American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Airway Immune Signatures in Severe and Fatal Infection with COVID-19.","authors":"Naresh Doni Jayavelu, Jing Jing Qi, Slim Fourati, Farrah Kheradmand, Charles R Langelier, Lauren I R Ehrlich, Joann Diray-Arce, Annmarie Hoch, Monica Kraft, Patrice M Becker, Matthew C Altman, Ruth R Montgomery","doi":"10.1165/rcmb.2024-0462LE","DOIUrl":"10.1165/rcmb.2024-0462LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 6","pages":"708-712"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186259","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":"The Bi-steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis.","authors":"Jilly F Evans, Owen A Ledwell, Yan Tang, Ryan Rue, Alexander R Mukhitov, Rémi Diesler, Susan M Lin, Kanth Swaroop Vanka, Maria C Basil, Edward Cantu, Elizabeth P Henske, Vera P Krymskaya","doi":"10.1165/rcmb.2024-0242OC","DOIUrl":"10.1165/rcmb.2024-0242OC","url":null,"abstract":"<p><p>Mutations in the TSC (tuberous sclerosis complex) genes result in the hyperactivation of the mTORC1 (mechanistic/mammalian target of rapamycin 1) growth pathway in mesenchymal pulmonary cells. Rapamycin (sirolimus), a naturally occurring macrolide, is the only therapeutic approved for women with lymphangioleiomyomatosis (LAM), a progressive, destructive lung disease caused by TSC gene mutations and mTORC1 hyperactivation. However, on cessation of the drug, lung function decline continues. We demonstrated here that pulmonary LAM cancer stem-like state (SLS) cells most highly expressed the eIF4E (eukaryotic translation initiation factor 4E)-dependent translation initiation genes. We also showed that the 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) gene has the lowest expression in these cells, indicating that the 4E-BP1/eIF4E ratio in LAM SLS cells favors unrestrained eIF4E oncogenic mRNA translation. The bi-steric mTORC1-selective compound RMC-5552 prevented growth of LAM-associated fibroblasts and phosphorylation of proteins in the ribosomal protein S6K1/ribosomal protein S6 (S6K1/S6) and 4E-BP1/eIF4E translation mTORC1-driven pathways, whereas rapamycin only blocked the S6K/S6 axis. Rapamycin inhibition of LAM-associated fibroblast growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"643-652"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612234","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":"Parasympathetic Airway Hyperreactivity Is Enhanced in Acute but Not Chronic Eosinophilic Asthma Mouse Models.","authors":"Alexandra B Pincus, Aubrey B Pierce, Nicole Kappel, Katie M Lebold, Matthew G Drake, Allison D Fryer, David B Jacoby","doi":"10.1165/rcmb.2024-0360OC","DOIUrl":"10.1165/rcmb.2024-0360OC","url":null,"abstract":"<p><p>Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations <i>in vivo</i>, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic activation of airway nerves <i>in vivo</i> to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: <i>1</i>) acute challenge with house dust mite antigen; and <i>2</i>) chronic airway hypereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as measured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optogenetic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole-mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen-challenged and IL-5-transgenic mice than in their respective controls but were not significantly different between the two asthma models. Thus, even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen-challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eosinophil-nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"698-707"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765568","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":"Peripheral Transcriptome of Severe Sarcoidosis Involves Dysregulation of Multiple Immunologic Systems.","authors":"Kai Huang, Jessica M Lee, Wangfei Wang, Christen Vagts, Christian Ascoli, Yue Huang, Maria M Tsoukas, Nadera J Sweiss, David L Perkins, Patricia W Finn","doi":"10.1165/rcmb.2024-0199LE","DOIUrl":"10.1165/rcmb.2024-0199LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 6","pages":"712-715"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186261","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":"Targeting S1PR2 in Sepsis, One Fragmented Mitochondrion at a Time.","authors":"Chao He, Jennifer L