American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Donor Lung <i>Prevotella</i> Predicts Favorable Early FEV1 Trajectory Following Lung Transplantation.","authors":"Mark E Snyder, Ghady Haidar, Kelvin Li, Georgios D Kitsios, Adam Fitch, Anna Zemke, Carlo Iasella, Christopher Musgrove, Marvi Bukhari, Barbara A Methé, John F McDyer, Alison Morris","doi":"10.1165/rcmb.2024-0441LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0441LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961019","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":"Pioglitazone Reverses Alcohol-induced HIV Replication and IL-1β Expression in Alveolar Macrophages.","authors":"Moses New-Aaron, Sarah S Chang, Xian Fan, Bashar S Staitieh, Michael Koval, Samantha M Yeligar","doi":"10.1165/rcmb.2024-0448OC","DOIUrl":"10.1165/rcmb.2024-0448OC","url":null,"abstract":"<p><p>Approximately 50% of people living with HIV (PWH) in the United States misuse alcohol, and they are at increased risk of chronic lung inflammation despite antiretroviral therapy. Acetaldehyde, a metabolite of alcohol, circulates systemically and directly impacts alveolar macrophages (AMs), the primary reservoir of HIV in the lungs. Acetaldehyde promotes AM HIV replication and triggers interleukin (IL)-1β release. We explored the mechanisms by which alcohol-derived acetaldehyde drives HIV replication and IL-1β release in AMs. Further, we tested if the transcription factor peroxisome proliferator-activated receptor (PPAR)γ agonist, pioglitazone, attenuates AM HIV replication and IL-1β release. Primary mouse AMs (mAMs), MH-S cells (an AM cell line), and THP-1 (human monocyte cell line)-derived macrophages were treated with alcohol-derived acetaldehyde (acetaldehyde generating system, AGS), HIV 1_ADA, and EcoHIV, a chimeric HIV that infects murine cells. HIV expression was confirmed by HIV gag RNA (qRT-PCR) and p24 release (ELISA). IL-1β was measured by qRT-PCR and ELISA. Extracellular hydrogen peroxide (H₂O₂) release was quantified by Amplex Red assay. Further, immunoblot analysis of ERK1/2, PPARγ, and nuclear factor (NF)-ĸB/p65 (p65) was used to identify how acetaldehyde potentiates HIV replication and IL-1β activation in AMs. AGS increased H₂O₂, leading to ERK1/2 phosphorylation, which deactivated PPARγ. AGS drove nuclear p65 translocation in HIV-infected cells, which enhanced HIV replication and IL-1β release. Treatment with pioglitazone decreased nuclear p65, attenuating AGS-induced HIV replication and IL-1β activation in AMs. We identified mechanisms underlying acetaldehyde-induced inflammatory activation and potentiation of HIV replication in AMs, which could be therapeutically targeted with pioglitazone to decrease HIV-related respiratory comorbidities among PWH who misuse alcohol.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967569","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":"Vaping-induced Oxidation of CBD Causes Adduction of TOP2A and Interferes with Cellular Proliferation.","authors":"Charlotte A Love, Hye-Young H Kim, Keri A Tallman, Phillip W Clapp, Kevin D Schichlein, Ned A Porter, Ilona Jaspers","doi":"10.1165/rcmb.2024-0501OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0501OC","url":null,"abstract":"<p><p>Cannabidiol (CBD) vaping products pose a significant public health risk due to high cannabinoid concentrations, additives and contaminants, unsubstantiated claims of health benefits, and their implication in e-cigarette, or vaping, product use-associated lung injury (EVALI). However, research on the respiratory health effects of vaping CBD is limited. Here we show that the reactive electrophile CBD quinone (CBDQ) is present in significant quantities in commercial CBD vaping products. The effect of vaping on CBDQ concentration was variable across products, indicating that the additives and contaminants we detected in commercial products, including plasticizers, flavorings, and solvents, may play a role in catalyzing or inhibiting vaping-induced CBD oxidation. Using the UNC Vaping Product Exposure System (VaPES) and click chemistry methodologies, we demonstrate that, in human airway epithelial cells, CBDQ and commercial CBD liquids form covalent adducts with TOP2A, a key protein in DNA replication and cell division. CBDQ downregulated cell-cycle genes in an airway epithelial cell line, a finding that was replicated in differentiated human bronchial epithelial cells (HBECs) exposed to commercial CBD vaping products. In addition, CBDQ and vaped CBD products inhibited cell proliferation. We also show that CBDQ is ubiquitous in commercial CBD vaping products, may increase after vaping, and significantly alters the respiratory transcriptome, most notably inhibiting cell-cycle genes. Together these data suggest that CBD vaping products have significant effects on normal airway function and with chronic use could pose health risks including impaired wound healing and increased susceptibility to infections, diseases, and other environmental exposures.