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

{"title":"The emerging role of integrin signaling in pulmonary vascular disease.","authors":"Annika S Bai, Grith Lykke Sørensen, Aparna B Sundaram, Wenhan Chang, Rubin M Tuder, Brian B Graham, Michael H Lee","doi":"10.1152/ajplung.00387.2025","DOIUrl":"10.1152/ajplung.00387.2025","url":null,"abstract":"<p><p>Integrin signaling promotes cellular proliferation, inflammation, and fibrosis in various forms of lung diseases, including pulmonary fibrosis, asthma, and acute respiratory distress syndrome. Recent studies suggest the promising role of integrins in the pathogenesis of pulmonary arterial hypertension, a morbid and incurable disease. In this review, we explore the biologic basis of integrins in potentiating pulmonary vascular disease and their candidacy as treatment targets. Specifically, we explore integrin-derived effects implicated in the pathobiology of pulmonary vascular disease, such as transforming growth factor-β activation, neointima formation, and inflammatory cell recruitment. We discuss intracellular pathways involving cytoplasmic kinases and matrisomal integrin ligands that are studied in the specific context of pulmonary vascular disease, focusing on recent therapeutic animal studies targeting integrin biology. Finally, we summarize unanswered knowledge gaps in the pursuit of therapeutic translation of integrin modulation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L476-L486"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13361853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479418","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":"Mitochondrial acid-sensing ion channel 1a deficiency induces mitochondrial dysfunction in pulmonary arterial smooth muscle cells.","authors":"Megan N Tuineau, Lindsay M Herbert, Heaven E Medina, Jay S Naik, Thomas C Resta, Nikki L Jernigan","doi":"10.1152/ajplung.00324.2025","DOIUrl":"10.1152/ajplung.00324.2025","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a progressive vascular disease driven by pulmonary arterial remodeling, characterized by cellular hyperproliferation, resistance to apoptosis, and phenotypic plasticity. Our laboratory has shown that the proton-gated cation channel, acid-sensing ion channel 1a (ASIC1a), is essential for the development of chronic hypoxia (CH)-induced PH in rodents. Importantly, ASIC1a activation occurs without changes in total ASIC1a levels but reflects a hypoxia-dependent redistribution to the plasma membrane in pulmonary arterial smooth muscle cells (PASMCs). In neurons, mitochondrial-localized ASIC1a (mtASIC1a) contributes to oxidative stress-induced mitochondrial membrane potential (ΔΨm) depolarization and apoptosis. Although mtASIC1a has not been described in vascular cells, its role in PASMCs may be relevant to mitochondrial dysfunction and apoptosis resistance in PH. We hypothesize that mtASIC1a is a crucial regulator of PASMC mitochondrial homeostasis, and its loss following CH promotes mitochondrial dysfunction and apoptosis resistance. Consistent with this, mtASIC1a localization was decreased in PASMCs and intrapulmonary arteries from CH rats compared with controls. Functionally, PASMCs from CH rats or <i>Asic1a</i> knockout mice exhibited ΔΨm hyperpolarization, elevated mitochondrial Ca²⁺ and superoxide, impaired mitophagy, and reduced cleaved caspase-3. Transmission electron microscopy revealed mitochondrial morphological changes, including increased size and circularity, decreased aspect ratio, and reduced mitochondrial number per cell, whereas fusion/fission proteins remained largely unchanged. Lentiviral restoration of mtASIC1a prevented ΔΨm hyperpolarization and restored caspase-3 cleavage. These findings identify mtASIC1a as a novel regulator of mitochondrial function in PASMCs, where its loss following CH promotes ΔΨm hyperpolarization, impaired mitophagy, and resistance to apoptosis.<b>NEW & NOTEWORTHY</b> This study identifies mitochondrial acid-sensing ion channel 1a (mtASIC1a) as a novel regulator of mitochondrial homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Critically, mtASIC1a deficiency in PASMCs following in vivo chronic hypoxia or genetic deletion promotes mitochondrial membrane potential (ΔΨm) hyperpolarization, Ca²⁺ and superoxide (O₂^-) accumulation, impaired mitophagy, and caspase inhibition. Restoring mtASIC1a by lentiviral transduction prevents ΔΨm hyperpolarization and restores caspase cleavage, highlighting its importance in mitochondrial signaling and hypoxic pulmonary hypertension pathophysiology.