American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Pirfenidone Mitigates Transforming Growth Factor-β-induced Inflammation after Viral 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":"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-β (TGF-β) in COPD may amplify lung inflammation during infections while advancing fibrosis. In the present study, we investigated potential repurposing of pirfenidone, currently used as an antifibrotic for idiopathic pulmonary fibrosis, as a nonsteroidal 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 postinfection, and inhaled pirfenidone and GCS treatment preinfection were also compared. Tissue and BAL were assessed for viral replication, inflammation, and immune responses. Overexpression of TGF-β enhanced the severity of IAV infection, contributing to unrestrained airway inflammation. Mechanistically, TGF-β reduced innate immune responses to IAV by blunting IFN-regulated gene expression and suppressing production of antiviral 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 antiinflammatory GCS in COPD. Pirfenidone can mitigate damaging viral 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":"545-558"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","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":"Warifteine Alleviates Acute Lung Injury and Inhibits NETosis by Decreasing Reactive Oxygen Species-induced Gasdermin D Oligomerization.","authors":"Qian Xiang, Yaqin Du, Zhukai Cong, Yutian Xiao, Zhi Lu, Mingjie Shao, Jian Xie","doi":"10.1165/rcmb.2024-0472OC","DOIUrl":"10.1165/rcmb.2024-0472OC","url":null,"abstract":"<p><p>Acute lung injury (ALI) is characterized by exaggerated inflammatory reactions and high clinical mortality rates, but targeted therapeutic interventions are lacking. Warifteine, which is a traditional remedy known for its antiinflammatory properties, has been identified, but its potential effects on ALI remain unexplored. In this study, a murine model of ALI was established by injecting LPS into wild-type (WT) or neutrophil-specific <i>Gsdmd</i> (Gasdermin D)-deficient mice. Pulmonary function was evaluated, and lung samples were collected for immunofluorescence staining and RNA sequencing analysis. Additionally, live imaging of the lungs as well as histological, biochemical, and molecular investigations were performed to assess the progression of LPS-induced ALI in mice. Mouse bone marrow-derived neutrophils were isolated and cultured to investigate the effects of warifteine <i>in vitro</i>. Our findings indicate that warifteine effectively mitigates LPS-induced lung pathology and dysfunction in mice. Mechanistic studies revealed that warifteine protects against ALI by inhibiting neutrophil extracellular trap formation and the resulting cytokine storm. Subsequent research demonstrated that warifteine influences neutrophil extracellular trap formation by inhibiting GSDMD oligomerization through the regulation of reactive oxygen species production by neutrophils. Collectively, these findings reveal a novel role for warifteine in the protection against ALI and suggest that modulating GSDMD oligomerization may be an innovative therapeutic strategy.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"559-571"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603539","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":"Nasal Epithelial Extracellular Vesicles Correlate with Type 2 Inflammation during Aspirin-induced Respiratory Reactions.","authors":"Kaitlyn E Bunn, Zachary J Bressman, Grant K Nation, Pingsheng Wu, Taneem Amin, Courtney Lehman, Anabel Lin, Carleigh J Gray, Tanya M Laidlaw, Katherine N Cahill, Heather H Pua","doi":"10.1165/rcmb.2024-0414OC","DOIUrl":"10.1165/rcmb.2024-0414OC","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are membrane-bound particles secreted by cells with emerging roles in intercellular communication during tissue homeostasis and disease. Although EVs are abundant in respiratory biofluids, their cellular sources, critical cargos, and functions in the airway remain poorly understood. To determine how EV populations are changed in respiratory fluids during a chronic tissue inflammatory response, nasal EVs were assayed in 23 control participants and 22 participants with aspirin-exacerbated respiratory disease (AERD). Nasal lining fluid from participants was found to contain abundant EVs by electron microscopy and tunable resistive pulse sensing. Subset-specific EV subpopulations defined by the macrophage marker CD14 or the epithelial marker CD133/1 were increased in participants with AERD. To test how EVs