1165/rcmb.2025-0167ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"461-463"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051915/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.","authors":"Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk","doi":"10.1165/rcmb.2023-0249OC","DOIUrl":"10.1165/rcmb.2023-0249OC","url":null,"abstract":"<p><p>Changes in metabolic activity are key regulators of macrophage activity. Proinflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas prorepair macrophages rely on oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, 6-diazo-5-oxo-L-norleucine (DON). We found that compared with BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM, but not AM, increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"563-577"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581617","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":"From Epithelium to Therapy: Transitional Cells in Lung Fibrosis.","authors":"Sarah Y Shin, Jichao Chen, Irit Milman Krentsis, Yair Reisner, Rodeo Abrencillo, Rahat Hussain, Danielle Wu, Harry Karmouty-Quintana","doi":"10.1165/rcmb.2024-0372TR","DOIUrl":"10.1165/rcmb.2024-0372TR","url":null,"abstract":"<p><p>Patients with idiopathic pulmonary fibrosis and lung fibrosis secondary to infections such as influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5⁺ or KRT8⁺ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells' potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both <i>in vivo</i> models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells precultured as three-dimensional organoids.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"472-483"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789483","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}