American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"A Single Early-Life Acetaminophen Exposure Causes Persistent Abnormalities in the Murine Lung.","authors":"Maya R Grayck, Bradford J Smith, Alexander Sosa, Emma Golden, William C McCarthy, Mack Solar, Natarajan Balasubramaniyan, Lijun Zheng, Evgenia Dobrinskikh, Mercedes Rincon, David J McCulley, David J Orlicky, Clyde J Wright","doi":"10.1165/rcmb.2024-0452OC","DOIUrl":"10.1165/rcmb.2024-0452OC","url":null,"abstract":"<p><p>Whether early-life acetaminophen (APAP) exposures injure the developing lung is controversial. We sought to correlate murine pulmonary developmental expression profiles of <i>Cyp2e1</i> to susceptibility to APAP exposure. Postnatal day 14 (P14) C57BL/6 mice were exposed to APAP (140 mg/kg × 1 i.p.) and assessed for evidence of a histologic, metabolic, functional, and/or transcriptional pulmonary response. Similar experiments were performed in P14 IL6^-/- mice, given the controversial role of IL-6 in APAP-induced tissue injury. No evidence of hepatic injury was noted in APAP-exposed P14 mice. In contrast, within 6 hours of exposure, pulmonary tissue demonstrated histologic and functional evidence of injury and increased mitochondrial load by fluorescence lifetime imaging microscopy. The pulmonary transcriptional response was marked by increased expression of <i>Cyp2e1</i>, Nrf2 targets, and proinflammatory genes. Specifically, APAP exposure increased pulmonary IL-6 mRNA, protein, and associated STAT3 signaling. In contrast, IL6^-/- mice demonstrated attenuated STAT3 signaling and injury at 6 hours of exposure. At P28, functional and stereologic assessment of both wild-type and IL6^-/- mice exposed to a single dose of APAP at P14 revealed persistent abnormalities consistent with lung enlargement and alveolar simplification. Developmentally regulated surges in pulmonary <i>Cyp2e1</i> expression correlate with sensitivity to APAP exposures that do not cause recognizable hepatic injury. A single exposure during this developmental window is enough to cause persistent functional and stereological abnormalities. These results highlight the need to further study the relationship between developmentally regulated pulmonary <i>Cyp2e1</i> expression, APAP exposures, and long-term pulmonary dysfunction.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"232-250"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997709","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":"When Autophagy Fails: <i>ATG7</i> Variants and Their Impact on Radiation Lung Injury.","authors":"Alina X Yang, Yang Zhou","doi":"10.1165/rcmb.2025-0006ED","DOIUrl":"10.1165/rcmb.2025-0006ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"163-165"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188138","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":"Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice.","authors":"Joanna M Poczobutt, Nicholas Egersdorf, Max S Hiltabidle, Koichi Nishino, Matthew J Justice, Tanner Rivera, Betty Dubois, Alexander Borowiec, S Ali Mousavi-Aghdas, Katrina Kopf, Fabienne Gally, Jennifer Matsuda, Evgeny V Berdyshev, Irina Petrache","doi":"10.1165/rcmb.2024-0380OC","DOIUrl":"10.1165/rcmb.2024-0380OC","url":null,"abstract":"<p><p>Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick disease that, in type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional <i>Smpd1</i> (<i>Smpd1^-/-</i> mouse) deletion causes lung inflammation with foamy dysfunctional macrophages but is protective against acute lung injury. It is unknown whether these manifestations are a result of progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, CAGG-CreERTM × Smpd1^fl/fl, induced by tamoxifen (5 wk), with decreased <i>Smpd1</i> expression (by 75%) and ASM activity (by up to 40%). We investigated how brief postdevelopmental ASM insufficiency affects lung sphingolipids and pathology, including after LPS-induced injury. Compared with control animals, Smpd1^fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios and increased <i>de novo</i> sphingolipid synthesis and sphingosine-1-phosphate concentrations. At 3 days after LPS instillation (20 μg), control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1^fl/fl mice showed more exuberant inflammation, but had significantly reduced apoptosis, particularly in endothelial cells. During repair phase (6-9 d), Smpd1^fl/fl lungs had increased cell proliferation with reduced accumulation of autophagosome-tagging p62/SQSTM1. These results indicate that before developing lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and may stimulate repair after inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of Niemann-Pick disease and the role of distinct sphingolipid metabolites in lung injury and repair.