American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Inhaled vitamin A mitigates hyperoxia-induced acute and chronic lung damage in a neonatal rat model of bronchopulmonary dysplasia.","authors":"Craig A Gelfand, Ying Wang, Reiko Sakurai, Jie Liu, Celia Yu, Gourav Chandan, Sabrina Madrigal, Lisette Juan, Robert Segal, Virender K Rehan","doi":"10.1093/ajrcmb/aanag171","DOIUrl":"10.1093/ajrcmb/aanag171","url":null,"abstract":"<p><strong>Rationale: </strong>Prevention of bronchopulmonary dysplasia (BPD) remains a critical unmet need.</p><p><strong>Objectives: </strong>We continued evaluating aerosolized vitamin A in a neonatal rat hyperoxia-injury model of BPD, testing whether lung-targeted inhalation yields superior outcomes compared to enteral or intramuscular (IM) delivery.</p><p><strong>Methods: </strong>Rat pups were exposed to continuous 95% hyperoxia for seven days to induce lung damage. Vitamin A was administered from post-natal day (PD) 1-7 by inhalation, enteral or IM dosing. Persisting effectiveness of inhaled vitamin A was examined at PD 21, dwelling in normoxia after all interventions were discontinued at PD 7.</p><p><strong>Measurements and main results: </strong>Comprehensive analyses include alveolar morphometrics, in vivo pulmonary function testing, assessment of hepatic vitamin A level, and quantitating gene and protein expression of relevant biomarkers of lung maturation, inflammation and damage/repair, employing singlex and multiplexed assays and whole-genome gene expression.</p><p><strong>Conclusions: </strong>Inhaled vitamin A suppressed hyperoxia-induced lung damage, with key hallmarks of BPD, including lung morphometrics and biomarkers associated with lung damage and inflammation, being effectively indistinguishable from healthy controls at both PD 7 and 21, Natural reparative processes were enhanced, with normal alveolarization and pulmonary function at PD 21. Despite raising hepatic vitamin A levels, enteral dosing was ineffective in restoring alveolar morphology at PD 7. Consistent with previous reporting, IM dosing yielded modest effect at PD 7 but with little evidence of benefit to pulmonary function at PD 21. Observation of dose-dependent effects with aerosolized vitamin A strengthens the evidence of the benefits of lung-targeted delivery, supporting further development of inhaled vitamin A as a BPD preventive strategy.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787153","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":"Poly I:C-induced monocyte-macrophages alleviate type 2 immunopathology in a murine asthma model.","authors":"Rui Suna, Seungmin Pyoa, Erin Warda, Savannah Dunberrya, James G Martin","doi":"10.1093/ajrcmb/aanag169","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag169","url":null,"abstract":"<p><strong>Rationale: </strong>Pathogen-associated molecular patterns (PAMPs) are known to initiate pro-inflammatory responses, but emerging evidence has revealed their roles in inducing macrophage-dependent immunomodulatory pathways that dampen inflammation.</p><p><strong>Objectives: </strong>We explored the interactions between the asthma-associated type 2 immunopathology and immune response to poly I:C, a PAMP mimicking double-stranded RNA, in ovalbumin (OVA) sensitized and challenged mice.</p><p><strong>Methods: </strong>Following intranasal co-administration of Poly I:C during OVA challenges, we performed immunophenotyping of the lung and measured airway responses to inhaled methacholine (MCh). We characterized the pulmonary macrophages by flow cytometry and examined the effects of monocyte-derived (Ly6C+) macrophage depletion and c-c motif chemokine receptor 2 (CCR2) deficiency on inflammation and responses to MCh. The role of IL-10 was assessed by antibody inhibition of the IL-10 receptor.</p><p><strong>Measurements and main results: </strong>Poly I:C attenuated allergen-induced type 2 immunopathology and airway hyperresponsiveness. Unexpectedly, the poly I:C receptors and poly I:C-induced cytokines were suppressed in the co-administered group compared to poly I:C only group. We observed an enrichment of lung Ly6C+ macrophages in co-administrated mice, which featured alternatively activated- (M2) and a myeloid-derived suppressor cell-like phenotype, expressed immunoregulatory factor IL-10, and inhibited in vitro T cell activation. Poly I:C did not inhibit Th2 immunopathology in mice depleted of Ly6C+ macrophages or deficient in CCR2, which mediates monocyte recruitment. Lastly, the blockade of the IL-10 receptor reversed the Th2-suppressing effect of co-administered poly I:C.