American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Construction of an Indole-induced Transgenic System and Its Therapeutic Effects on Allergic Rhinitis.","authors":"Guangyao Li, Shengju Li, Fangzhou Ye, Keguang Chen, Hongmeng Yu","doi":"10.1165/rcmb.2025-0085OC","DOIUrl":"10.1165/rcmb.2025-0085OC","url":null,"abstract":"<p><p>Allergic rhinitis (AR) is a prevalent chronic condition that significantly impacts patients' quality of life and strains healthcare systems. Current treatments, primarily involving therapeutic proteins such as antibodies and cytokines, have limitations, including injection requirements, short half-lives, and potential side effects. This study developed an indole-induced transgene system (ITS), utilizing the olfactory receptor Olfr205 to activate gene expression in response to indole. Incorporated in an adeno-associated virus vector, the ITS was tested in a mouse model of AR, with functionality assessed through <i>in vitro</i> experiments in Hana3A cells and <i>in vivo</i> studies. Cellular assays, flow cytometry, ELISA, and histopathological analyses were used to measure therapeutic protein expression, immune cell profiles, inflammatory cytokines, IgE levels, and tissue inflammation. The results demonstrated that the ITS effectively controlled gene expression, reduced inflammation, and improved tissue morphology, offering promise for targeted gene therapy in AR and other chronic inflammatory diseases.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"310-321"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966056","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 CELA1 to Improve Septation in the Mouse Hyperoxia Model of Impaired Alveolar Development.","authors":"Noah J Smith, Rashika Joshi, Hitesh Deshmukh, Jerilyn Gray, Andrea D Edwards, Elham Shahreki, Brian M Varisco","doi":"10.1165/rcmb.2024-0378LE","DOIUrl":"10.1165/rcmb.2024-0378LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"325-327"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590256","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 Functional Variant <i>rs2122031</i> in <i>ATG7</i> Is Associated with the Risk of Radiation Pneumonitis.","authors":"Bo Liu, Yulong Yu, Wan Qin, Li Yang, Minxiao Yi, Lingyan Xiao, Yongbiao Huang, Xiao Zhou, Shiying Yu, Yihua Wang, Cong-Yi Wang, Yang Tang, Xianglin Yuan","doi":"10.1165/rcmb.2024-0238OC","DOIUrl":"10.1165/rcmb.2024-0238OC","url":null,"abstract":"<p><p>Radiation pneumonitis (RP) is characterized by inflammation and is associated with autophagy. However, the relationship between functional genetic variants of autophagy-related genes and RP remains unknown. In this study, we aimed to investigate whether genetic variants of genes involved in autophagy are associated with RP. Genotyping was conducted on a total of 301 patients for 13 SNPs of 5 genes in the autophagy pathway using MassArray and Sanger sequencing. Two radiation oncologists independently measured the degree of RP by chest X-ray or computed tomography. The multivariate Cox hazard analysis and multiple testing showed that <i>ATG7:rs2122031 GA/GG</i> significantly decreased the risk of RP grade ⩾3 (hazard ratio, 0.369; 95% confidence interval, 0.189-0.720; <i>P</i> = 0.003, corrected <i>P</i> = 0.039). Furthermore, qRT-PCR and immunohistochemical analysis demonstrated that the <i>ATG7:rs2122031 AA</i> genotypes were related to decreased expression of ATG7 (autophagy-related protein 7). Loss of autophagy by deletion of ATG7 in fibroblasts or conditional <i>ATG7</i>-knockout mice was proven to increase RP. Single-cell RNA sequencing revealed regulation of autophagy-related genes enriched after irradiation stress in conditional <i>ATG7</i>-knockout mice. Our findings indicated that genetic variants of <i>ATG7</i> were associated with RP and may therefore be used to predict RP before radiation therapy. Loss of ATG7 was also shown to promote RP, which suggested that ATG7 may be an intervention target for RP.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"221-231"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027900","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":"Early Sepsis Metabolic Changes in Kidney and Liver Precede Clinical Evidence of Organ Dysfunction.","authors":"Marc R McCann, Christopher Fry, Michael D Maile, Evan A Farkash, Brandon C Cummings, Thomas L Flott, Laura McLellan, Michael A Puskarich, Alan E Jones, Michael W Sjoding, Jean Nemzek, Robert P Dickson, Kathleen A Stringer","doi":"10.1165/rcmb.2024-0391OC","DOIUrl":"10.1165/rcmb.2024-0391OC","url":null,"abstract":"<p><p>Organ-specific metabolic pathways, including those related to mitochondrial metabolism, could provide insight into mechanisms underlying sepsis-induced organ dysfunction. However, it remains unclear if metabolic changes result from or precede clinical organ dysfunction. To determine if blood concentrations of the mitochondrial metabolites