change during an acute exacerbation, nasal lining fluid EVs were assessed in participants with AERD, who were repeatedly sampled during an aspirin-induced respiratory reaction. The abundance of several EV subpopulations dynamically correlated with concentrations of cysteinyl leukotrienes and tryptase in AERD nasal lining fluid. Together, these data implicate EVs in a dynamic signaling network that drives tissue inflammation during aspirin-induced type 2 immune activation in AERD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"623-633"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630008","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":"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":"10.1165/rcmb.2024-0441LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"637-640"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","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":"CXCR4 Blockade Alleviates Pulmonary and Cardiac Outcomes in Early Chronic Obstructive Pulmonary Disease.","authors":"Isabelle Dupin, Pauline Henrot, Elise Maurat, Reshed Abohalaka, Sébastien Chaigne, Dounia El Hamrani, Edmée Eyraud, Renaud Prevel, Pauline Esteves, Maryline Campagnac, Marielle Dubreuil, Guillaume Cardouat, Clément Bouchet, Olga Ousova, Jean-William Dupuy, Thomas Trian, Matthieu Thumerel, Hugues Bégueret, Pierre-Olivier Girodet, Roger Marthan, Maeva Zysman, Véronique Freund-Michel, Patrick Berger","doi":"10.1165/rcmb.2024-0303OC","DOIUrl":"10.1165/rcmb.2024-0303OC","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL/6J mice were exposed to cigarette smoke for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last 5 weeks to mimic exacerbations. The number of cells expressing CXCR4 was increased in the blood of individuals with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both patients with early COPD and exposed mice. Exposed mice presented mild airflow obstruction, peribronchial fibrosis, and right heart thickening. The density of fibrocyte-like cells expressing CXCR4 increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4, as well as pharmacological inhibition of CXCR4 with plerixafor injections, improved lung function, reduced inflammation, and protected against cigarette smoke and poly(I:C)-induced airway and cardiac remodeling. CXCR4^-/--treated and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peribronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. Although these preclinical findings are encouraging, further research is needed to explore the potential for transferring these insights into clinical applications, including drug repurposing.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"530-544"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810251","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":"Esrrg Inhibition Protects against Fine Particulate Matter-induced Asthma Aggravation by Reducing Pde3b.","authors":"Zhihua Zhang, Tao Cai, Xin Zhang, Xingbin Li, Xin Wang","doi":"10.1165/rcmb.2024-0461OC","DOIUrl":"10.1165/rcmb.2024-0461OC","url":null,"abstract":"<p><p>Particulate matter ⩽2.5 μm in aerodynamic diameter (PM_2.5), exposure is closely linked to the exacerbation of asthma. Esrrg (estrogen-related receptor-γ), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM_2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM_2.5 to establish a mouse model of asthma aggravation by PM_2.5. In view of mRNA sequencing, <i>Esrrg</i> was the only member of the nuclear receptor superfamily in the upregulated differentially expressed genes in OVA compared with naive groups as well as OVA + PM_2.5 compared with OVA groups (|log₂ (fold change)| > 1 and <i>P</i> < 0.05). <i>In vivo</i>, adenoassociated virus (AAV) carrying <i>Esrrg</i> shRNA (AAV-shEsrrg) was applied to silence Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist, GSK5182. AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM_2.5-aggravated asthmatic mice. <i>In vitro</i>, isolated mouse primary tracheobronchial epithelial cells from mice were identified by detecting cytokeratin 7-positive cells. The treatment of adenovirus vector with shEsrrg or GSK5182 mitigated the cell damage induced by PM_2.5. Notably, Pde3b (phosphodiesterase 3B) expression was decreased by Esrrg inhibition <i>in vivo</i> and <i>in vitro</i>. Dual luciferase reporter and chromatin immunoprecipitation PCR assays showed the binding of Esrrg to the <i>Pde3b</i> promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM_2.5-deteriorated asthmatic mouse model and prevented PM_2.5-driven mouse primary tracheobronchial epithelial cell injury through binding to the <i>Pde3b</i> promoter, which might contribute to further study of therapies for PM_2.5-aggravated asthma.