</p><p><strong>Conclusions: </strong>Concurrent poly I:C and allergen exposure at the airway mucosa evokes macrophage-mediated immunomodulation that suppresses allergic airway reactions.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787193","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":"Modified RNA Extraction Methods to Eliminate Agarose Impurities in Human Precision-Cut Lung Slices.","authors":"Reina Rangel, Sabina Anderson, Giuseppe DeIuliis, Edward P Manning, Farida Ahangari, Abhay Pandit, Naftali Kaminski, Joan Marti-Munoz","doi":"10.1093/ajrcmb/aanag164","DOIUrl":"10.1093/ajrcmb/aanag164","url":null,"abstract":"<p><p>Precision-cut lung slices (PCLS) have emerged as a powerful tool for studying the biology of viable human lung tissue. However, the presence of agarose impurities compromises RNA yield and integrity during extraction. We tested whether using an alternative Plant kit extraction to wash agarose impurities or pre-dissolution of agarose from PCLS by immersion in a dissolving buffer for routine RNA isolation in gel electrophoresis would improve RNA quantity, quality, and integrity. Our results show that RNA quantity and integrity are highly compromised when using a conventional method of RNA extraction. The Plant kit and dissolution of agarose efficiently removed agarose impurities and increased the RNA quantity from < 0.028 µg/PCLS (below the detection limit) to 0.42 ± 0.11 and 0.65 ± 0.17 µg/PCLS (measured by the Qubit) and integrity number from 2.27 ± 0.87 to 6.60 ± 0.59 and 9.13 ± 0.39 (measured by the Bioanalyzer), respectively. The presence of phenol impurities in conventional and Plant kit extractions led to an overestimation of the RNA quantity and quality using the NanoDrop. The Plant kit and agarose dissolution showed a significant transcription amplification increase of housekeeping GUSB (p < 0.0001) and COL1A1 (p < 0.05) by qPCR, validating these methods over conventional extraction. We encourage laboratories applying PCLS experimentation to implement alternative methods that efficiently remove agarose impurities during RNA extraction, as well as to rely on sensitive RNA quantitative techniques, such as the Qubit and Bioanalyzer, for quantification and integrity assessment.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760923","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":"Consensus Lung Cell Reference: The Collaborative Cross-Consortium and Country Lung Cell Nomenclature Project (C3LCN). An Official American Thoracic Society Workshop Report.","authors":"Gloria S Pryhuber, Martijn Nawijn, Denise Al Alam, Bruce Aronow, Martin Banchero, Nicholas Banovich, Pascal Barbry, Maria Basil, Kevin Burns, Janette Burgess, Wellington V Cardoso, Geremy Clair, Rachel Clifford, Soula Danopoulos, Gail Deutsch, Thu Elizabeth Duong, Joshua Fortriede, David Frank, Reinoud Gosens, Mingxia Gu, Minzhe Guo, James Hagood, Raphael Kfuri-Rubens, Gerard H Koppelman, Stephanie Krick, Jonathan A Kropski, Qing Sara Lin, Clare Lloyd, Malte D Luecken, Susan Majka, Kerstin Meyer, Alexander Misharin, Ravi S Misra, Ana Mora, Enid Neptune, Terren K Niethamer, Kenichi Okuda, David Osumi-Sutherland, Anna Karina Perl, Joseph D Planer, Aleix Puig-Barbé, Ellen M Quardokus, Rod Rahimi, Jayaraj Rajagopal, Scott Randell, Elizabeth Redente, Eniko Sajti, Nathan Salomonis, Christos Samakovlis, Richard Scheuermann, Janine Schniering, Xin Sun, Purushothama Tata, Alexandra-Chloé Villani, Matthew S Walters, Kathryn A Wikenheiser-Brokamp, Yan Xu, Laure-Emmanuelle Zaragosi","doi":"10.1093/ajrcmb/aanag144","DOIUrl":"10.1093/ajrcmb/aanag144","url":null,"abstract":"<p><p>Rapid advances in single-cell technologies now allow measurement of thousands of transcripts and other molecular features of individual cells offering unprecedented insight into lung biology in homeostasis and in disease. The accelerated generation of multimodal data has, however, been accompanied by the reporting of putatively \"novel\" cell types described without consensus regarding their ontogeny, identity, function, or defining markers. To fully realize the value of the technological advances and to enable rigorous