acetylcarnitine and l-carnitine correlate with organ-specific signals of sepsis-induced dysfunction, we performed a series of translational analyses of two cohorts of human sepsis and experiments using a murine model of polymicrobial sepsis. We evaluated the association between mitochondrial metabolites and clinical indices of organ function. In the blood of patients with sepsis or septic shock, we found metabolic signals of dysfunctional mitochondrial β-oxidation that were correlated with clinical measures of renal and liver dysfunction. The relevance of these findings was corroborated in an experimental model that showed distinct patterns of change in organ metabolism that correlated with the blood acetylcarnitine to l-carnitine ratio. In addition, sepsis-induced changes in organ metabolism were distinct in the liver and kidney, highlighting the unique energy economies of each organ. Importantly, metabolic changes preceded changes in clinical indices of organ function and histological evidence of cellular apoptosis. On the basis of these findings, sepsis-induced disruption in blood concentrations of specific metabolites could serve as more physiologically relevant indicators of early organ dysfunction than those we presently use. These early metabolite signals provide mechanistic insights into altered metabolism that may hold the key to timely identification of impending organ dysfunction. This could lead to strategies directed at the interruption of sepsis-induced organ failure.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"299-309"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370129","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":"Best Practices in the Development and Use of Experimental Models of Bacterial Pneumonia: An Official American Thoracic Society Workshop Report.","authors":"Amali E Samarasinghe, Scott H Randell, Hrishikesh S Kulkarni, Jeffrey N Weiser, Lee J Quinton, Robert P Dickson, Joseph P Mizgerd, Carlos J Orihuela, Dane Parker, Keven M Robinson, Alice S Prince, Scott E Evans, Jay K Kolls, Janet S Lee, Samithamby Jeyaseelan, Antoni Torres, Lisa A Miller, David J Hamilton, Marisa I Gómez, Bethany B Moore, Rebecca L Walker, Layla J Barkal, Jaime L Hook, Gee W Lau, Jyotika Sharma, Martin Witzenrath, Charles S Dela Cruz","doi":"10.1165/rcmb.2025-0322ST","DOIUrl":"10.1165/rcmb.2025-0322ST","url":null,"abstract":"<p><p>The global incidence of respiratory infectious diseases caused by bacteria continues to increase, with acute lower respiratory tract infections contributing to significant morbidity and mortality. Preclinical models designed to investigate such respiratory bacterial diseases are of utmost importance to decipher their pathogenesis and develop novel targets for intervention and treatment. Animal models offer the powerful ability to investigate different pneumonia types at varying stages of infection and disease. However, the same models can promote important variations in outcome, potentially confounding scientific understanding in the field. Therefore, an expert panel was convened to deliberate best practices in animal models of bacterial pneumonia to identify validated methodologies and acknowledge limitations in the use of animal and non-animal models in this field of study. Herein, we summarize this American Thoracic Society workshop on animal models of bacterial pneumonia. This workshop further includes review of non-animal complementary or alternative models for studying bacterial pneumonia. Emphasis was placed on discussion of bacterial pathogens that frequently cause community- and hospital-acquired pneumonia, highlighting key aspects in modeling infection. Animal models discussed included small and large animals, based on their strengths. Finally and most importantly, the ethical considerations in the use of animal modeling for the study of bacterial lung infections was discussed. This workshop report is intended to provide insights to investigators in the field and may serve as a starting point for formal recommendations in the future.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"73 2","pages":"178-199"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758963","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":"(Inter)feron the Reaper: New Insights on an Old Cytokine in Secondary Bacterial Pneumonia.","authors":"Prashant Rai, Michael B Fessler","doi":"10.1165/rcmb.2025-0026ED","DOIUrl":"10.1165/rcmb.2025-0026ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"166-167"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370125","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":"August Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.73i2RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.73i2RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"73 2","pages":"iii-iv"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758962","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":"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 