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L390-L403"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13074392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300826","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":"Ovarian hormones and obesity drive Th17-mediated airway inflammation through estrogen receptor-α signaling.","authors":"Emely Henriquez Pilier, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, Elie Tannous, Alessandra Tomasello, Kaitlin E McKernan, R Stokes Peebles, Katherine N Cahill, Jeffrey C Rathmell, Dawn C Newcomb","doi":"10.1152/ajplung.00400.2025","DOIUrl":"10.1152/ajplung.00400.2025","url":null,"abstract":"<p><p>Obesity is a risk factor for increased prevalence and severity of asthma, particularly in females. As adults, females have an increased prevalence of asthma compared with males. Yet, the mechanisms remain unclear on how sex hormones and obesity increase airway inflammation. We hypothesize that estrogen signaling through estrogen receptor-alpha (ER-α) in T cells increased airway inflammation in the context of obesity. To test our hypothesis, we utilized a high-fat diet on female and male mice that underwent ovariectomy or gonadectomy or in <i>Esr1</i>^fl/fl <i>X Cd4</i>^Cre+ male and female mice. As controls, mice in similar groups were fed normal chow. After 8-12 wk on diets, house dust mite sensitization and challenge occurred in all mice. Lungs and bronchoalveolar lavage fluid were harvested 24 h after the last challenge. Ovarian hormones and ER-α signaling in T cells increased eosinophils, neutrophils, and Th17-mediated airway inflammation in the lungs of obese female mice. In addition, using peripheral blood mononuclear cells (PBMCs) from a well-characterized cohort of asthmatic participants, we determined that women with asthma and obesity had increased Th17 cells compared with men with asthma and obesity. Our results show that ER-α signaling in T cells increases Th17-mediated airway inflammation in obese mice and that Th17 cells circulate at higher frequencies in women with asthma compared with men with asthma. Further research into the interplay between hormonal signaling and immune responses in asthma is essential for developing personalized treatments.<b>NEW & NOTEWORTHY</b> Estrogen receptor-alpha (ER-α) signaling increased obesity and allergen-induced airway inflammation in mice. In addition, women with obesity and asthma had increased circulating Th17 cells compared with men with obesity and asthma. These findings provide mechanistic insights into the intersection of obesity, sex hormones, and airway inflammation-underscoring the importance of personalized approaches to managing individuals with obesity and asthma.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L267-L273"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13023106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177349","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":"A fatal connection: TGF-β signaling and CFTR dysfunction as interlinked drivers of chronic lung inflammation and disease.","authors":"Lasti Erfinanda, Wolfgang M Kuebler","doi":"10.1152/ajplung.00370.2025","DOIUrl":"10.1152/ajplung.00370.2025","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L431-L433"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430205","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":"Mechanical compression causes lung hypoplasia in congenital diaphragmatic hernia with GATA4 genetic variants.","authors":"Betty Pham, Zhuowei Li, Gidsela Luna, Nicole Talaba, Na Zhang, Giangela M Stokes, Mark Wienhold, Jinhao Xu, Yujuan Su, Rebecca Hernan, Wendy K Chung, Xin Sun, David J McCulley","doi":"10.1152/ajplung.00203.2025","DOIUrl":"10.1152/ajplung.00203.2025","url":null,"abstract":"<p><p>Congenital diaphragmatic hernia (CDH) is a common and severe structural malformation in which the high rate of morbidity and mortality is caused by lung hypoplasia and pulmonary hypertension. The severity of lung and pulmonary vascular defects in patients with CDH is heterogeneous with both intrinsic defects during development and mechanical compression playing important roles. Genetic variants have been identified in 30% of CDH patients and are associated with increased morbidity and mortality, but it is unclear how these variants impact lung and pulmonary vascular defect severity. Deletions of 8p23.1 account for 3-5% of cases and encompass <i>GATA4</i>, a transcription factor that directs gene expression throughout the developing embryo. CDH patients with GATA4 haploinsufficiency have high mortality, severe lung hypoplasia, and pulmonary hypertension. Given this information, our aim was to characterize the role of GATA4 during lung and pulmonary vascular development. We generated mice with lung-specific deletion of <i>Gata4</i> and found that GATA4 is not required during lung or pulmonary vascular development. However, mice with diaphragm-specific inactivation of <i>Gata4</i> die after birth with abnormal diaphragm formation and lung hypoplasia. Mechanical compression of the embryonic lungs was associated with abnormal gene expression and increased phosphorylation of mechanosensory protein YAP1 resulting in decreased cell cycling. Our data suggest that the lung and pulmonary vascular phenotype of patients with CDH and GATA4 haploinsufficiency is due to mechanical compression. Strategies that promote lung growth before delivery such as fetal tracheal occlusion may be beneficial in these patients.