comparison across studies, respiratory research will benefit from standardized, quantitative, and biologically grounded cell classifications and nomenclature. Achieving the transformative potential of the multimodal data will depend on common, machine- and human-readable nomenclature, structured and expandable dictionary and atlas resources, and clear methodological standards that ensure consistency as technologies evolve. The American Thoracic Society (ATS) recognized the importance of promoting a common nomenclature to enhance equitable access and utility of the vast amounts of multimodal data generated by the lung research community. The Collaborative Cross-Consortium and Country Lung Cell Nomenclature Project (C3LCN) was adopted as an ATS Assembly Project in 2024. This is the consensus report outlining the goals and framework of the Project to foster coordinated progressive lung cell research to include: 1) providing best practices for analysis, publication and reporting of lung single-cell transcriptomic datasets; 2) establishing a contemporary lexicon for healthy adult human cells of the lower respiratory tract with structured, persistent, and resolvable identifiers; 3) defining a scalable taxonomy to organize a common lung cell nomenclature; 4) offering tools to support collaboration, knowledge dissemination, and translational advances rooted in modern lung biology augmenting, not replacing, pre-genomic biological knowledge; and 5) describing an infrastructure capable of incorporating new ontological refinements as higher-resolution, multimodal single-cell and spatial datasets emerge, cellular heterogeneity is better defined, and disease-associated abnormal cell types and reactive cell states are increasingly recognized and mechanistically interrogated. Together, this coordinated effort aims to provide the foundation necessary for a robust, harmonized, and expandable nomenclature for lung science.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757162","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":"GPCR Biology-Informed Drug Discovery in Asthma.","authors":"Raymond B Penn","doi":"10.1093/ajrcmb/aanag168","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag168","url":null,"abstract":"<p><p>Advances in GPCR biology and drug-discovery technology are simultaneously reshaping what can be targeted in asthma and how those strategies must be validated. Recent insights into biased signaling, receptor dimerization and signaling microdomains have revealed new therapeutic opportunities beyond the limitations of traditional β₂-agonist bronchodilation and cytokine-targeted biologics. At the same time, innovations in structural biology, computational modeling, machine learning, biosensor-based pharmacology, and physiologically relevant airway models have transformed the interrogation of GPCRs and the engineering of therapeutics that target them. This review synthesizes these developments, emphasizing how emerging GPCR concepts inform modern discovery platforms, how receptor- and post-receptor signaling control points can be targeted, and how validation across artificial and physiologic systems improves translational fidelity. We further discuss how GPCR therapeutics may reshape clinical development and complement existing biologic therapies in asthma.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759111","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":"Glutaminase regulates alveolar regeneration through autophagy-YAP/TAZ in pulmonary fibrosis.","authors":"Morgan A Pantuck, Xiaoying Zhang, Fatemeh Meshkini, Yinfei Tan, Adam Karami, Adam Chatoff, Nathaniel Snyder, Walter J Koch, Beata Kosmider, Ying Tian","doi":"10.1093/ajrcmb/aanag145","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag145","url":null,"abstract":"<p><strong>Rationale: </strong>Impaired alveolar regeneration is a central feature of chronic lung diseases. Type 2 alveolar epithelial cells (AT2) serve as lung stem/progenitor cells that differentiate into type 1 cells (AT1) to restore gas exchange following injury. However, the metabolic determinants governing this regenerative process remain poorly understood.</p><p><strong>Objectives: </strong>This study aimed to determine the role of glutamine metabolism via glutaminase 1 (GLS1) in regulating AT2-to-AT1 differentiation and alveolar regeneration after lung injury.