American journal of physiology. Lung cellular and molecular physiology最新文献

{"title":"Inhibition of extracellular tissue transglutaminase activity attenuates development of pulmonary fibrosis in a novel rabbit model.","authors":"Thomas H Thatcher, Margaret A T Freeberg, Sarah V Camus, Linghong Huang, John Atkinson, Shannon H Lacy, Wade Narrow, Robert M Kottmann, Khoa Huynh, Jinze Liu, Valentina Robila, Timothy S Johnson, Patricia J Sime","doi":"10.1152/ajplung.00037.2026","DOIUrl":"10.1152/ajplung.00037.2026","url":null,"abstract":"<p><p>Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase (TG2) is believed to promote lung fibrosis by cross linking extracellular matrix components and activating latent transforming growth factor β. This study evaluates the contribution of TG2 to pulmonary fibrosis in human lung tissue from donors with idiopathic pulmonary fibrosis (IPF) and in a novel rabbit model of pulmonary silicosis, using a therapeutic TG2 blocking antibody to inhibit extracellular matrix cross linking. Human IPF tissue expressed elevated levels of TG2 antigen and Tgm2 RNA as detected by in situ hybridization and antigen. Silica-treated rabbits developed lung fibrosis with increased collagen and increased TG2 enzymatic activity. Treatment with TG2 inhibitory antibody rbBB7, a rabbitized version of the human therapeutic antibody zampilimab, reduced TG2 activity and attenuated fibrosis by 50% when used in either a prevention or treatment strategy, which was associated with reductions in interstitial collagen accumulation. TG2 has previously been reported to contribute to pulmonary fibrosis in the mouse bleomycin model, leading to the conclusion that TG2 contributes significantly to the pathogenesis of pulmonary fibrosis as demonstrated in human tissue specimens and two independent animal models with different fibrotic stimuli. Blockade of TG2 extracellular cross-linking activity with a therapeutic antibody significantly attenuated the development of fibrosis when given in a prevention strategy or treatment strategy. Blockade of extracellular TG2 activity has exciting therapeutic potential.<b>NEW & NOTEWORTHY</b> Evidence is presented that the multifunctional enzyme tissue transglutaminase (TG2) is a driver of fibrosis pathology in the lung. Here, we investigate a candidate therapeutic antibody that blocks the protein cross-linking function of TG2, in a novel rabbit model of silica-induced pulmonary fibrosis. Our results show that treatment with zampilimab can reduce accumulation of fibrotic tissue and hydroxyproline content by 50% compared with control, suggesting that zampilimab may represent a novel therapy for pulmonary fibrosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L421-L437"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029920","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":"ROS/HIF-1 signaling in alveolar macrophages: implications for lung fibrosis.","authors":"E Jenkins, D R Thickett, D Parekh, A Scott","doi":"10.1152/ajplung.00192.2026","DOIUrl":"10.1152/ajplung.00192.2026","url":null,"abstract":"<p><p>Alveolar macrophages (AMs) in idiopathic pulmonary fibrosis (IPF) display stabilization of hypoxia-inducible factor (HIF)-1α despite their residence within the well-oxygenated alveolar space. This highlights a contradiction between oxygen supply and hypoxic signaling in the fibrotic lung. This inconsistency implies that nonclassical environmental factors may influence macrophage phenotype and reprogramming during the pathogenesis of lung fibrosis. AMs are dynamic, adaptable responders to cues from the inhaled environment and local tissue. In patients with IPF, oxidative stress is a feature of the lung and circulation which may arise from endogenous metabolic activity or inhaled environmental factors. A key signaling intermediate, therefore, may be found in reactive oxygen species (ROS) and their ability to stabilize HIF-1α, inducing a pseudohypoxic environment. This presents a potential link between environmental exposures and HIF-1-mediated transcriptional responses in AMs. This review interrogates ROS-HIF-1α cross talk and how it may shape the AM program in the fibrotic lung. We integrate evidence from cell lines, circulating and tissue-resident macrophages, and experimental fibrosis models to hypothesize how ROS-dependent HIF-1α stabilization could alter the behavior of AMs, inducing profibrotic programmes and limiting normal homeostatic capacity. We synthesize mechanisms from the literature regarding redox-sensitivity of prolyl-hydroxylase