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

{"title":"Alternative splicing of toll-like receptor pathway mRNAs in lung immune cells from patients with ARDS.","authors":"William J Janssen, Matthew Lapinig, Elizabeth Wynn, Martin Aguilar, Kara J Mould, Patrick S Hume, Jazalle D McClendon, Frank Fang Yao Lee, Camille M Moore, Scott Alper","doi":"10.1152/ajplung.00128.2026","DOIUrl":"10.1152/ajplung.00128.2026","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) is characterized by robust inflammation in the lungs and systemic circulation. In this context, the toll-like receptor (TLR) signaling pathway plays a major role, driving inflammation that promotes host defense but also causing pathological tissue damage. To limit excessive inflammation, TLR signaling must be tightly controlled. One mechanism that modulates TLR signaling is alternative splicing of TLR pathway pre-mRNAs, which balances production of positively acting inflammatory mediators with alternative splice forms that terminate inflammation. To determine whether altered TLR pathway splicing contributes to pathological inflammation in ARDS, we evaluated two central mediators of the TLR signaling pathway, the MyD88 signaling adapter and the IRAK1 signaling kinase, in leukocytes isolated from bronchoalveolar lavage (BAL) of patients with ARDS. We found that <i>MyD88</i> gene expression was decreased in BAL immune cells, whereas <i>IRAK1</i> gene expression was increased. In parallel, we monitored long proinflammatory (MyD88-L and IRAK1) and shorter anti-inflammatory (MyD88-S and IRAK1c) splice forms and determined that IRAK1 splicing was shifted in a proinflammatory direction in patients with ARDS. Finally, we evaluated relationships between MyD88 isoform levels in BAL leukocytes and clinical outcomes. We conclude that pre-mRNA splicing of TLR pathway genes is altered in lung immune cells in patients with ARDS, that monitoring splicing of these genes may provide important prognostic information, and that manipulating splicing of these genes may be a useful novel therapeutic approach that needs further investigation.<b>NEW & NOTEWORTHY</b> We found that <i>MyD88</i> expression is decreased, that <i>IRAK1</i> expression is increased, and that IRAK1 splicing is shifted in a proinflammatory direction, in lung immune cells in patients with ARDS. We also find that <i>MyD88</i> expression levels may correlate with survival in patients with ARDS. Thus, changes in expression and splicing of these two genes offer potential novel prognostic and therapeutic targets for ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L155-L164"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13379275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269980","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":"Lifelong hypoxia produces multigenerational developmental lung disease and pulmonary hypertension in mice.","authors":"Luca Zazzeron, Helena Tattersfield, Elizabeth Moore, Xiao Xiao, Eizo Marutani, Haobo Li, Fumito Ichinose","doi":"10.1152/ajplung.00199.2026","DOIUrl":"10.1152/ajplung.00199.2026","url":null,"abstract":"<p><p>Chronic hypoxia during development can impair lung and pulmonary vascular growth, but most mouse models of hypoxia-induced pulmonary hypertension expose adult animals for limited periods and do not capture lifelong or multigenerational hypoxic exposure. We developed a multigenerational model of lifelong moderate hypoxia by maintaining wild-type C57BL/6J mice at 13% inspired oxygen fraction ([Formula: see text]), beginning before fertilization and continuing through gestation, postnatal development, and adulthood. This exposure permitted breeding over two generations. Pregnancy and delivery rates were largely preserved, but second-generation litters had fewer pups alive at birth and reduced overall survival to weaning, primarily because of fetal or perinatal loss. Among surviving adults, both first- and second-generation hypoxia-exposed mice developed pulmonary hypertension, right ventricular systolic dysfunction, right ventricular hypertrophy, and reduced exercise capacity compared with age-matched room air control mice. These functional abnormalities were accompanied by alveolar simplification, increased lung compliance, increased muscularization of small pulmonary arterioles, and reduced peripheral pulmonary vascular density. Several measures, including right ventricular systolic pressure and right ventricular remodeling, were modestly worse in second-generation mice. Hemoglobin concentration was increased in both hypoxia-exposed generations, whereas exploratory analysis of gastrocnemius muscle showed no detectable reduction in skeletal muscle capillary density in first-generation mice. Thus, lifelong exposure to 13% [Formula: see text] establishes a survivable but pathological model of developmental hypoxia that permits multigenerational studies while producing persistent lung developmental abnormalities, pulmonary vascular disease, right ventricular dysfunction, erythrocytosis, and exercise limitation.<b>NEW & NOTEWORTHY</b> Lifelong exposure of C57BL/6J mice to 13% inspired oxygen fraction ([Formula: see text]) permits multigenerational breeding while producing persistent developmental lung disease, pulmonary vascular remodeling, pulmonary hypertension, right ventricular dysfunction, erythrocytosis, and reduced exercise capacity. Second-generation mice show reduced perinatal viability and modestly worse pulmonary vascular/right ventricular remodeling. This model enables investigation of chronic prenatal and postnatal hypoxia without the severe early mortality observed with more extreme hypoxic exposure.