</p><p><strong>Methods: </strong>We used primary murine AT2 cells, alveolar organoids, and lineage-tracing mouse models of bleomycin-induced lung injury. The effects of AT2-specific GLS1 deletion on epithelial differentiation were assessed in vitro and in vivo. Chloroquine and bafilomycin A1, two autophagy inhibitors with distinct molecular mechanisms of action, were used for mechanistic rescue experiments.</p><p><strong>Measurements and main results: </strong>GLS1 expression increased during AT2-to-AT1 differentiation and was accompanied by metabolic reprogramming characterized by enhanced glycolysis and increased glutamine entry into the TCA cycle. AT2-specific GLS1 deletion impaired differentiation in vitro and in vivo, resulting in defective alveolar repair and exacerbated pulmonary fibrosis. Mechanistically, GLS1 deficiency induced excessive autophagy and promoted degradation of the Hippo pathway effectors YAP and TAZ, key regulators of epithelial cell fate decisions. Inhibition of autophagy with either chloroquine or bafilomycin A1 restored YAP/TAZ levels, rescued AT2-to-AT1 differentiation, reduced fibrosis, and improved lung function.</p><p><strong>Conclusions: </strong>GLS1-mediated glutaminolysis is essential for alveolar stem/progenitor cell differentiation through regulation of autophagy and YAP/TAZ stability. Modulation of autophagy may represent a therapeutic strategy to enhance lung regeneration in fibrotic lung diseases.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710996","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":"Survival and Homeostasis of Alveolar Macrophages in Vivo Depend on mTOR Signaling.","authors":"Samson Hennessy-Strahs, Xiaojun Su, Si Sun, Ge Deng, Wen Muo, Jiarui Li, Tasha Miller, Xiang Xiao, Xian Chang Li","doi":"10.1093/ajrcmb/aanag139","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag139","url":null,"abstract":"<p><p>Alveolar homeostasis depends on tissue-resident professional phagocytes known as alveolar macrophages (AMs) that catabolize pulmonary surfactant. Pulmonary alveolar proteinosis (PAP) arises from impaired surfactant clearance due to loss or dysfunction of AMs, most commonly from disrupted GM-CSF-dependent AM homeostasis and less frequently from congenital defects in surfactant synthesis or processing. PAP has also been reported as a pulmonary toxicity associated with mTOR inhibitor-based immunosuppressive therapy. Although mTOR activity regulates macrophage metabolism and proliferation, its requirement for AM survival and lipid homeostasis remains unclear. Here, we examined the role of mTOR in AM survival and surfactant homeostasis, using complementary genetic and pharmacologic approaches in vivo, and GM-CSF-driven AM-like cell culture models in vitro. Myeloid-specific deletion of mTOR caused progressive, preferential depletion of AMs among tissue-resident macrophage populations, accompanied by impaired phagocytosis, intracellular lipid accumulation, and development of PAP-like lung pathology. In vivo, pharmacologic mTOR inhibition with temsirolimus reproduced key features of genetic mTOR deletion, including AM depletion, apoptosis, lipid accumulation, and PAP-like pathology. In vitro, mTOR activity was required to sustain GM-CSF-dependent expansion, maturation, and survival of AM-like cells. Mechanistically, mTOR loss reduced expression of PPARγ and pro-survival Bcl-2 family members, linking mTOR activity to AM viability and lipid handling capacity. In summary, these findings identify mTOR as a nonredundant, cell-intrinsic regulator of alveolar macrophage survival and function required to maintain alveolar homeostasis. This work provides experimental support for AM-intrinsic mechanisms contributing to mTOR inhibitor-associated pulmonary toxicity, including PAP.