American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"CXCR4 Blockade Alleviates Pulmonary and Cardiac Outcomes in Early COPD.","authors":"Isabelle Dupin, Pauline Henrot, Elise Maurat, Reshed Abohalaka, Sébastien Chaigne, Dounia El Hamrani, Edmée Eyraud, Renaud Prevel, Pauline Esteves, Marilyne Campagnac, Marielle Dubreuil, Guillaume Cardouat, Clément Bouchet, Olga Ousova, Jean-William Dupuy, Thomas Trian, Matthieu Thumerel, Hugues Begueret, Pierre-Olivier Girodet, Roger Marthan, Maeva Zysman, Véronique Freund-Michel, Patrick Berger","doi":"10.1165/rcmb.2024-0303OC","DOIUrl":"https://doi.org/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 (CS) for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last five 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 early COPD patients and exposed mice. Exposed mice presented mild airflow obstruction, peri-bronchial 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 CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4^-/- and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. While 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":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-08","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":"BDNF-TrkB Signaling Maintains AT2 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 Alcazar","doi":"10.1165/rcmb.2024-0198OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0198OC","url":null,"abstract":"<p><p>Oxygen supplementation causes an arrest of alveolar formation and a depletion of alveolar epithelial type2 cells (AT2) in preterm infants, both characteristics of bronchopulmonary dysplasia (BPD). BDNF is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, (i) wild-type mice were exposed to 85% O2 (HYX) or 21% O2 (NOX) from birth to postnatal day (P)28, followed by spatio-temporal profiling of pulmonary BDNF-signaling on P3-P70. (ii) MLE12 cells, primary murine AT2 (mAT2), and precision-cut ling slices (PCLS) were treated with non-selective Trk inhibitor (K252a), selective TrkB antagonist (Ana12), and TrkB agonist (7,8-dihydroxyflavone). (i) 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. While 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. (ii) Blockade of Trk(B) reduced survival of MLE12 and mAT2 with a loss of epithelial AT1 and AT2 markers, whereas the TrkB agonist increased survival and regulated AT2 maintenance in PCLS after HYX. 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 BPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-08","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 Human Single-Nuclei Atlas Reveals Novel Cell States During the Pseudoglandular-to-Canalicular Transition.","authors":"Laurent Renesme, Flore Lesage, David P Cook, Adithya Achuthan, Shumei Zhong, Satu M Hänninen, Olli Carpén, Ivana Mižik, Bernard Thébaud","doi":"10.1165/rcmb.2024-0244OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0244OC","url":null,"abstract":"<p><p>Most of our knowledge on human lung development derived from morphologic studies and extrapolations of the underlying molecular mechanisms from animal models. Here we describe developmental changes in human fetal lungs during the pseudoglandular and early canalicular period, detailing this critical, but previously poorly described transition period. We report the cellular composition and cell-to-cell communication on a single-nuclei dataset from nine human fetal lungs between 14 and 19 weeks of gestation. We identified nine main and 19 sub-populations, including the rare pulmonary neuroendocrine cells. For each population, marker genes were reported, and selected markers were validated. Enrichment analysis were performed to explore the potential molecular mechanisms and pathways within individual populations according to gestational age. Lastly, cell-to-cell communication was studied using ligand-receptor analysis among the different cell types. General developmental pathways, as well as pathways involved in vasculogenesis, neurogenesis, and immune regulation were identified. This study provides an important background to generate research hypotheses in projects studying normal or impaired lung development and help to validate surrogate models (e.g. lung organoids) to study human lung development.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810233","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":"Tartrate-Resistant Acid Phosphatase 5 (TRAP5) Promotes Eosinophil Migration During Allergic Asthma.","authors":"Médea Padra, Jesper Bergwik, Anna Adler, Genevieve Marcoux, Ravi K V Bhongir, Praveen Papareddy, Arne Egesten","doi":"10.1165/rcmb.2024-0304OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0304OC","url":null,"abstract":"<p><p>Allergic asthma is characterized by type 2 inflammation and eosinophilia. Tartrate-resistant acid phosphatase 5 (TRAP5/ACP5) is a metallophosphatase expressed by alveolar macrophages that dephosphorylates osteopontin (OPN), a phosphoglycoprotein with increased expression in asthma. To investigate the role of TRAP5 during