enzymes and iron-dependent control of HIF-1α turnover to highlight how regulation could be targeted in future research. Investigating the ROS-HIF-1α axis proposes a link between environmental exposures and how macrophages may accelerate fibrosis in IPF. This review synthesizes evidence to understand how macrophages may translate environmental oxidative stress into cellular responses and fibrosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L409-L420"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029904","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":"Basal Stem Cell Signaling Pathways Regulating Collective Epithelial Cell Migration and Airway Repair.","authors":"Sahana Nagarajan, Emily C Liu, Amy L Ryan","doi":"10.1152/ajplung.90005.2026","DOIUrl":"https://doi.org/10.1152/ajplung.90005.2026","url":null,"abstract":"<p><p>The airway epithelium serves as a critical barrier against pathogens, allergens, and other environmental insults. Disruption of this barrier contributes to respiratory diseases such as chronic obstructive pulmonary disease, making rapid epithelial repair essential for maintaining lung function. Basal cells (BCs), the primary regenerative cell population of the proximal airway epithelium, drive repair through coordinated collective cell migration rather than isolated cellular behaviors. This process is closely linked to dynamic transitions between jammed and unjammed tissue states that regulate migratory capacity and tissue remodeling. Emerging evidence identifies extracellular matrix (ECM) remodeling, Wnt, and transforming growth factor-β (TGF-β) signaling as key regulators of these multicellular responses. ECM remodeling establishes the mechanical substrate for migration, while non-canonical Wnt signaling promotes cytoskeletal reorganization, cell polarity, and coordinated BC movement. TGF-β signaling acts as a context-dependent regulator of BC migration, differentiation, epithelial jamming, and cytoskeletal remodeling through canonical and non-canonical pathways. ECM-integrin signaling links the extracellular environment to cytoskeletal dynamics and collective migration, while inflammatory and mechanical cues modify these responses. Integrin αvβ5/αvβ6-mediated interactions with the ECM connect mechanical forces to focal adhesion signaling and activation of latent TGF-β, linking tissue mechanics to epithelial repair. Together, integration of inflammatory, biochemical, and biomechanical signals that coordinate collective migration and epithelial restoration. This mini-review highlights recent advances supporting a model where coordinated ECM remodeling, Wnt signaling, and TGF-β signaling regulate BC migration and restore epithelial barrier integrity following injury, and examines how disruption of these processes contributes to abnormal repair in chronic lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102693","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":"Early to mid-gestational testosterone excess leads to adverse lung programming in sheep offspring.","authors":"Md Rahatullah Razan, Kel Vin Woo, Divya Purswani, David Bernal, Bashar Alkhatib, Tiandao Li, Vasantha Padmanabhan, Arpita Kalla Vyas","doi":"10.1152/ajplung.00034.2026","DOIUrl":"https://doi.org/10.1152/ajplung.00034.2026","url":null,"abstract":"<p><p>Prenatal testosterone (T) excess programs sex-specific cardiovascular dysfunction in sheep offspring. Given the close reciprocal relationship between the cardiopulmonary system, we hypothesized that prenatal T excess would also adversely program the offspring's pulmonary system in a sex-specific manner from fetal life into adulthood. Pregnant ewes received intramuscular injections of T propionate (100 mg) or a vehicle control (C) twice weekly from gestational days (GD) 30-90 (term 147 days). Offspring lungs were collected at GD120 (n=6-7 per group), and at 24 months of age (n=4-6 per group) for histological and molecular analyses. Data were analyzed using two-way ANOVA (fetal) and/or sex-specific stratified t-tests for adults and Cohen's effect size analyses. Prenatal T significantly increased fetal lung collagen deposition in males. Prenatal T treatment had a significant overall treatment main effect on fetal lung apoptosis and the ratio of small to total blood vessels. Some adverse effects of prenatal T excess persisted into adulthood, including a significant increase in lung collagen in both sexes. Fetal lung transcriptome revealed differential enrichment of pathways involved in regulation of hormone biosynthetic process, and neuron apoptotic process in T- treated males, whereas pathways related to bicarbonate transport and regulation of muscle cell differentiation were enriched in T- treated females. Overall, early- to mid-gestational T excess adversely reprograms the offspring's lungs in a sex-specific manner, from fetal life extending into adulthood.