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705049","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 post-translational rheostat of TGF-β signaling controlling lung cancer metastasis.","authors":"Jazmin Calyeca, Victor J Thannickal","doi":"10.1093/ajrcmb/aanag161","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag161","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711005","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":"ZDHHC11-Mediated Palmitoylation of PPM1A Regulates Lung Cancer Metastasis via the TGF-β1-Smad2/3 Signaling Pathway.","authors":"Yulong Li, Yu Zhou, Peng Zhao, Min Shi, Zhiyan Wang, Zhijian Zhang, Geping Qu","doi":"10.1093/ajrcmb/aanag156","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag156","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer remains the most common cause of cancer-related mortality worldwide. The transforming growth factor-beta 1 (TGF-β1) pathway promotes epithelial-mesenchymal transition (EMT), invasion, and metastasis in advanced disease via mothers against decapentaplegic homolog 2 (Smad2) and Smad3. This study investigated how post-translational modifications regulate TGF-β1-Smad signaling.</p><p><strong>Methods: </strong>Lung cancer cell lines and a mouse metastasis model were used to explore the roles of protein phosphatase magnesium-dependent 1A (PPM1A) palmitoylation, zinc finger DHHC-type palmitoyltransferase 11 (ZDHHC11), and ubiquitin-specific peptidase 5 (USP5) in regulating Smad2/3 signaling. Palmitoylation-deficient and wild-type PPM1A constructs were introduced by lentiviral transduction. Protein levels, modifications, and interactions were analyzed by western blot, immunoprecipitation, and immunofluorescence. Palmitoylation was measured using acyl-resin-assisted capture (Acyl-RAC). Cell invasion and migration were assessed using Transwell assays.</p><p><strong>Results: </strong>Palmitoylation of PPM1A at cysteine 71 enhanced the interaction between PPM1A and Smad2/3, promoted Smad2/3 dephosphorylation, and suppressed lung cancer cell invasion and metastasis. ZDHHC11 was identified as the enzyme responsible for PPM1A palmitoylation; its loss diminished this modification and accelerated metastasis in vivo. TGF-β1 downregulated ZDHHC11 expression, weakened PPM1A-Smad2/3 binding, and increased cell migration. Additionally, USP5 stabilized Smad2/3 by preventing their ubiquitin-mediated degradation, and TGF-β1 further amplified this effect by limiting PPM1A access.</p><p><strong>Conclusion: </strong>This study identified a novel palmitoylation-dependent mechanism regulating TGF-β1-Smad signaling in lung cancer. Upregulating the ZDHHC11-PPM1A axis or targeting USP5 may offer new strategies to inhibit metastasis in lung cancer.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700510","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":"Targeting the S100A2-RAGE Pathway Restores AT2 Cell Identity and Mitigates Lung Fibrosis.","authors":"Changli Zhou, Jack H Wellmerling, Alireza Jian Bagherpoor, Wei Deng, Daniel Tschumperlin, Qi Tan","doi":"10.1093/ajrcmb/aanag133","DOIUrl":"10.1093/ajrcmb/aanag133","url":null,"abstract":"<p><p>Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), represents a spectrum of progressive interstitial lung diseases characterized by disrupted epithelial repair, fibroblast activation, and excess extracellular matrix accumulation. A central feature of fibrotic progression is the loss of alveolar type 2 epithelial (AT2) cell identity and the emergence of aberrant transitional states that fail to support normal regeneration. Based on our re-analysis of multiple publicly available scRNA-seq datasets from the IPF Cell Atlas, S100A2 expression is tightly associated with basal-like reprogramming of AT2 cells and is a top upregulated gene at both mRNA and protein levels in IPF lungs. Furthermore, scRNA-seq data from human lung organoid models reveal that AT2 cells co-cultured with fibroblasts acquire a basal-like phenotype and express high levels of S100A2. Functionally, overexpression of S100A2 in human iPSC-derived lung alveolar epithelial type 2 (iAT2) cells leads to loss of AT2 cellular identity, increased generation of reactive oxygen species, and activation of RAGE signaling pathway. We demonstrate that pharmacologic inhibition of RAGE using Azeliragon preserves AT2 cell populations, associated with reduced oxidative stress in iAT2 cells, and significantly attenuates collagen deposition in bleomycin-induced lung fibrosis models. Collectively, our results indicate that S100A2 is a key driver of epithelial dysfunction in lung fibrosis, promoting loss of AT2 identity, aberrant basal fate acquisition, and persistent epithelial injury. Targeting the unrecognized S100A2-RAGE pathway may offer a new therapeutic strategy to restore epithelial homeostasis in lung fibrosis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705037","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}