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"275-287"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370132","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":"Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection.","authors":"Sunil Palani, Md Bashir Uddin, Michael McKelvey, Shengjun Shao, Wenzhe Wu, Xiaoyong Bao, Jiaren Sun, Keer Sun","doi":"10.1165/rcmb.2024-0552OC","DOIUrl":"10.1165/rcmb.2024-0552OC","url":null,"abstract":"<p><p>Exposure to influenza A virus, respiratory syncytial virus, and human metapneumovirus is well known to increase the risk of <i>Streptococcus pneumoniae</i> (<i>SPn</i>) pneumonia in humans. Type I IFN (IFN-I) is a hallmark response to acute viral infections, and alveolar macrophages (AMs) constitute the first line of airway defense against opportunistic bacteria. Our study reveals that virus-induced IFNAR1 (IFN-I receptor) signaling directly impairs AM-dependent antibacterial protection. Using <i>Ifnar1</i> conditional knockout mouse models, <i>in vivo</i> antibodies, bone marrow chimeric mice, and AM reconstitution, we demonstrate that IFN-I intrinsically targets AMs to drive hypersusceptibility to <i>SPn</i> following influenza A virus infection. Importantly, we show that respiratory syncytial virus and human metapneumovirus infection induces robust IFN-I signaling in AMs, coinciding with lethal susceptibility to secondary <i>SPn</i> pneumonia. In contrast, seasonal human coronavirus induces neither significant IFN-I signaling in AMs nor immune predisposition to <i>SPn</i>. Therefore, we conclude that IFN-I inhibition of AMs represents a crucial mechanism underlying antibacterial complications following otherwise asymptomatic or mild respiratory viral infections.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"264-274"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063234","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":"Unveiling Organ Failure in the Critically Ill: Insights through the Metabolite Lens.","authors":"Isabell Nessel, Samuel N Paul, Zudin A Puthucheary","doi":"10.1165/rcmb.2025-0036ED","DOIUrl":"10.1165/rcmb.2025-0036ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"173-175"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456883","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":"Switching On Gene Therapy for Allergic Rhinitis: The AAVITS Approach.","authors":"Hongpeng Jia","doi":"10.1165/rcmb.2025-0241ED","DOIUrl":"10.1165/rcmb.2025-0241ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"176-177"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224038","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":"Bubble Trouble: Epithelial Extracellular Vesicles and Their microRNA Mischief in Chronic Obstructive Pulmonary Disease.","authors":"Isaac Kirubakaran Sundar","doi":"10.1165/rcmb.2024-0583ED","DOIUrl":"10.1165/rcmb.2024-0583ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"157-158"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027822","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":"Senescence at the Crossroads of Lung Development and Injury.","authors":"Kent A Willis, Namasivayam Ambalavanan","doi":"10.1165/rcmb.2024-0564ED","DOIUrl":"10.1165/rcmb.2024-0564ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"161-162"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334876/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Don't Just Do Something, Stand There: Pressing Pause on Acetaminophen Use in Infants and Children.","authors":"Jennifer M S Sucre, Anne Hilgendorff, Laurie C Eldredge","doi":"10.1165/rcmb.2025-0014ED","DOIUrl":"10.1165/rcmb.2025-0014ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"159-160"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188135","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":"Molecular Maestro in the Lung: The Sphingolipid Rheostat.","authors":"Joselyn Rojas-Quintero, Francesca Polverino","doi":"10.1165/rcmb.2025-0067ED","DOIUrl":"10.1165/rcmb.2025-0067ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"170-172"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456882","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}