asthma, we used a murine model of ovalbumin (OVA) induced allergic airway inflammation as well as IL-33 induced airway inflammation including <i>Trap5^-/-</i> and wild-type (WT) mice. Histological analyses of murine lung revealed that OVA-induced inflammation induced the formation of inflammatory lesions and increased mucus production in both WT and <i>Trap5^-/-</i> mice. However, lower cytokine levels (including IL-5 and IL-13) were detected by multiplex immunoassay in <i>Trap5^-/-</i> mice after OVA-induced inflammation. Furthermore, qPCR analysis detected different gene expression profile of <i>Trap5^-/-</i>/OVA mice, including upregulation of <i>Il-17a</i> and downregulation of <i>Il-33</i>. Lower eosinophil numbers were measured in bronchoalveolar lavage fluid of <i>Trap5^-/-</i>/OVA mice using flow cytometry analysis, whereas immunofluorescence staining revealed high eosinophil number in lung tissue of both groups with OVA challenge. In the IL-33 model of type 2 inflammation, both WT and <i>Trap5^-/-</i> mice showed similar inflammatory responses with regard to cytokine levels and cell recruitment patterns. <i>In vitro</i>, eosinophil chemotaxis was facilitated by non-phosphorylated but not phosphorylated OPN, an effect inhibited by an α4β1 integrin inhibitor. The results suggest that TRAP5 is important in the recruitment of immune cells, including eosinophils, as well as in shaping the profile and amplification of the inflammatory response during allergic airway inflammation. Thus, TRAP5 may serve as a therapeutic target in allergic asthma. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770942","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":"SOX17 Prevents Endothelial-Mesenchymal Transition of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertension through Mediating TGF-β/Smad2/3 Signaling.","authors":"Xiaozhou Zou, Mengnan Yuan, Wei Zhou, Anqi Cai, Yili Cheng, Zibo Zhan, Yiwen Zhang, Zongfu Pan, Xiaoping Hu, Shuilian Zheng, Ting Liu, Ping Huang","doi":"10.1165/rcmb.2023-0355OC","DOIUrl":"10.1165/rcmb.2023-0355OC","url":null,"abstract":"<p><p>Endothelial-to-mesenchymal transition (EndMT) has been reported to contribute to pulmonary vascular remodeling in patients with pulmonary hypertension (PH). Our study demonstrates that SOX17, a member of the SOX (SRY-Box) transcription factor family, plays a role in regulating pulmonary arterial homeostasis through extracellular vesicles in an autocrine and paracrine manner. However, the role of SOX17 in mediating EndMT of pulmonary arterial endothelial cells (PAECs) and its intracellular mechanisms remain unclear. Here we present evidence showing that downregulation of SOX17 expression is accompanied by significant pulmonary arterial EndMT and activation of the TGF-β/Smad2/3 signaling pathway in patients with idiopathic PH and rats with PH induced by Sugen 5416/hypoxia. In primary human PAECs, canonical TGF-β (transforming growth factor-β) signaling inhibits the expression of SOX17. Overexpression of SOX17 reverses TGF-β- and hypoxia-induced EndMT. These findings suggest that SOX17 is essential for human PAECs to undergo TGF-β-mediated EndMT. Mechanistically, our data demonstrate that SOX17 prevents TGF-β-induced EndMT by suppressing ROCK1 (Rho-associated kinase 1) expression through binding to the specific promoter region of ROCK1, thereby inhibiting MYPT1 (myosin phosphatase target subunit 1) and MLC (myosin light chain) phosphorylation. Furthermore, we show that Tie2-Cre rats with endothelial cell-specific overexpression of SOX17 are protected against Sugen/hypoxia-induced EndMT and subsequent pulmonary vascular remodeling. Consistent with the <i>in vitro</i> results, compared with Tie2-Cre rats treated with Sugen/hypoxia alone, rats overexpressing SOX17 exhibited reduced levels of ROCK1 as well as decreased phosphorylation levels of MYPT1 and MLC. Overall, our studies unveil a novel TGF-β/SOX17/ROCK1 pathway involved in regulating PAECs' EndMT process, and we propose the targeting of SOX17 as a potential therapeutic strategy for alleviating pulmonary vascular remodeling in PH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"364-379"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399133","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":"Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction.","authors":"Naoko Hara, Dorota S Raclawska, Leslie E Morgan, James C NeeDell, Lucie Dao, Ayako Kato, Ana M Jaramillo, Patrick S Hume, Fernando Holguin, William J Janssen, Eszter K Vladar, Christopher M Evans","doi":"10.1165/rcmb.2024-0216OC","DOIUrl":"10.1165/rcmb.2024-0216OC","url":null,"abstract":"<p><p>Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma and contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Because of the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2. <i>Fut2</i> gene-deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model that may help improve therapeutic targeting of airway mucus.