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

{"title":"Mathematical Representation of Lung Disease: The Frontier that Could Transform Treatment.","authors":"Jerome Cantor","doi":"10.1152/ajplung.90112.2026","DOIUrl":"https://doi.org/10.1152/ajplung.90112.2026","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317140","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":"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":"Early to midgestational 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":"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 with 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 day (GD)30 to GD90 (term 147 days). Offspring lungs were collected at GD120 (<i>n</i> = 6 or 7 per group) and at 24 mo of age (<i>n</i> = 4-6 per group) for histological and molecular analyses. Data were analyzed with two-way ANOVA (fetal) and/or sex-specific stratified <i>t</i> 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 midgestational T excess adversely reprograms the offspring's lungs in a sex-specific manner, from fetal life extending into adulthood.<b>NEW & NOTEWORTHY</b> Early to midgestational testosterone (T) excess adversely programs lung development in a sex-specific manner, with effects extending from fetal life into adulthood. Fetal lung transcriptomics reveal distinct sex-specific molecular responses to prenatal T exposure. Together, these findings suggest that prenatal androgen excess may represent a developmental mechanism linking fetal lung programming to persistent pulmonary remodeling in adulthood.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L565-L584"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","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":"Correction for Soni et al., volume 320, 2020, p. L73-L83.","authors":"","doi":"10.1152/ajplung.00099.2020_COR","DOIUrl":"https://doi.org/10.1152/ajplung.00099.2020_COR","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"331 5","pages":"L585"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293859","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":"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</i>-expressing neutrophil subpopulation. Functional experiments revealed that both neutrophil depletion and colony-stimulating factor 1 (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 PPF.<b>NEW & NOTEWORTHY</b> We show that neutrophils and colony-stimulating factor 1 (CSF1) signaling promote the expansion of monocyte-derived alveolar macrophages in progressive pulmonary fibrosis. We identify a distinct <i>Csf1</i>-expressing neutrophil subpopulation in a progressive pulmonary fibrosis model, suggesting that neutrophil-derived CSF1 may represent one potential mechanism contributing to macrophage expansion. These findings provide new mechanistic insight into how persistent macrophage accumulation contributes to progressive fibrotic remodeling.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L487-L502"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","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":"Dynamics of airway macrophage responses and lung function changes after ozone exposure in humans.","authors":"Jared Radbel, Emily R Stevenson, Raymond C Rancourt, Kathleen G Black, Adriana De Resende, Derek Ge, Aesha Jobanputra, Jessica Cervelli, Jeffrey D Laskin, Howard M Kipen, Andrew J Gow, Debra L Laskin","doi":"10.1152/ajplung.00120.2026","DOIUrl":"10.1152/ajplung.00120.2026","url":null,"abstract":"<p><p>Ozone is a ubiquitous ambient air pollutant known to cause lung injury and exacerbate pulmonary disease. Although rodent studies suggest that macrophages contribute to both ozone-induced lung injury and subsequent repair, their specific roles in humans remain unclear. We hypothesized that recovery from ozone-induced lung injury in humans depends on a dynamic balance between macrophage subsets. To test this hypothesis, 44 healthy male and female adults (18-40 yr old) were enrolled in a randomized, single-blind crossover study involving paired 3-h exposures to ozone (0.2 ppm) and filtered air. Participants were evaluated 24, 48, or 72 h after each exposure, at which time induced sputum was collected for myeloid cell analysis. Pulmonary function testing was performed before and immediately after each exposure and repeated at the follow-up visit. Compared with filtered air, ozone exposure resulted in a significant increase in the percentage of monocytes at 24 h and monocyte-derived macrophages at 24-72 h, whereas neutrophil percentages decreased at 48-72 h. Immediately after ozone exposure, participants showed significant reductions in FEV₁, FVC, and the FEV₁/FVC ratio, along with increases in distal airway resistance measures (R5 and R10). These functional impairments were not evident at 24-72 h. Improvements in large airway lung function from 24 to 72 h post-ozone exposure correlated with a higher airway monocyte-derived macrophage-to-neutrophil ratio, whereas improvement in R5 was associated with a higher monocyte-derived macrophage-to-monocyte ratio. These findings provide new insight into the temporal sequence of human airway macrophage responses following ozone-induced lung injury and highlight coordinated macrophage dynamics that may contribute to recovery.