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959798","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":"Transcriptomic Profiling of Long COVID in Interstitial Lung Disease Patients Reveals Dysregulation of Mitochondrial Oxidative Phosphorylation.","authors":"Katherine A Aracena, Grace C Nwankwo, Cathryn T Lee, Rasika Karnik, Iazsmin Ventura, Dylan Douglas, Inem Udofia, Mengjie Chen, Lydia Chelala, Hae Kyung Im, Mary E Strek, Ayodeji Adegunsoye","doi":"10.1165/rcmb.2024-0595LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0595LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959995","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":"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":"https://doi.org/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 (AAV) vector (AAVITS), the system 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TBX4 in Pulmonary Hypertension: Linking Lung Development to Precision Therapy.","authors":"Wadih El Khoury, Stephen Y Chan","doi":"10.1165/rcmb.2025-0164ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0164ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061941","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":"Gene-ius at Work: Decoding Cell States Through Expression.","authors":"Soula Danopoulos, Denise Al Alam","doi":"10.1165/rcmb.2025-0168ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0168ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957131","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":"Pirfenidone Mitigates TGF-β-induced Inflammation Following Virus Infection.","authors":"Belinda J Thomas, Keiko Kan-O, Michael P Gantier, Ian Simpson, Julia G Chitty, Maggie Lam, Lovisa Dousha, Timothy A Gottschalk, Kate E Lawlor, Michelle D Tate, Saleela Ruwanpura, Huei Jiunn Seow, Kate L Loveland, Sheetal Deshpande, Xun Li, Kais Hamza, Paul T King, Jack A Elias, Ross Vlahos, Jane E Bourke, Philip G Bardin","doi":"10.1165/rcmb.2024-0433OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0433OC","url":null,"abstract":"<p><p>Infection by influenza A virus (IAV) and other viruses causes disease exacerbations in chronic obstructive pulmonary disease (COPD). Immune responses are blunted in COPD, a deficit compounded by current standard-of-care glucocorticosteroids (GCS) to further predispose patients to life-threatening infections. The immunosuppressive effects of elevated transforming growth factor-beta (TGF-β) in COPD may amplify lung inflammation during infections whilst advancing fibrosis. In the current study, we investigated potential repurposing of pirfenidone, currently used as an anti-fibrotic for idiopathic pulmonary fibrosis, as a non-steroidal treatment for viral exacerbations of COPD. Murine models of lung-specific TGF-β overexpression or chronic cigarette smoke exposure with IAV infection were used. Pirfenidone was administered daily by oral gavage commencing pre-or post-infection, while inhaled pirfenidone and GCS treatment pre-infection were also compared. Tissue and bronchoalveolar lavage were assessed for viral replication, inflammation and immune responses. Overexpression of TGF-β enhanced severity of IAV infection contributing to unrestrained airway inflammation. Mechanistically, TGF-β reduced innate immune responses to IAV by blunting interferon regulated gene (IRG) expression and suppressing production of anti-viral proteins. Prophylactic pirfenidone administration opposed these actions of TGF-β, curbing IAV infection and airway inflammation associated with TGF-β overexpression and cigarette smoke-induced COPD. Notably, inhaled pirfenidone caused greater inhibition of viral loads and inflammation than inhaled GCS. These proof-of-concept studies demonstrate that repurposing pirfenidone and employing a preventative strategy may yield substantial benefit over anti-inflammatory GCS in COPD. Pirfenidone can mitigate damaging virus exacerbations without attendant immunosuppressive actions and merits further investigation, particularly as an inhaled formulation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953647","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":"Insights Into the Cellular and Molecular Mechanisms Behind the Antifibrotic Effects of Nerandomilast.","authors":"Dennis Reininger, Felix