{"title":"June Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.72i6RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.72i6RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 6","pages":"iii-iv"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186260","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}
Christina Sul, Caitlin V Lewis, Janelle Posey, Mariah Jordan, Daniel Colon Hidalgo, Timothy Porfilio, Hanan Elajaili, Genevieve McCormack, Samuel Burciaga, Cassidy Delaney, Eva S Nozik
{"title":"Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.","authors":"Christina Sul, Caitlin V Lewis, Janelle Posey, Mariah Jordan, Daniel Colon Hidalgo, Timothy Porfilio, Hanan Elajaili, Genevieve McCormack, Samuel Burciaga, Cassidy Delaney, Eva S Nozik","doi":"10.1165/rcmb.2024-0292OC","DOIUrl":"10.1165/rcmb.2024-0292OC","url":null,"abstract":"<p><p>Acute respiratory distress syndrome is a serious illness accounting for 10% of ICU admissions and has a high mortality of 31-45%, with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of acute respiratory distress syndrome. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme EC-SOD (extracellular superoxide dismutase) are protected against <i>Staphylococcus aureus</i> pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue-binding affinity and elevated alveolar and plasma EC-SOD amounts, although the redox-regulated mechanisms responsible for protection against <i>S. aureus</i> are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against <i>S. aureus</i> pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared with wild-type mice with <i>S. aureus</i> pneumonia, platelet activation, formation of platelet-neutrophil aggregates, and influx of neutrophils and platelet-neutrophil aggregates into the lung are decreased in the infected R213G mice. Furthermore, pretreatment with a MnTE-2-PyP SOD mimetic protects against <i>S. aureus</i>-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of <i>S. aureus</i>-induced acute lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"653-662"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612225","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}
Barbara Zhao, Jacob Socha, Andrea Toth, Sharlene Fernandes, Helen Warheit-Niemi, Brandy Ruff, Gurjit K Khurana Hershey, Kelli L VanDussen, Daniel Swarr, William J Zacharias
{"title":"The Homeobox Transcription Factor CUX1 Coordinates Postnatal Epithelial Developmental Timing but Is Dispensable for Lung Organogenesis and Regeneration.","authors":"Barbara Zhao, Jacob Socha, Andrea Toth, Sharlene Fernandes, Helen Warheit-Niemi, Brandy Ruff, Gurjit K Khurana Hershey, Kelli L VanDussen, Daniel Swarr, William J Zacharias","doi":"10.1165/rcmb.2024-0147OC","DOIUrl":"10.1165/rcmb.2024-0147OC","url":null,"abstract":"<p><p>Lung epithelial progenitors use a complex network of known and predicted transcriptional regulators to influence early lung development. In this study, we evaluated the function of one predicted regulator, CUX1, that we identified from transcriptional regulatory analysis of the SOX9<sup>+</sup> distal lung progenitor network. We generated a new <i>Cux1</i>-floxed mouse model and created an epithelium-specific knockout of CUX1 using <i>Shh-Cre</i> (Cux1<sup>ShhCre-LOF</sup>). Postnatal Cux1<sup>ShhCre-LOF</sup> animals recapitulated key skin phenotypic features found in prior constitutive CUX1 knockout animals, confirming the functionality of our new floxed model. Postnatal Cux1<sup>ShhCre-LOF</sup> mice displayed subtle alveolar simplification and a transient delay in alveologenesis and alveolar type 1 cell development without persistent lung phenotypes. Cux1<sup>ShhCre-LOF</sup> mice developed failure to thrive in their second and third weeks of life because of delayed ileal maturation, which similarly resolves by Postnatal Day 35. Finally, we challenged Cux1<sup>ShhCre-LOF</sup> with influenza-mediated lung injury to demonstrate that Cux1<sup>ShhCre-LOF</sup> mice undergo productive alveolar regeneration that is indistinguishable from that in wild-type animals. Together, these findings indicate that epithelium-specific loss of CUX1 leads to transient developmental delays in the skin, lung, and intestine without defects in definitive organogenesis. We conclude that CUX1 function is required for temporal optimization of developmental maturation in multiple organs with implications for susceptibility windows in developmental disease pathogenesis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"678-687"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715033","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 Sound of Silence: Suppressing CBX5 Decreases Fibrosis by Inhibiting Fibroblasts.","authors":"Mauricio Rojas, Ana L Mora","doi":"10.1165/rcmb.2024-0618ED","DOIUrl":"10.1165/rcmb.2024-0618ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"605-606"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998373","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}
Xiangyang Yu, Xin Hu, Dongdong Wang, Ping Cui, Min Zeng, Min Li, Chenchen Gong, Dongqin Huang, Yan Wang, Kai Zhang, Xiangming Fang
{"title":"Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation.","authors":"Xiangyang Yu, Xin Hu, Dongdong Wang, Ping Cui, Min Zeng, Min Li, Chenchen Gong, Dongqin Huang, Yan Wang, Kai Zhang, Xiangming Fang","doi":"10.1165/rcmb.2024-0161OC","DOIUrl":"10.1165/rcmb.2024-0161OC","url":null,"abstract":"<p><p>Macrophage mitochondrial dysfunction is associated with immunosuppression and poor prognosis of patients with sepsis. Mitochondrial fragmentation drives mitochondrial dysfunction. Our previous study has found that S1PR2 (sphingosine-1-phosphate receptor 2) regulates macrophage phagocytosis during sepsis, whereas the role of S1PR2 in immunosuppression and the mechanisms require further study. This study aimed to unveil the relationship between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression, as well as the S1PR2-related mechanisms thereof. Peripheral blood monocytes were collected from healthy control subjects (<i>n</i> = 12), nonseptic critical control subjects (<i>n</i> = 13), and patients with sepsis (<i>n</i> = 19). Peritoneal macrophages were harvested from wild-type and <i>S1pr2</i><sup>-/-</sup> mice (Mutant Mouse Regional Resource Centers strain ID, 12830) after cecal ligation and puncture (CLP). Mitochondrial ultrastructure was evaluated using transmission electron microscopy. The impact of mitochondrial ultrastructure alteration on immunosuppression of monocyte-macrophages was evaluated. Compared with nonseptic and healthy control subjects, peripheral blood monocytes from patients with sepsis exhibited increased S1PR2 expression, mitochondrial fragmentation, and mitochondrial dysfunction. Mitochondrial fragmentation was negatively associated with HLA-DR (human leukocyte antigen-DR isotype) expression. S1PR2 expression was positively correlated with mitochondrial fragmentation and negatively correlated with HLA-DR expression. In mice subjected to CLP, S1PR2 depletion ameliorated macrophage mitochondrial fragmentation and dysfunction, boosted immunity, and improved survival. Mechanistically, in response to sepsis, S1PR2 activates ROCK I to induce Drp1 phosphorylation, resulting in Drp1-dependent mitochondrial fragmentation of macrophages. Drp1 inhibition by Mdivi-1 mitigated S1PR2-induced macrophage immunosuppression and improved the prognosis of mice after CLP. In conclusion, S1PR2-induced mitochondrial fragmentation is a crucial factor mediating septic immunosuppression, highlighting its potential as a promising therapeutic target in sepsis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"615-626"},"PeriodicalIF":5.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765567","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}
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
{"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}
Alexandra B Pincus, Aubrey B Pierce, Nicole Kappel, Katie M Lebold, Matthew G Drake, Allison D Fryer, David B Jacoby
{"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}
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
{"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}
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
{"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}