<b>NEW & NOTEWORTHY</b> Macrophage involvement in the human response to ozone remains poorly defined. In this human crossover exposure study, we characterized ozone-induced changes in airway macrophage populations at 24, 48, and 72 h post-exposure. Ozone exposure caused immediate declines in pulmonary function, which improved 24-72 h later; recovery was associated with increases in airway monocyte-derived macrophage-to-neutrophil and monocyte-derived macrophage-to-monocyte ratios. These findings highlight coordinated, time-related macrophage dynamics that may contribute to recovery from ozone-induced lung injury.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L474-L486"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13718308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057008","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":"Adenoviral-mediated SIRT1 expression restores lung architecture and reduces fibrotic progression in experimental models.","authors":"Liliana Faridi Saavedra-Salazar, Nayabei Ruiz-Ramirez, Hugo Christian Monroy-Ramírez, Ana Sandoval-Rodríguez, Víctor Ruiz, Marina Galicia-Moreno, Blanca Estela Bastidas-Ramírez, Jorge Gutiérrez-Cuevas, Luis Felipe Jave-Suarez, Juan Armendariz-Borunda, Jesús García-Bañuelos","doi":"10.1152/ajplung.00111.2026","DOIUrl":"10.1152/ajplung.00111.2026","url":null,"abstract":"<p><p>Pulmonary fibrosis (PF) involves remodeling of lung architecture, and limited therapeutic options are available. Sirtuin 1 (SIRT1), an epigenetic regulator, has emerged as a promising antifibrotic target due to its role in apoptosis, inflammation, and chromatin remodeling. We evaluated the effects of a recombinant adenovirus expressing human SIRT1 (Ad-SIRT1) both in vitro and in vivo. Human alveolar epithelial cells (A549) were transduced with Ad-SIRT1 or Ad-green fluorescent protein (Ad-GFP) and subjected to bleomycin (BLM)-induced injury. Transduction efficiency, cell viability (MTT assay), SIRT1 localization (immunofluorescence), and expression of acetylated p53 and histone H3K9 (Western blot) were assessed. Pharmacological modulation of SIRT1 was also tested using the activator SRT1720 and the inhibitor EX527. For the in vivo experiments, mice with bleomycin-induced PF received intratracheal Ad-SIRT1 on <i>day 15</i> after injury. Histological, immunohistochemical, and molecular analyses were performed on <i>day 21</i>. Ad-SIRT1-transduced A549 cells showed increased nuclear SIRT1 overexpression that restored viability of bleomycin-injured cells and reduced p53 and H3K9 acetylation, consistent with a protective deacetylating effect. These changes mirrored those obtained with SRT1720 and were reversed by EX527 treatment. In vivo, Ad-SIRT1 attenuated collagen deposition, reduced α-smooth muscle actin (α-SMA) expression, and decreased p53 and H3K9 acetylation. The histological scores were significantly improved compared with those of the fibrotic control group. Adenoviral SIRT1 gene delivery exerts protective effects on the alveolar epithelium in vitro and reverses established PF in vivo through epigenetic regulation of key profibrotic pathways. This dual approach highlights the translational potential of SIRT1 as a therapeutic target for PF.<b>NEW & NOTEWORTHY</b> This study demonstrates that by epigenetically modifying p53 and histone H3K9 acetylation, adenoviral Sirtuin 1 (SIRT1) gene delivery reverses established pulmonary fibrosis and restores epithelial cell viability. Unlike previous techniques that relied on pharmacological activation, our results support the translational potential of SIRT1 as a therapeutic intervention for pulmonary fibrosis by establishing its overexpression as a gene-based antifibrotic strategy.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L438-L454"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966101","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":"10.1152/ajplung.00213.2026","url":null,"abstract":"<p><p>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 acute respiratory distress syndrome (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. 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. 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. Airspace fluid syndecan-1 is associated with the severity of hypoxemia, impaired lung mechanics, and worse clinical outcomes in patients with ARDS. These results support further research into therapeutics to restore the integrity of the epithelial glycocalyx in ARDS.<b>NEW & NOTEWORTHY</b> We demonstrate that airspace fluid syndecan-1, a marker of alveolar epithelial glycocalyx degradation, is associated with impaired lung mechanics, severe hypoxemia, prolonged mechanical ventilation, and increased mortality in patients with ARDS. Other airspace biomarkers of lung injury, Ang2, receptor for glycation end products (RAGE), IL6, and IgM, were not associated with lung mechanics.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L556-L564"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","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}