Larson-Casey","doi":"10.1165/rcmb.2024-0561ED","DOIUrl":"10.1165/rcmb.2024-0561ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"603-604"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811763","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":"Fetal Tracheal Occlusion Correlates with Normalized YAP Expression and Alveolar Epithelial Differentiation in Congenital Diaphragmatic Hernia.","authors":"Ophelia Aubert, Yuichiro Miyake, Gaurang M Amonkar, Olivia M Dinwoodie, Brian M Varisco, Mario Marotta, Caiqi Zhao, Richard Wagner, Ya-Wen Chen, Alessandra Moscatello, Caterina Tiozzo, Xaralabos Varelas, Paul H Lerou, Jose L Peiro, Richard Keijzer, Xingbin Ai","doi":"10.1165/rcmb.2024-0323OC","DOIUrl":"10.1165/rcmb.2024-0323OC","url":null,"abstract":"<p><p>Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"688-697"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811750","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":"KLF5 Shapes Developing Respiratory Tubules by Inhibiting Actin Asymmetry in Epithelial Cells.","authors":"Qing Li, Yong Liao, Junwei Zeng, Silu Hu, Chunjie Li, Jeffrey A Whitsett, Yi Zheng, Fengming Luo, Chang Xu, Taozhen He, Xinhua Lin, Huajing Wan","doi":"10.1165/rcmb.2024-0140OC","DOIUrl":"10.1165/rcmb.2024-0140OC","url":null,"abstract":"<p><p>Tubulogenesis depends on precise cell shape changes driven by asymmetric tension from the actin cytoskeleton. How actin asymmetry is dynamically controlled to coordinate epithelial cell shape changes required for respiratory tubulogenesis remains unknown. Herein, we unveiled a critical role for the transcription factor KLF5, regulating actin asymmetry, inducing epithelial cell shape changes by balancing RHOA and CDC42 GTPase activity via RICH2. Conditional <i>Klf5</i> expression or deletion in pulmonary epithelial cells affected apical actin organization and the positioning of apical polarity proteins in cell membranes, disrupting branching and sacculation of respiratory tubules during mouse lung morphogenesis. Increased KLF5 concentrations were observed in epithelial cells lining dilated tubules in lungs from patients with congenital pulmonary airway malformation. Together, our results demonstrate that dynamic regulation of apical actin organization by KLF5 is essential for respiratory tubulogenesis, providing a mechanistic framework for comprehending the morphogenesis of respiratory tubules.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"663-677"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646691","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":"Targeting the Epigenetic Regulator CBX5 Promotes Fibroblast Metabolic Reprogramming and Inhibits Lung Fibrosis.","authors":"Jeongmin Hong, Tho X Pham, Jisu Lee, Ahmed A Raslan, Kristina Nicolas, Andrei Sharov, Jeffrey A Meridew, Raul A Urrutia, Gwen Lomberk, Steven K Huang, Giovanni Ligresti","doi":"10.1165/rcmb.2024-0255OC","DOIUrl":"10.1165/rcmb.2024-0255OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here, we show that the epigenetic regulator CBX5 (chromobox protein homolog 5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin-induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including <i>Cthrc1</i>, <i>Col1a1</i>, and <i>Spp1</i>, and by the upregulation of metabolic genes with antifibrotic activity such as <i>Ppara</i> and <i>Pparg</i>. Single-cell RNA sequencing and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-sequencing analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited transforming growth factor-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts <i>in vitro</i> and in IPF lung explants <i>ex vivo</i> synergistically potentiated the activation of metformin-induced AMP-activated protein kinase activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"627-642"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789484","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":"Improved Annotation of Asthma Gene Variants with Cell Type Deconvolution of Nasal and Lung Expression Quantitative Trait Loci.","authors":"Zaid W El-Husseini, Tatiana Karp, Andy Lan, Tessa E Gillett, Cancan Qi, Dmitry Khalenkow, Thys van der Molen, Chris Brightling, Alberto Papi, Klaus F Rabe, Salman Siddiqui, Dave Singh, Monica Kraft, Bianca Beghé, Philippe Joubert, Yohan Bossé, Don Sin, Ana H Cordero, Wim Timens, Corry-Anke Brandsma, Ke Hao, David C Nickle, Judith M Vonk, Martijn C Nawijn, Maarten van