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102667","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":"Neutrophil Control of Immune Cell Recruitment and Acute Lung Injury in SARS-CoV-2-infected Mice.","authors":"Kenneth R McLeish, Madhavi J Rane, Michelle T Barati, Xiaoling Hu, Hong Li, Shweta Tandon, Charles D Anderson, Adlen A Asta, Lalit Batra, Chithra C Sreenivasan, Jon D Gabbard, Silvia M Uriarte, Jiapeng Huang, Jian Zheng, Jun Yan","doi":"10.1152/ajplung.00155.2026","DOIUrl":"https://doi.org/10.1152/ajplung.00155.2026","url":null,"abstract":"<p><p>Neutrophils are postulated to contribute to the severity of acute lung injury induced by SARS-CoV-2 infection. Neutrophils play both protective and damaging roles in bacterial and viral pneumonia. The present study examined the hypotheses that neutrophils play multiple roles in the pathophysiology of SARS-CoV-2 infection and that granule exocytosis is a contributor to immune cell recruitment and lung injury. Neutrophils were depleted beginning one day prior to, or one day after, infection of 8-10 month old C57BL/6 mice with a mouse-adapted SARS-CoV-2. In separate experiments neutrophil exocytosis was inhibited by administration of TAT-SNAP-23 beginning 1 to 3 days after infection. Lung tissue, BALF, and blood were obtained on day 5. SARS-CoV-2 pneumonia was associated with recruitment of mature and immature neutrophils, activated macrophages, and activated dendritic cells, but reduced anti-inflammatory macrophages. Mature neutrophil depletion prior to infection did not prevent lung injury or alter the changes in lung macrophages and dendritic cells. Depletion starting one day after infection significantly reduced lung injury and recruitment of macrophages and dendritic cells. A significant increase in immature neutrophils occurred with mature neutrophil depletion. Inhibition of neutrophil exocytosis significantly reduced lung injury and impaired recruitment of mature and immature neutrophils without altering macrophage or dendritic cell recruitment. We conclude that the presence or absence of mature neutrophils during the initial post-infection period altered myeloid cell recruitment and determined the pathway of acute lung injury. Neutrophil exocytosis is an important contributor to acute lung injury induced by SARS-CoV-2 and is a potential therapeutic target.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102690","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":"Functional and biochemical characterization of Alyftrek components reveals high-potency rescue of F508del-CFTR.","authors":"Sandra Mirval, Louise Damy, Auguste Sauvage-de-Gérando, Christine Barrault, Isabelle Fixe, Edouard Sage, Christelle Coraux, Benjamin Simonneau, Bénédicte Duriez, Pascale Fanen, Anne Cantereau, Clarisse Vandebrouck, Frédéric Becq","doi":"10.1152/ajplung.00103.2026","DOIUrl":"10.1152/ajplung.00103.2026","url":null,"abstract":"<p><p>Alyftrek (vanzacaftor/tezacaftor/deutivacaftor, VTD) is a triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy for patients with cystic fibrosis. In this study, we characterized the pharmacological properties of vanzacaftor and deutivacaftor using functional and biochemical assays in patient-derived primary human bronchial epithelial (HBE) cells (F508del/F508del, F508del/R1162X, F508del/W1282X) and in CFBE41o^- cells expressing F508del-CFTR. Cells were treated with Alyftrek components across a range of concentrations. The <i>S</i>- and <i>R</i>-enantiomers of vanzacaftor were evaluated separately, and the activity of deutivacaftor was compared with that of ivacaftor. CFTR function was assessed by short-circuit current measurements and whole cell patch-clamp recordings, whereas CFTR protein maturation was analyzed by Western blotting. Treatment with <i>S</i>-vanzacaftor alone restored F508del-CFTR-dependent chloride currents with an EC₅₀ of 130 nM, which decreased markedly to 8 nM when combined with tezacaftor. Substitution of ivacaftor with deutivacaftor in triple combinations (VTI vs. VTD) yielded comparable functional responses. Both VTD and VTI promoted the concentration-dependent appearance of the mature, fully glycosylated CFTR C-band with an EC₅₀ of 11 nM. The <i>R</i>-enantiomer of vanzacaftor was markedly less potent in rescuing F508del-CFTR and antagonized the effect of the <i>S</i>-enantiomer. Concentration-reduction experiments further showed that 10%-50% of the initial VTI/VTD concentrations were sufficient to achieve substantial F508del-CFTR rescue. Collectively, these findings demonstrate the high potency of <i>S</i>-vanzacaftor at nanomolar concentrations, both alone and in combination with tezacaftor. The potentiator deutivacaftor exhibited efficacy comparable to that of ivacaftor.