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"408-417"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493010","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":"Can ENaC \"TIP\" the Scales to Reduce Endothelial Reactive Oxygen Species and Vascular Leak during Pneumococcal Lung Injury?","authors":"Alison W Ha, Eleftheria Letsiou, Steven M Dudek","doi":"10.1165/rcmb.2024-0486ED","DOIUrl":"10.1165/rcmb.2024-0486ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"349-351"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602771","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":"Volume-Regulated Anion Channel Complex Modulates Mechano-Electrical Signal Responses in Human Airway Smooth Muscle Shortening.","authors":"Joanna Woo, Gaoyuan Cao, Nikhil Karmacharya, Jordan Lee, Justin Lee, Kingsley C Duru, Conor McClenaghan, Steven S An, Reynold A Panettieri, Joseph A Jude","doi":"10.1165/rcmb.2024-0160OC","DOIUrl":"10.1165/rcmb.2024-0160OC","url":null,"abstract":"<p><p>LRRC8A (leucine-rich repeat containing 8A) is an obligatory constituent of the volume-regulated anion channel (VRAC) that is fundamental to a wide range of biological processes, including regulating cell size, proliferation, and migration. Here we explored the physiological role of VRAC in excitation-contraction (E-C) coupling and shortening of human airway smooth muscle (HASM). In HASM cells, pharmacological inhibition of VRAC with DCPIB (4-[2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl]) (0.1-10 μM) markedly attenuated swell-activated Cl^- conductance, and contractile agonist (histamine or carbachol)-induced cellular stiffening as measured by single-cell patch-clamp and optical magnetic twisting cytometry, respectively. In addition, HASM cells treated with DCPIB or transfected with LRRC8A-targeting siRNA showed reduced agonist-induced phosphorylation of protein kinase B (i.e., AKT), paxillin, MYPT1, and myosin light chain. Consistent with the changes of these E-C coupling effectors, DCPIB appreciably decreased agonist-induced small airways narrowing in human precision-cut lung slices. Taken together, our findings shed new light on the mechanistic link between HASM shortening and regulatory volume decrease via LRRC8A, revealing a previously unrecognized nodal point for modulation of E-C coupling and acute airway constriction.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"418-428"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520727","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":"Endothelial Dysfunction in Pulmonary Hypertension: Does ADP Ribosylation Factor 6-mediated HIF-2α Stabilization Matter?","authors":"Fenja Knoepp, Simone Kraut, Christine Veith","doi":"10.1165/rcmb.2024-0465ED","DOIUrl":"10.1165/rcmb.2024-0465ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"352-353"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674905","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":"Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.","authors":"Maritza J Romero, Qian Yue, Won Mo Ahn, Jürg Hamacher, Yusra Zaidi, Stephen Haigh, Supriya Sridhar, Joyce Gonzales, Martina Hudel, Yuqing Huo, Alexander D Verin, Betty S Pace, Brian K Stansfield, Mazharul Maishan, Enid R Neptune, Perenlei Enkhbaatar, Yunchao Su, Trinad Chakraborty, Graydon Gonsalvez, Edith Hummler, William B Davis, Vladimir Y Bogdanov, David J R Fulton, Gabor Csanyi, Michael A Matthay, Douglas C Eaton, Rudolf Lucas","doi":"10.1165/rcmb.2023-0440OC","DOIUrl":"10.1165/rcmb.2023-0440OC","url":null,"abstract":"<p><p>Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NOX2 (nicotinamide adenine dinucleotide phosphate hydrogen [NADPH] oxidase 2), involving the pneumococcal virulence factor PLY (pneumolysin). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of ENaC (epithelial sodium channel) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function-measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans blue dye incorporation in mouse lungs-after infection with pneumococci. PLY-induced hyperpermeability in human lung microvascular endothelial cell monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47^phox subunit (Western blotting) <i>in vitro</i> and by colocalization of CD31 and gp91^phox in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α knockout (enENaC-α knockout) mice develop increased capillary leak upon intratracheal instillation with PLY or pneumococci, compared with wild-type animals. TIP peptide diminishes capillary leak in <i>Streptococcus pneumoniae</i>-infected wild-type mice, without significantly increasing lung bacterial load. Lung slices from <i>S. pneumoniae</i>-infected enENaC-α knockout mice have significantly increased endothelial NOX2 expression, compared with infected cyclization recombination mice. In conclusion, enENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in acute respiratory distress syndrome, without impairing host defense.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"429-440"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455963","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}