conference, senior and junior investigators in vascular biology, pulmonary hypertension, and right heart failure engaged in pro and con debates on research paradigms. These discussions explored how evolving disease frameworks fit within the context of traditional research, emphasizing the balance between newer multiomics approaches and classical hypothesis-driven science. Three key objectives were addressed: <i>1</i>) integrating unbiased analytic methods with traditional frameworks, <i>2</i>) interpreting new multiomics findings within known pathobiological pathways, and <i>3</i>) reviewing modern imaging methods for the right ventricle to improve disease understanding. Although 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 be achieved only 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":"200-209"},"PeriodicalIF":5.3,"publicationDate":"2025-08-01","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":"Influenza A Virus Following Radiotherapy Amplifies Lung Injury and Monocyte-derived Macrophage Responses.","authors":"Angela M Groves, Carl J Johnston, Nicole D Paris, Noah Salama, Matthew D McGraw, Romeo Blanc, Eric Hernady, Jacob Finkelstein, Brian Marples","doi":"10.1165/rcmb.2025-0113OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0113OC","url":null,"abstract":"<p><p>Improvements in radiation therapy (RT) for thoracic cancers have increased survival, thus preventing radiotoxicity in normal lung tissue becomes even more important. Respiratory infection is a lung stressor that increases the risk of RT toxicity. However, this risk factor remains under-studied with no effective treatment approaches. While RT is toxic to tissue-resident alveolar macrophages, recruited monocyte-derived macrophages (MDMs) drive fibrogenesis. We therefore investigated how these macrophage populations are impacted by a respiratory infection subsequent to lung RT. Mice received whole thorax RT (5-12.5 Gy) then influenza A virus (IAV) 1 or 20 weeks later. Chronic lung injury and acute and chronic macrophage responses were evaluated. RT plus IAV was lethal at doses that were well-tolerated when either were administered singly. IAV potentiated chronic pathology from even a benign RT dose of 5 Gy, even when IAV was delayed for 20 weeks. Macrophage dynamics shifted towards more predominant pro-inflammatory, pro-fibrotic MDM responses. Acutely, RT plus IAV amplified loss of tissue-resident alveolar macrophages but increased inflammatory MDMs. Expression of maturation receptors and antigen presentation factors by inflammatory MDMs decreased while pro-fibrotic factors increased. These novel findings warrant further investigation of the risks of respiratory infection for those receiving thoracic radiation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752057","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":"Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development.","authors":"Boris Minasenko, Dongxue Wang, Jessica Chan, ViLinh Tran, Theresa W Gauthier, Carmen J Marsit, Dean P Jones, Young-Mi Go, Cherry Wongtrakool, Chang Su, Xin Hu","doi":"10.1165/rcmb.2024-0563OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0563OC","url":null,"abstract":"<p><p>Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communities through food and water consumption. We have shown that prenatal co-exposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell-type-specific mechanisms remain elusive. Here we examined early embryonic lungs (E12) from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (scATAC-seq+scRNA-seq) and high-resolution metabolomics, we present a multifaceted landscape of Cd and As-induced molecular and cellular disruption. We identified 19 cell states exhibiting state-specific changes in gene expression related to cell proliferation and differentiation. Velocity analysis integrating RNA splicing and chromatin kinetics showed profound disruptions in cell fate, particularly affecting differentiation of ^Sox2+ proximal progenitors and <i>Wnt2+</i> mesenchymal progenitors. Gene regulatory network analysis pinpointed the diminished function of <i>Gata6</i> and <i>Gli2</i> as central to these disruptions, which was further confirmed by their reduced protein expression in exposed E12, E14.5 and E17 lungs. Additionally, metabolomic alterations in polyamine, tyrosine and fatty acid biosynthesis correlated with changes in gene expression of catalytic enzymes. These findings demonstrate that Cd and As at levels relevant to human exposure impair early airway formation across multiple regulatory levels, including chromatin accessibility, transcription and cell metabolism, and provide insights into the factors central to cell resilience during this vulnerable stage of lung development.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752059","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}