<b>NEW & NOTEWORTHY</b> Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) was evaluated in cystic fibrosis (CF) airway models. <i>S</i>-vanzacaftor showed high potency, restoring F508del-CFTR function at nanomolar concentrations, enhanced by tezacaftor. Deutivacaftor matched ivacaftor efficacy in triple combinations. Both regimens improved CFTR maturation. The <i>R</i>-enantiomer was less effective and antagonistic. Notably, reduced doses retained substantial activity, supporting lower dosing strategies. These findings highlight <i>S</i>-vanzacaftor potency and validate deutivacaftor as an effective potentiator in CF therapy.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L345-L358"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787172","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":"Neutrophils and CSF1 promote the expansion of monocyte-derived alveolar macrophages in progressive pulmonary fibrosis.","authors":"Kazumasa Kase, Satoshi Watanabe, Masafumi Horie, Atsushi Muto, Kazuhiko Iwasaki, Kyota Akasaki, Takafumi Kobayashi, Sachiko Arai, Hayato Koba, Kenta Yamamura, Shigeki Nanjo, Yuichi Tambo, Noriyuki Ohkura, Miki Abo, Tomohiro Iba, Hitoshi Ando, Takashi Matsushita, Hisamichi Naito, Seiji Yano","doi":"10.1152/ajplung.00123.2026","DOIUrl":"https://doi.org/10.1152/ajplung.00123.2026","url":null,"abstract":"<p><p>Progressive pulmonary fibrosis (PPF) is a fatal lung condition characterized by persistent inflammation and progressive fibrotic remodeling. Monocyte-derived alveolar macrophages (Mo-AMs) are key drivers of fibrogenesis; however, the mechanisms underlying their persistence in fibrotic lungs remain unclear. Using lineage tracing and single-cell transcriptomics in a murine PPF model induced by continuous bleomycin infusion, we demonstrated the progressive accumulation of lineage-labeled Mo-AMs within fibrotic niches. Pharmacological depletion of monocytes and Mo-AMs attenuated fibrosis, underscoring their critical role in disease progression. Single-cell analysis identified a previously unrecognized <i>Csf1-expressing</i> neutrophil subpopulation. Functional experiments revealed that both neutrophil depletion and CSF1 neutralization significantly reduced the expansion of Mo-AMs, indicating that neutrophils and CSF1 signaling contribute to Mo-AM expansion during fibrotic progression. Consistent with these findings, bronchoalveolar lavage fluid from patients with pulmonary fibrosis contained elevated CSF1 levels, and <i>CSF1</i>-expressing neutrophils were detected within fibrotic lung regions. Together, these findings demonstrate that neutrophils and CSF1 signaling contribute to Mo-AM expansion during progressive pulmonary fibrosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102764","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":"MicroRNAs in IPF and lung cancer: convergent and divergent mechanisms: a systematic review.","authors":"Sara Gangi, Sofia Marrucci, Chiara Diana, Laura Bergantini, Paolo Cameli, Elena Bargagli","doi":"10.1152/ajplung.00119.2026","DOIUrl":"10.1152/ajplung.00119.2026","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) are distinct pathological entities; however, growing evidence indicates that they share convergent cellular and molecular mechanisms. As central posttranscriptional regulators, microRNAs (miRNAs) orchestrate critical pathogenetic processes including epithelial-mesenchymal transition (EMT), transforming growth factor-β (TGF-β) signaling, fibroblast activation, and extracellular matrix remodeling. Circulating miRNA signatures represent a promising class of minimally invasive biomarkers for early detection, risk stratification, and disease monitoring, whereas emerging therapeutic strategies based on miRNA mimics or inhibitors have shown encouraging results in preclinical models. Understanding the complex interplay of miRNAs at the interface between fibrogenesis and oncogenesis may facilitate the development of novel translational approaches, ultimately improving patient outcomes in both IPF and LC. Dysregulation of specific miRNAs has been implicated in both IPF and LC, some of which have concordant expression patterns, such as miR-21, miR-155, and miR-200, promoting fibrosis and tumor progression, and others exhibiting divergent roles, including miR-204 5-p and members of the miR-20a e miR-425, exerting opposing effects in fibrotic and neoplastic contexts. By systematically integrating mechanistic and regulatory evidence, this review provides a framework for understanding miRNA dysregulation in IPF and LC, with direct implications for biomarker validation and therapeutic targeting.