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

{"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}

{"title":"Obese adipocytes induce fibroblast-to-myofibroblast transition through TGF-β1 signaling: implications in asthma pathogenesis.","authors":"Nour Jalaleddine, Mahmood Hachim, Alexander Giddey, Mellissa Gaudet, Qutayba Hamid, Mohammed Uddin, Saba Al Heialy","doi":"10.1152/ajplung.00208.2025","DOIUrl":"10.1152/ajplung.00208.2025","url":null,"abstract":"<p><p>Obesity, a key risk factor for severe asthma, is associated with worsening symptoms and poor responses to conventional therapies. Recent studies have highlighted the presence of adipocytes within airway walls, which correlates positively with body mass index (BMI). However, the role of adipocytes in asthma pathogenesis remains largely unknown. This study aims to explore their potential contribution to airway fibrosis, a progressive form of the disease, through fibroblast-to-myofibroblast transition (FMT). In vitro coculture models were developed to investigate the interactions between adipocytes (derived from patients with and without obesity) and fibroblasts (from patients with and without asthma) on FMT. Proteomic and multiplex analyses were used to identify potential mediators of adipocyte-induced FMT. Our data revealed a significant increase in fibrogenic markers, such as alpha-smooth muscle actin and vimentin, in fibroblasts cocultured with obese (Ob) adipocytes. Notably, this transition was more pronounced in asthmatic fibroblasts compared with healthy fibroblasts. Proteomic profiling of cocultured Ob-adipocytes and asthmatic fibroblasts identified several significantly upregulated proteins linked to the regulation of the transforming growth factor-beta (TGF-β) signaling pathway, including inhibin A, latent TGF-β binding protein 1, thrombospondin 1, and follistatin. The role of TGF-β was further substantiated by multiplex assays, which demonstrated a significant increase in TGF-β and leptin production by Ob-adipocytes following coculture. These findings suggest that Ob-adipocytes may promote FMT in fibroblasts, especially asthmatic fibroblasts, by activating the TGF-β signaling pathway. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.<b>NEW & NOTEWORTHY</b> Adipocytes have been found in the airway wall of patients with obesity. This study is the first to show that adipocytes derived from patients with obesity can induce features of airway remodeling that is seen in patients with asthma such as fibroblast-to-myofibroblast transition via the TGF-beta signaling pathway in an indirect mode of cellular communication. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L419-L430"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257021","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":"MicroRNA-enriched EVs from mesenchymal stromal cells: a novel approach to suppress biofilm and inflammation in CF airway epithelium.","authors":"Anushka Raghubansi, Catherine M Greene","doi":"10.1152/ajplung.00353.2025","DOIUrl":"10.1152/ajplung.00353.2025","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L416-L418"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257099","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":"Receptor agonist of NFκB signaling ligand directs lung epithelial cell expansion through RANK signaling.","authors":"Habibie Habibie, Jelmer R Vlasma, Kurnia S S Putri, Shanshan Song, Marina H de Jager, Arjen Petersen, Carian E Boorsma, Robbert H Cool, Wim Quax, Martijn C Nawijn, Wim Timens, Janette K Burgess, Corry-Anke Brandsma, Barbro N Melgert","doi":"10.1152/ajplung.00176.2025","DOIUrl":"10.1152/ajplung.00176.2025","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, with progressive emphysema driven by repeated epithelial damage and impaired repair. Recently, we found that secretion of cytokine receptor agonist of nuclear factor κB signaling ligand (RANKL) is higher from lung fibroblasts of patients with COPD compared with control and that RANKL reduces lung epithelial cell death. However, the underlying mechanisms, their conservation across species, and the specific epithelial cell types involved remain unclear. To investigate how RANKL affects lung epithelial cells, we used in vitro and in vivo models. Primary lung organoids from human and mouse epithelial cells assessed progenitor activation and expansion. Furthermore, we used a murine model of elastase-induced alveolar injury to examine which epithelial cell types were affected by RANKL in vivo and whether this was altered upon lung damage. RANKL supplementation increased alveolar organoid formation in both murine and human cultures compared with vehicle-treated controls. In elastase-treated mice, RANKL administration during the early repair phase enhanced the proportion of EpCAM⁺ epithelial cells and increased transitional epithelial cell states characterized by keratin 8 (Krt8) and major histocompatibility complex II (MHCII) expression following elastase-induced injury. RANKL signaling promoted epithelial regeneration by expanding alveolar progenitor and transitional epithelial cell populations, with consistent effects across human and murine models. These findings identify RANKL as a novel modulator of epithelial repair and suggest that controlled activation of this pathway could enhance lung regeneration in diseases such as COPD.<b>NEW & NOTEWORTHY</b> This study describes for the first time a role for bone cytokine RANKL in lung epithelial repair following lung damage. Using both murine and human models, we describe how RANKL-mediated signaling promotes epithelial expansion by acting on epithelial transitional cell states. For diseases with substantial lung damage, modulating RANKL signaling during the early repair phase following lung injury could represent a strategy to enhance epithelial regeneration.