den Berge, Reinoud Gosens, Alen Faiz, Gerard H Koppelman","doi":"10.1165/rcmb.2024-0251MA","DOIUrl":"10.1165/rcmb.2024-0251MA","url":null,"abstract":"<p><p>Asthma is a genetically complex inflammatory airway disease associated with more than 200 SNPs. However, the functional effects of many asthma-associated SNPs in lung and airway epithelial samples are unknown. Here, we aimed to conduct expression quantitative trait loci (eQTL) analysis using a meta-analysis of nasal and lung samples. We hypothesize that incorporating cell type proportions of airway and lung samples enhances eQTL analysis outcomes. Nasal brush (<i>n</i> = 792) and lung tissue (<i>n</i> = 1,087) samples were investigated separately. Initially, a general eQTL analysis identified genetic variants associated with gene expression levels. Estimated cell type proportions were adjusted based on the Human Lung Cell Atlas. In addition, the presence of significant interaction effects between asthma-associated SNPs and each cell type proportion was explored and considered evidence for cell type-associated eQTL. In nasal brush and lung parenchyma samples, 44 and 116 asthma-associated SNPs were identified as eQTL. Adjusting for cell type proportions revealed eQTL for an additional 17 genes (e.g., <i>FCER1G</i>, <i>CD200R1</i>, and <i>GABBR2</i>) and 16 genes (e.g., <i>CYP2C8</i>, <i>SLC9A2</i>, and <i>SGCD</i>) in nose and lung, respectively. Moreover, we identified eQTL for nine SNPs annotated to genes such as <i>VASP</i>, <i>FOXA3</i>, and <i>PCDHB12</i> displayed significant interactions with cell type proportions of club, goblet, and alveolar macrophages. Our findings demonstrate increased power for identifying eQTL among asthma-associated SNPs by considering cell type proportion of the bulk RNA-sequencing data from nasal and lung tissues. Integration of cell type deconvolution and eQTL analysis enhances our understanding of asthma genetics and cellular mechanisms, uncovering potential therapeutic targets for personalized interventions.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"607-614"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998045","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":"Pulmonary Fibrosis - Focusing on the Future: Aspen Lung Conference 2024 Summary.","authors":"Margaret A T Freeberg, Elizabeth F Redente, Apostolos Perelas, David Wh Riches, David A Schwartz, Patricia J Sime","doi":"10.1165/rcmb.2025-0137TR","DOIUrl":"10.1165/rcmb.2025-0137TR","url":null,"abstract":"<p><p>As medical and scientific communities, we have enjoyed exciting advances in our mechanistic understanding, diagnosis, and therapy of different types of lung fibrosis. However, much still needs to be learned as we are challenged to make earlier diagnoses, improve our ability to assess active disease and risks for disease progression, advance our understanding of the complex interplay of molecular, genetic and cellular crosstalk processes that underly the disease, and develop transformative therapeutic options to treat and prevent progressive lung fibrosis. Elucidating cellular phenotypes, function and signaling, and the interplay with matrices and aspects of mechanobiology has the potential to help us identify future targets and even reprogram or rebuild a damaged lung. Key to potential future opportunities will be understanding what aspects of fibrogenesis can be prevented or reversed. Bringing together a group of diverse and respected medical and scientific thought leaders, the 66th Annual Thomas L. Petty Aspen Lung Conference focused on \"Pulmonary Fibrosis-Focusing on the Future\". The conference topics included concepts and technologies for identification of early disease and progression using imaging and omics approaches, identifying and understanding cellular phenotypes and their function, and cross talk between different cell types, matrices, and matrix receptors. A central theme throughout was the integration of these scientific advances to advance novel targets for therapy including aspects of reprogramming and rebuilding a damaged lung. The conference provided an inclusive forum for discussion, debate and exchange of ideas with leaders and trainees in the field with the goal to help advance our shared mission of preventing and curing pulmonary fibrotic disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186258","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}