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L375-L386"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720241","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":"Respiratory chemoreception across internal states.","authors":"Stephen B G Abbott, Jerry Hou, Harsha Thakkalapally, Kaleigh I West, Daniel S Stornetta","doi":"10.1152/ajplung.00174.2026","DOIUrl":"10.1152/ajplung.00174.2026","url":null,"abstract":"<p><p>The respiratory chemoreflexes help maintain arterial Pco₂ and Po₂ within a narrow range by adjusting lung ventilation. In any given moment, the sensitivity of the respiratory chemoreflexes to Pco₂ and Po₂ is influenced by internal state, a term that refers to how the brain processes incoming information. This review examines how interactions between neural mechanisms underpinning the respiratory chemoreflexes and internal state account for the respiratory response to exercise, acute psychological stress, pregnancy, and the sensation of air hunger. Together, these examples highlight internal state as a key determinant of homeostatic respiratory motor output and emphasize that the respiratory effects of hypercapnia and hypoxia cannot be understood independently of the state in which they occur.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L396-L405"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890568","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":"Alveolar epithelial glycocalyx degradation is associated with impaired lung mechanics, lung injury severity, and clinical outcomes in ARDS.","authors":"Avery M Bogart, Lisa Yun, Nancy E Wickersham, Anna Garcia, Ryan Kelley, Sarah Obeidalla, John R Francisco, Ivor Douglas, V Eric Kerchberger, Ciara M Shaver, Eric P Schmidt, Michael A Matthay, Julie A Bastarache, Lorraine B Ware, Alicia N Rizzo","doi":"10.1152/ajplung.00213.2026","DOIUrl":"https://doi.org/10.1152/ajplung.00213.2026","url":null,"abstract":"<p><p><b>Background:</b> The alveolar epithelial glycocalyx is a layer of glycosaminoglycans (GAGs) and proteoglycans (e.g., syndecan-1) that is located between the apical alveolar epithelium and the surfactant layer. It is degraded in murine models of lung injury and in patients with ARDS. Targeted degradation of the epithelial glycocalyx impairs surfactant function in mice. We sought to determine the relationship between epithelial glycocalyx degradation, pulmonary physiology, and clinical outcomes in patients with ARDS. <b>Methods:</b> We first analyzed the relationship between the concentration of syndecan-1 (a marker of glycocalyx shedding) in directly aspirated pulmonary edema fluid and both lung injury severity and patient outcomes in a retrospective cohort of patients with ARDS or hydrostatic pulmonary edema. Subsequently, we prospectively collected heat-moisture-exchange (HME) filter fluid, a noninvasive approach to distal airspace sampling, at two additional centers and determined the relationships between syndecan-1, respiratory mechanics, patient outcomes, and other established ARDS biomarkers. <b>Results:</b> Airspace fluid syndecan-1 was associated with impaired lung mechanics (static respiratory system compliance and driving pressure), more severe hypoxemia, prolonged mechanical ventilation, and increased mortality. Other airspace biomarkers of lung injury were not associated with lung mechanics. These findings were observed similarly across multiple cohorts, using either directly aspirated pulmonary edema fluid or noninvasively collected HME fluid. <b>Conclusions:</b> Airspace fluid syndecan-1 is associated with the severity of hypoxemia, impaired lung mechanics, and worse clinical outcomes in ARDS patients. These results support further research into therapeutics to restore the integrity of the epithelial glycocalyx in ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102677","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}