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"330 4","pages":"L274-L287"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479553","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":"Sex chromosomes and gonadal sex interactions in airway and immune responses to allergen challenge.","authors":"Carolyn Damilola Ekpruke, Dustin Rousselle, Rachel Alford, Omar Borges-Sosa, Maksat Babayev, Shikha Sharma, Lyidia Dinwiddie, Erik Parker, Sarah Bradley, Matthew Louis Retzner, Patricia Silveyra","doi":"10.1152/ajplung.00210.2025","DOIUrl":"10.1152/ajplung.00210.2025","url":null,"abstract":"<p><p>Asthma is a chronic respiratory condition influenced by genetic, environmental, and sex-related factors. Women experience greater asthma severity, airway hyperresponsiveness (AHR), and inflammation than men, likely due to sex-linked genetic and hormonal differences. However, the independent contributions of sex chromosomes and gonadal sex to these responses remain unclear. This study examines their roles in allergic airway responses using the four core genotype (FCG) mouse model, which distinguishes between chromosomal and gonadal influences. We hypothesized that XX-mice and those with female gonads would exhibit heightened airway inflammation and immune activation in response to house dust mite (HDM) challenge. Using a controlled, moderate 5-wk HDM exposure paradigm that reliably induced allergic airway inflammation, we aimed to capture biologically relevant sex- and genotype-dependent variations rather than a maximal inflammatory phenotype. FCG mice (XXF, XXM, XYF, and XYM) underwent 5 wk of HDM exposure, followed by assessments of airway lung function and inflammation. Our results showed that HDM challenge differentially increased airway resistance and elastance in FCG mice, with specific contributions of sex chromosomes and gonadal sex. Histological analysis showed higher lung inflammation and goblet cell hyperplasia in challenged mice with female gonads than in those with male gonads. Flow cytometry assessment revealed elevated eosinophils in XXF mice. Combined, our findings show that both sex chromosomes and gonadal sex influence airway inflammation and immune responses to allergen challenge, with mice bearing XX chromosomes and female gonads exhibiting greater susceptibility.<b>NEW & NOTEWORTHY</b> This study provides new insights into how sex chromosomes and gonadal sex independently and interactively shape immune cell responses during allergic airway inflammation. Using the four core genotype (FCG) mouse model, we show that both genetic and hormonal factors significantly influence pulmonary immune cell populations after allergen exposure. These findings advance our understanding of the biological basis for sex differences in asthma and highlight the need for sex-informed approaches in respiratory disease research and therapy development.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L288-L303"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123550","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":"Genetic and chemical correction of cystic fibrosis reduces airway susceptibility to SARS-CoV-2.","authors":"Stuart D Rollins, Adam J Hume, Da-Yuan Chen, Ruth-Love Yeboah, Pushpinder Singh Bawa, Chantelle Simone-Roach, Jianing Yin, Alice Little, Anam Fatima, Hiroaki Murano, Luciana P Tavares, Kenichi Okuda, Jessie Huang, Darrell N Kotton, Mohsan Saeed, Elke Mühlberger, Ruobing Wang","doi":"10.1152/ajplung.00223.2025","DOIUrl":"10.1152/ajplung.00223.2025","url":null,"abstract":"<p><p>The airway epithelium, a primary target for viral infection, plays a critical role in disease response-particularly in individuals with preexisting airway conditions such as cystic fibrosis (CF). At the onset of the SARS-CoV-2 pandemic, individuals with CF were expected to have severe outcomes based on earlier viral outbreaks; however, those on effective CF transmembrane conductance regulator (CFTR) modulators showed milder disease. Patients with CF on the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) combination therapy showed attenuated viral infection and reduced airway epithelial damage. To investigate how this is accomplished, we used an induced pluripotent stem cells (iPSC)-derived airway epithelium model of CF and syngeneic CFTR-corrected cells to examine responses to SARS-CoV-2 infection. CF iPSC-airways were significantly more susceptible to viral infection and epithelial injury compared with their corrected counterparts, despite comparable expression of viral entry factors. Strikingly, pretreatment with ETI conferred significant protection in CFTR-corrected and non-CF, wild-type (WT) airway epithelia, as well as in iPSC-derived and primary epithelia. Single-cell RNA sequencing analysis confirmed a heightened infection and proinflammatory response in CF iPSC-airways, whereas ETI treatment significantly reduced these responses in both CF and CFTR-corrected iPSC-airways. Mechanistically, ETI treatment led to increased type I interferon signaling and induction of antiviral genes, whereas expression of many other proinflammatory genes was suppressed in both CF and non-CF iPSC-airways. These results underscore the therapeutic promise of CFTR-modulators such as ETI in mitigating SARS-CoV-2 infection and inflammation, not only in CF airways but also in non-CF airways, highlighting the broad applicability of CFTR-modulators as a therapeutic strategy in viral pneumonia and inflammatory lung disease.<b>NEW & NOTEWORTHY</b> Using rigorously controlled iPSC-derived airway models, the study shows that CFTR-deficient cells are more vulnerable to SARS-CoV-2 and display stronger inflammation than syngeneic CFTR-corrected controls. The CFTR modulator ETI reduces viral injury and boosts antiviral pathways in both CF and non-CF cells. Even at baseline, CFTR modulation enhances antiviral responses and lowers inflammation. Overall, the findings reveal a broad protective antiviral effect of CFTR modulators and highlight their therapeutic promise in inflammatory lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L344-L367"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008523","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}