{"title":"Hypoxic intensity reveals distinct carotid body O₂-sensing mechanisms.","authors":"Nanduri R Prabhakar, Ying-Jie Peng","doi":"10.1152/ajplung.90003.2026","DOIUrl":"10.1152/ajplung.90003.2026","url":null,"abstract":"<p><p>Carotid bodies (CBs) sense arterial blood O₂ levels. Hypoxemia activates the carotid sinus nerve (CSN) afferent activity to elicit cardiorespiratory reflexes to maintain tissue oxygenation. This brief review presents emerging evidence suggesting that CBs use distinct O₂-sensing mechanisms depending on the severity of hypoxia. During physiologically relevant moderate hypoxia (Po₂ ∼40 mmHg), glomus cells use the heme oxygenase-2 (HO-2)/carbon monoxide (CO)/cystathionine-γ-lyase (CSE)/hydrogen sulfide (H₂S) signaling to stimulate CSN activity and the breathing response to hypoxia. Basal CO restrains CSN activity during normoxia, whereas hypoxia reduces CO and stimulates CSN activity through H₂S. Olfactory receptor 78 (Olfr78) is required for H₂S-mediated CSN activation. CO-H₂S pathway contributes to cardiorespiratory adaptations to sustained hypoxia and to the pathophysiology of diseases characterized by carotid body (CB) hyperactivity. In contrast, glomus cells respond to severe hypoxia (Po₂ ∼5-15 mmHg) through mitochondrial complex I (NDUFS2) and complex III. Thus, CBs appear to use severity-dependent hypoxic sensing mechanisms, wherein moderate hypoxia engages the CO-H₂S pathway to activate CSN activity and drive homeostatic cardiorespiratory responses. Severe hypoxia primarily alters mitochondrial function and glomus cell metabolism. The physiological relevance of severe hypoxia remains uncertain, because severe low O₂ levels suppress both CB and CSN activity and ventilation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L522-L529"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102703","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":"Multiomics analysis of glucocorticoid receptor cross talk with type I and type II inflammatory signaling in human airway smooth muscle cells.","authors":"Sarah K Sasse, Vineela Kadiyala, Min Chen, Michael R Weaver, Shelly C McCain, Arnav Gupta, Reynold A Panettieri, Anthony N Gerber","doi":"10.1152/ajplung.00281.2025","DOIUrl":"10.1152/ajplung.00281.2025","url":null,"abstract":"<p><p>Airway smooth muscle (ASM) dysfunction in obstructive airway disease is treated with glucocorticoids. Through RNA-sequencing (RNA-seq) analysis of cultured human ASM, we identified repressive effects of dexamethasone (dex), a glucocorticoid, on the baseline expression of a subset of genes that are induced by either IL1B or IL13, which model type I and type II inflammation, respectively. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of glucocorticoid receptor (GR) and the p65 subunit of NF-κB occupancy indicated that canonical motifs for both factors occur at sites of p65 occupancy but did not provide biochemical support for significant repressive tethering between GR and p65. Instead, an assay for transposase-accessible chromatin sequencing (ATAC-seq) revealed significant chromatin remodeling and increased accessibility at binding motifs for the NF-κB complex in association with dex + IL1B cotreatment in comparison to IL1B treatment alone. Our data support a competition-based primary repressive effect of glucocorticoids on both IL1B and IL13 signaling and provide evidence for transcriptional cooperation between GR and NF-κB on a genome-wide basis in ASM, including at regulatory elements that control expression of anti-inflammatory genes.<b>NEW & NOTEWORTHY</b> Airway smooth muscle is clinically targeted by glucocorticoids in asthma. Our study is the first to provide molecular data indicating that transrepression is not a major mechanism of glucocorticoid action in this critical cell type. Instead, we implicate increased epigenetic access at NF-κB motifs as contributing to cooperation between glucocorticoids and inflammatory signals in controlling the expression of anti-inflammatory genes.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L455-L473"},"PeriodicalIF":3.8,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928716","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}