<b>NEW & NOTEWORTHY</b> Congenital diaphragmatic hernia (CDH) is a common and severe malformation associated with abnormal lung and pulmonary vascular development. This study investigates <i>GATA4</i> haploinsufficiency, a common CDH-associated variant linked to higher morbidity and mortality. We establish mechanical compression as the mechanism leading to abnormal lung and pulmonary vascular development, which differs from other CDH-associated variants. Findings support using patient genotype to identify those most likely to benefit from fetal procedures that improve lung growth and survival.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L457-L475"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353421","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":"Coal dust complexes host cell iron to impact metal homeostasis and pneumoconiosis.","authors":"Andrew J Ghio, Joleen M Soukup, Lisa A Dailey, Rahul G Sangani, Elizabeth N Pavlisko, Victor L Roggli","doi":"10.1152/ajplung.00156.2025","DOIUrl":"10.1152/ajplung.00156.2025","url":null,"abstract":"<p><p>Surface complexation of cell iron following particle exposure can be relevant to coal mine dust lung disease. We tested the postulate that <i>1</i>) coal dust and humic substances (HS), a specific component of coal, complex intracellular iron from cultured cells to initiate a functional metal deficiency, <i>2</i>) the functional cell iron deficiency that results after exposure to coal dust and HS impacts an increased release of both superoxide-related products and proinflammatory mediators, and <i>3</i>) the disruption in iron homeostasis after coal dust exposure is associated with pneumoconiosis in miners. Cell exposures to coal dust and HS initiated a functional iron deficiency, reflected by elevated expression of an importer (divalent metal transporter-1), which increased metal uptake measured as cell nonheme concentrations. Cell exposure to coal dust and HS increased <i>1</i>) the generation of superoxide, measured using nitro blue tetrazolium reduction and an Amplex Red assay, and <i>2</i>) the release of interleukin (IL)-6 and IL-8. These measures of oxidative stress and inflammatory mediator release were diminished with co-exposure to iron, supporting a relationship of both with a functional cell deficiency of the metal. Using a cohort of retired miners, blood ferritin levels were elevated in those diagnosed with a positive B read for coal workers' pneumoconiosis. Elevated blood ferritin concentrations correlated with progression of disease on B reads obtained 1 year later in the miners. It is concluded that coal dust and HS can initiate a disruption of iron homeostasis associated with superoxide generation, release of proinflammatory cytokines, and pneumoconiosis.<b>NEW & NOTEWORTHY</b> Following its inhalation, coal dust disrupts the homeostasis of iron in lung cells to decrease availability. This occurs through a complexation, or binding, of the cell's required iron by the coal dust. The decreased iron concentrations available to the cell initiate inflammatory and fibrotic lung injuries, with the latter recognized as coal workers' pneumoconiosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L434-L445"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257096","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":"Decreased AMP-kinase function in pulmonary artery smooth muscle cells contributes to pulmonary artery remodeling in persistent pulmonary hypertension of the newborn.","authors":"Emily A Mooers, Ujala Rana, Chintamani N Joshi, Adeleye J Afolayan, Ru-Jeng Teng, Girija G Konduri","doi":"10.1152/ajplung.00229.2025","DOIUrl":"10.1152/ajplung.00229.2025","url":null,"abstract":"<p><p>Pulmonary vascular remodeling contributes to persistent pulmonary hypertension of the newborn (PPHN); the mechanisms remain unknown. 5'-AMP-activated protein kinase (AMPK) is a critical regulator of energy balance and metabolism. We investigated the hypothesis that decreased AMPK function in pulmonary artery smooth muscle cells (PASMCs) leads to impaired mitochondrial capacity to perform oxidative phosphorylation and altered notch ligand expression, which together promote vascular remodeling in PPHN. Studies were performed in fetal lambs with PPHN induced by prenatal ductus arteriosus constriction and gestation-matched controls. For in vitro studies, PPHN PASMCs were treated with AMPK agonists, A769662 or metformin, and compared with untreated control and PPHN PASMCs. Expression of phosphorylated-AMPK (p-AMPK) and its downstream mediators, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial electron transport chain (ETC) complexes, differentiation markers, and notch ligands were assessed using immunoblotting in control and PPHN PASMCs. For in vivo studies, PPHN lambs were treated with metformin and were compared with untreated control and PPHN lambs. Lung sections from in vivo experiments were evaluated through immunofluorescence. Compared with controls, p-AMPK, PGC-1α, and ETC complexes were decreased in PPHN PASMCs and lung sections. PASMC differentiation marker, myosin heavy chain 11, was reduced in PPHN lung sections, whereas dedifferentiation marker, vimentin, was increased. Expression of Jag1 and Hey1 in Notch pathway was reduced in PPHN PASMCs and lung sections. A769662 and metformin increased the expression of PGC-1α, ETC complexes I and IV, Jag1, and Hey1 in PPHN PASMCs. Decreased AMPK function contributes to reduced mitochondrial oxidative phosphorylation capacity, less differentiated PASMCs, and imbalanced notch signaling, promoting remodeling in PPHN.