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"600-611"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735540","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":"October Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.73i4RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.73i4RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"73 4","pages":"iii-iv"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197943","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":"Biased Orthosteric Agonism and Allosteric Modulation: Emerging Strategies for Developing New Class of β-Agonists for Obstructive Airway Diseases.","authors":"Sushrut D Shah, Deepak A Deshpande","doi":"10.1165/rcmb.2025-0144TR","DOIUrl":"10.1165/rcmb.2025-0144TR","url":null,"abstract":"<p><p>The obstructive lung diseases (OLDs), such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by bronchoconstriction and difficulty in breathing. β₂-adrenergic receptor (β₂AR) agonists (β-agonists) represent the most commonly used class of bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long-acting β-agonists (LABAs) and ultralong-acting β-agonists. Although these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, their reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as \"biased agonism\" and \"allosteric modulation.\" These advancements stem from a deeper understanding of the molecular interactions between β₂ARs and various intracellular proteins (e.g., heterotrimeric G proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β₂AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"489-499"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172435","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":"BDNF-TrkB Signaling Maintains Alveolar Epithelial Type 2 Cell Survival and Is Blocked in Hyperoxia-induced Neonatal Lung Injury.","authors":"Celien Kuiper-Makris, Luise Fahle, Caroline Zeitouny, Christina Vohlen, Oleksiy Klymenko, Stephanie Stephan, Ivana Mižik, Inga Bae-Gartz, Jaco Selle, Dharmesh Hirani, Andreea Belu, Tim Hucho, Julian Koenig, Julian U G Wagner, Esther Mahabir, Werner Seeger, Jörg Dötsch, Miguel A Alejandre Alcázar","doi":"10.1165/rcmb.2024-0198OC","DOIUrl":"10.1165/rcmb.2024-0198OC","url":null,"abstract":"<p><p>Oxygen supplementation causes an arrest of alveolar formation and a depletion of alveolar epithelial type 2 (AT2) cells in preterm infants, both characteristics of bronchopulmonary dysplasia. BDNF (brain-derived neurotrophic factor) is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, <i>1</i>) wild-type mice were exposed to 85% O₂ or 21% O₂ from birth to postnatal day (P)28, followed by spatiotemporal profiling of pulmonary BDNF signaling on P3-P70; and <i>2</i>) lung epithelial cells (MLE12), primary murine AT2, and precision-cut lung slices were treated with nonselective Trk inhibitor (K252a), selective TrkB antagonist (Ana12), and TrkB agonist (7,8-dihydroxyflavone). Single-cell transcriptomic profiling revealed an expression of <i>Bdnf</i> in mesenchymal cells but no changes during postnatal development. In contrast, immunofluorescent staining showed a predominant localization of TrkB in AT2 and ACTA2⁺ cells; its expression and phosphorylation were increased at P7-P21. Although hyperoxia induced a 40-fold upregulation of lung <i>Bdnf</i> and a 3-fold elevation of serum BDNF, TrkB abundance and activation decreased by 90%. This was related to a lower <i>Sftpc</i> and increased <i>Acta2</i> in lungs. Blockade of Trk(B) reduced survival of MLE12 and murine AT2 with a loss of epithelial AT1 and AT2 markers, whereas the TrkB agonist increased survival and regulated AT2 maintenance in precision-cut lung slices after hyperoxia. Our data identified an important functional role of TrkB signaling in AT2 cells, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to arrest of alveolar growth in infants with bronchopulmonary dysplasia.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"517-529"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810240","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":"A Breath of Fresh Insight: Targeting CXCR4 in Early Chronic Obstructive Pulmonary Disease.","authors":"Rebecca E Bignold, Jill R Johnson","doi":"10.1165/rcmb.2025-0235ED","DOIUrl":"10.1165/rcmb.2025-0235ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"487-488"},"PeriodicalIF":5.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962713","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}