Wolf, Christoph H Mayr, Susanne L Wespel, Nadine Laufhaeger, Kerstin Geillinger-Kästle, Alec Dick, Florian Gantner, Peter Nickolaus, Franziska E Herrmann","doi":"10.1165/rcmb.2024-0614OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0614OC","url":null,"abstract":"<p><p>The quest for innovative pharmacologic interventions in idiopathic pulmonary fibrosis (IPF) is a challenging journey. The complexity of the disease demands a comprehensive approach targeting multiple cell types and pathways. This study examined the antifibrotic properties of nerandomilast, a preferential phosphodiesterase 4B inhibitor, focusing on its effects on myofibroblasts (MF)s and endothelial cells. Using cytokine-stimulated human IPF lung fibroblasts (IPF-HLF) and RNA-seq, we assessed the effect nerandomilast has on MF contractility, MF markers and differentiation mechanisms. In addition, using human microvascular endothelial cells, endothelial barrier integrity and monocyte adhesion were assessed in a 3D microfluidic chip. Our results show that nerandomilast significantly inhibited MF contractility and marker expression in cytokine-stimulated IPF-HLF cells. Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor (GPCR) signaling events while inhibiting mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta (TGFβ) signaling. Nerandomilast also significantly reduced microvascular permeability in cytokine-stimulated human lung microvascular endothelial cells. Finally, in an adeno-associated virus-human diphtheria toxin receptor/diphtheria toxin mouse model of acute lung injury, nerandomilast significantly inhibited total protein in lavage, total macrophages, neutrophils, cell count and VCAM-1 expression. In summary, our results demonstrate that nerandomilast induces the dedifferentiation of human IPF lung MFs and diminishes their contractility in vitro by interfering with TGFβ, MAPK phosphatase-1 and GPCR signaling pathways. It also mitigates vascular dysfunction by strengthening endothelial junctions and inhibiting adhesion protein expression. These findings highlight nerandomilast's potential therapeutic use in IPF by providing insights into its cellular and molecular actions. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966058","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":"Development of a Polidocanol-based Human <i>In Vitro</i> Model to Explore Airway Epithelial Repair.","authors":"Ashesh Chakraborty, Marie Zöller, Aydan Sardogan, Markus Klotz, Michal Mastalerz, Hannah Marchi, Raphael Meixner, Rudolf A Hatz, Jürgen Behr, Anne Hilgendorff, Misako Nakayama, Claudia A Staab-Weijnitz","doi":"10.1165/rcmb.2024-0117OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0117OC","url":null,"abstract":"<p><p>The human airway epithelium is a primary site of toxicant exposure and crucial in the pathogenesis of acute and chronic lung disease (CLD). In CLD, the airway epithelium is frequently altered and distorted, and its restoration is desirable. The mechanisms underlying human aberrant epithelial regeneration, however, are poorly understood. Importantly, our knowledge about airway epithelial injury and regeneration largely stems from mouse models, yet airways differ considerably between mice and humans. We hypothesized that treatment of differentiated primary human bronchial epithelial cells (phBECs, or HBEC) with polidocanol or naphthalene would allow for studying mechanisms of human airway epithelial injury and regeneration. Injury of differentiated phBECs with 0.04%, but not 0.1% PDOC, resulted in full restoration of a functional epithelium and epithelial barrier integrity as monitored by qRT-PCR analysis, immunofluorescence stainings, and transepithelial electrical resistance measurements. Regeneration was associated with a transient but not parallel increase of p21+ and KRT17+ cells. Providing proof-of-concept, DAPT, an inhibitor of Notch signaling, blunted the restoration of secretory cell types post 0.04% PDOC injury. Differentiation of phBECs in presence of cigarette smoke extract (CSE) or ethanol as first hit significantly impaired the regeneration capacity of phBECs. While naphthalene is known to specifically induce club cell depletion in mouse airways, it failed to do so in phBECs. In conclusion, using fully differentiated phBECs treated with PDOC, we successfully established and thoroughly characterized a human <i>in vitro</i> system that will facilitate studies of mechanisms involved in susceptibility to injury as well as human airway repair and regeneration.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960412","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}