<b>NEW & NOTEWORTHY</b> Our study reveals a novel mechanism for pulmonary vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN). We identify a decrease in the function of a key energy sensor, AMPK, as contributing to pulmonary vascular remodeling through decreased mitochondrial oxidative phosphorylation capacity, altered differentiation marker expression, and notch ligand imbalance. Our studies may provide translational significance as restoring AMPK function offers a new therapeutic target in PPHN to improve postnatal transition in PPHN.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L404-L415"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147289111","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":"Optimized primary organotypic culture from murine neonatal tracheal airway epithelial cells.","authors":"Yan Han, Rewa Kulkarni, Stephan Pribitzer, Steven F Ziegler, Jason S Debley, Laurie C Eldredge","doi":"10.1152/ajplung.00250.2025","DOIUrl":"10.1152/ajplung.00250.2025","url":null,"abstract":"<p><p>Neonatal airway development and injury are poorly understood, in part due to challenges of studying extremes of phenotype in human pathological samples and difficulties obtaining relevant comparator samples. Ex vivo model systems are needed to improve understanding of airway development, injury, and repair in the neonatal lung. We optimized a protocol for organotypic culture of primary murine neonatal tracheal epithelial cells (MNTECs). We compared expansion and differentiation properties of MNTECs in five different media conditions, ranging from previously published \"lab-made\" media to commercial sources of media. We measured the success of our organotypic cultures by quantifying the relative proportions of ciliated epithelium, TP63+ basal stem cells, and stromal cell contamination, as well as total cell numbers and air-liquid interface (ALI) thickness. Commercially available media performed better than standard lab-made media, with nearly 100% success and 20% success, respectively. Proliferation in commercial media improves expansion of TP63+ basal cells, inhibits growth of contaminating stromal cells, and improves differentiation to a polarized, ciliated pseudostratified airway epithelium, when compared with lab-made LP media. These results provide a reliable technique for studying neonatal airway epithelial cells in wild-type and genetically mutant mice.<b>NEW & NOTEWORTHY</b> In this study, we optimized murine neonatal tracheal epithelial cell (MNTEC) growth and differentiation for mechanistic studies of disrupted airway epithelial cell development, injury, and repair. Our protocol removes significant complexity and historical variability of murine air-liquid interface (ALI) cultures and is specifically designed for neonatal airway epithelial cell cultures with limited cell numbers. We also compared the transcriptomes of well-differentiated and poorly differentiated organotypic airway epithelial cultures to identify key genes for epithelial growth and polarization.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L368-L378"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130710","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":"Single-cell transcriptomics reveal alveolar macrophage-specific responses in single-hit ozone exposure model in mice.","authors":"Thao Vo, Ishita Choudhary, Sonika Patial, Yogesh Saini","doi":"10.1152/ajplung.00235.2025","DOIUrl":"10.1152/ajplung.00235.2025","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Alveolar macrophages (AMs), a highly plastic immune cell population, are among the first responders to inhaled ozone (O&lt;sub&gt;3&lt;/sub&gt;) and ozonated products in the lung airspaces. However, a comprehensive understanding of how AMs respond to O&lt;sub&gt;3&lt;/sub&gt;, particularly across different exposure concentrations, remains incomplete. To address this knowledge gap, we exposed adult male C57BL/6J mice to filtered air (FA), 1 ppm O&lt;sub&gt;3&lt;/sub&gt;, or 1.5 ppm O&lt;sub&gt;3&lt;/sub&gt; for 3 h. Mice were euthanized 22-24 h after the end of exposure, and experiments were conducted to assess cellular recruitment, inflammatory mediator analyses, and gene expression alterations. Compared with FA-exposed mice, O&lt;sub&gt;3&lt;/sub&gt;-exposed mice exhibited increased recruitment of AMs and neutrophils into the lung airspaces, consistent with elevated levels of the macrophage- and neutrophil-specific chemokines, i.e., monocyte chemotactic protein 3 (MCP-3), MCP-5, and macrophage inflammatory protein 2. To delineate the transcriptomic landscape of AMs following O&lt;sub&gt;3&lt;/sub&gt; exposure and determine how these alterations relate to AM heterogeneity and functional states, we subjected AMs to single-cell RNA sequencing analyses. Differentially expressed gene (DEG) analysis of the AM population revealed significant transcriptional changes in both the 1-ppm and 1.5-ppm O&lt;sub&gt;3&lt;/sub&gt;-exposed groups. Compared with AMs from the FA-exposed group, AMs from both O&lt;sub&gt;3&lt;/sub&gt;-exposed groups exhibited enrichment of pathways such as oxidative phosphorylation, eIF2 signaling, and noncanonical NF-κB signaling. Furthermore, AMs from 1-ppm O&lt;sub&gt;3&lt;/sub&gt;-exposed mice exhibited enrichment of the IL-10 signaling pathway, whereas AMs from 1.5-ppm O&lt;sub&gt;3&lt;/sub&gt;-exposed mice were uniquely enriched for DNA damage bypass and repair pathways. Interestingly, uniform manifold approximation and projection analysis of annotated AMs in three experimental groups identified five distinct subclusters. DEGs and ingenuity pathway analyses of these subclusters revealed O&lt;sub&gt;3&lt;/sub&gt; concentration-dependent enrichment of pathways associated with protein translation, cholesterol biosynthesis, and mitochondrial biogenesis. Further analyses revealed that exposure to different concentrations of O&lt;sub&gt;3&lt;/sub&gt; results in cluster-specific alterations in the expression of gene signatures associated with macrophage activation. In addition, AMs from 1.5-ppm O&lt;sub&gt;3&lt;/sub&gt;-exposed mice displayed increased expression of proliferation-associated gene signatures. Taken together, these findings identify O&lt;sub&gt;3&lt;/sub&gt; concentration-dependent transcriptomic alterations in AMs and associated functional modulations at single-cell resolution.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; This study addresses a critical knowledge gap regarding the response of alveolar macrophages to ozone, a potent inhaled toxicant. Specifically, we demonstrate that a single exposure to two experimentally relevant concentrations of ozone significantly alters functionally relevant gene","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L318-L343"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888586","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":"Contact-compression induces inflammatory and remodeling responses in bronchial epithelial cells.","authors":"Akash Gupta, Janette K Burgess, Theo Borghuis, Dirk-Jan Slebos, Simon D Pouwels","doi":"10.1152/ajplung.00247.2025","DOIUrl":"10.1152/ajplung.00247.2025","url":null,"abstract":"<p><p>Lung implantable devices, such as stents and valves, are used as treatment for lung cancer and chronic obstructive pulmonary disease (COPD). They apply continuous compressive stress to airway tissue, potentially triggering adverse effects such as chronic inflammation, granulation tissue hyperplasia, and fibrosis at the implant site. To identify the biological responses underlying this process, we developed an in vitro contact-compression model that applies variable compressive stress to bronchial epithelial cells. Confluent layers of bronchial epithelial cells (16HBE) were subjected to compressive stress using agarose-embedded weights (3, 6, 9, and 15 g). After 24 h, cell viability, inflammation, fibrosis, and mechano-transduction were assessed using cell viability assays, quantitative real-time PCR, ELISA, and immunofluorescent staining. Maximum compressive stress (15 g) led to reduced cell viability. Compression increased the expression of inflammation, <i>CXCL8</i>, <i>TNF</i>, <i>IL1α, GM-CSF,</i> and remodeling-related genes, <i>EGR1</i>, <i>TNC</i>, <i>COL1A1</i>, and <i>CTGF,</i> whereas no changes in <i>TGFB1</i>, <i>TNC</i>, and <i>FN1</i> expression were observed. These changes were reflected in protein levels with increased CXCL8, IL-1α, and connective tissue growth factor (CTGF) in supernatant upon compression. Compressed cells showed increased actin polymerization, mechanoreceptor relocalization, and Yes-associated protein (YAP) nuclear translocation, reflecting a mechanotransducive response. We developed a viable in vitro model to study contact-compression, showing biomechanical inflammatory and remodeling responses. With adjustable components, this model can be applied to further study tissue responses to lung implants.<b>NEW & NOTEWORTHY</b> Our research introduces a novel in vitro model to study how contact-compressive stress drives pathological wound-healing responses in bronchial epithelial cells. By linking mechanical loading to mechanosensory-redistribution, cytoskeletal remodeling, and both pro-inflammatory (<i>CXCL8</i>, <i>IL6, IL1A</i>, and <i>GM-CSF</i>) and profibrotic gene expression (<i>CTGF, COL1A1,</i> and <i>EGR1</i>), this work provides critical insights into the cellular mechanisms underlying lung implant-associated complications and offers a platform for future biomaterial and device testing.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L304-L317"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083946","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}