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L219-L229"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417642","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":"Correction for Sicher et al., volume 328, 2025, p. L350-L356.","authors":"","doi":"10.1152/ajplung.00318.2024_COR","DOIUrl":"https://doi.org/10.1152/ajplung.00318.2024_COR","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"331 2","pages":"L206"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618190","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":"DNA methylation as a driver of lung fibroblast senescence in COPD.","authors":"Yin Lyu, Maaike de Vries, Martin Banchero, Victor Guryev, Wim Timens, Maarten van den Berge, Federica Sarno, Corry-Anke Brandsma, Roy R Woldhuis","doi":"10.1152/ajplung.00035.2026","DOIUrl":"10.1152/ajplung.00035.2026","url":null,"abstract":"<p><p>Cellular senescence is increasingly recognized as a hallmark of chronic obstructive pulmonary disease (COPD), with higher levels in lung fibroblasts from COPD patients. Upon senescence, both hypomethylation and hypermethylation have been described but not in COPD-derived fibroblasts yet. This study investigated whether altered DNA methylation can be a driver of fibroblast senescence in COPD. Genome-wide gene expression and DNA methylation data were generated from primary lung fibroblasts of 11 COPD stage IV patients and 10 matched controls. Gene expression of six well-known senescence genes was compared between COPD and control. COPD-associated senescence genes were correlated with their related CpG sites in an expression quantitative trait methylation (eQTM) analysis. Methylation levels of significant eQTMs were compared between COPD and control fibroblasts. A causal relationship between altered DNA methylation and senescence was validated in 5-Aza-2'-deoxycytidine (5-Aza-2'-dC)-treated primary lung fibroblasts. Gene expression of <i>CDKN1A</i>, <i>CDKN2A</i>, and <i>CDKN2B</i> was higher, while <i>LMNB1</i> expression was lower in COPD-derived fibroblasts compared to controls. A total of 19 eQTMs were found for the COPD-associated senescence genes <i>CDKN1A</i> (9), <i>CDKN2A</i> (1), and <i>LMNB1</i> (9). Among these, seven CpG sites (4 for <i>CDKN1A</i> and 3 for <i>LMNB1</i>) exhibited differential methylation between COPD and control. Treatment with 5-Aza-2'-dC led to global demethylation and increased senescence and, importantly, confirmed the association between senescence and hypomethylation of the COPD-associated CpG site cg04924375. Altered DNA methylation is linked to fibroblast senescence in COPD, and seven CpG sites are identified as potential epigenetic regulators of the senescence genes <i>CDKN1A</i> and <i>LMNB1</i>.<b>NEW & NOTEWORTHY</b> This study identifies DNA methylation as a mechanistic contributor to lung fibroblast senescence in chronic obstructive pulmonary disease (COPD). By integrating DNA methylation data with the transcriptomic data of senescence-related genes, we uncovered seven COPD-associated CpG sites linked to the senescence regulators <i>CDKN1A</i> and <i>LMNB1</i>. Pharmacological demethylation induces fibroblast senescence and is consistent with a functional role for hypomethylation at cg04924375, providing new insight into epigenetic regulation of cellular senescence in COPD lung fibroblasts.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L207-L218"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410199","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":"Increased lung cell susceptibility to injury due to autophagic overload after exposure to nanoparticles.","authors":"Arnold Sipos, Kwang-Jin Kim, Juan R Alvarez, Edward D Crandall","doi":"10.1152/ajplung.00362.2025","DOIUrl":"10.1152/ajplung.00362.2025","url":null,"abstract":"<p><p>Autophagy is an intracellular process that helps maintain cellular homeostasis. In this study, we measured autophagic flux and cellular injury in alveolar epithelial cells (AECs) and lung adenocarcinoma (A549) cells exposed to polystyrene nanoparticles (PNPs: 20 nm, carboxylated, near-infrared dye-labeled) and a secondary insult to explore the effects of limited autophagic capacity. Rat AEC monolayers (RAECMs) and A549 cells were exposed for 24 h to <i>1</i>) PNP, <i>2</i>) rotenone (RT: inhibits mitochondrial respiratory chain complex I) or tunicamycin (TN: disrupts protein synthesis and induces the unfolded protein response), or <i>3</i>) RT or TN for an additional 24 h after 12 h of PNP preincubation. Release of lactate dehydrogenase served as an index of cellular damage. Autophagic flux was assessed using confocal imaging to quantify the rate of autophagosome production. PNP taken up into AEC and A549 cells induced autophagy, eliciting increased autophagic flux and reaching a steady state at ∼10-24 h. When RAECM or A549 cells were exposed to RT or TN alone for up to 24 h, autophagy was also activated, reaching steady-state autophagic flux similar to PNP exposure alone. In the presence of both PNP and RT (or TN), steady-state autophagic flux was similar to that with PNP, RT, or TN alone. Cellular damage due to RT or TN, in both AEC and A549 cells, became more severe after PNP preexposure, indicating that induction of autophagy by PNP makes AEC and A549 cells more susceptible to injury by each of two secondary insults due to finite autophagic capacity.<b>NEW & NOTEWORTHY</b> Autophagy plays a key role in maintaining cellular homeostasis and protecting cells from external stressors. However, our findings show that autophagic flux has a finite capacity, indicating that when autophagic flux is induced by one agent, cells become susceptible to greater injury when exposed to a second injurious agent because autophagic capacity cannot be increased beyond its finite capacity. In this study, we show that in the presence of autophagic flux-inducing nanoparticles, susceptibility to injury by exposure to a second agent (e.g., tunicamycin or rotenone) is increased. These findings provide insight into one mechanism by which exposure to ambient airborne nanoparticles can lead to lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L197-L205"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148120","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":"Hyperoxia and iron homeostasis in developing human airway smooth muscle.","authors":"Yamillie Ortiz, Maunick Lefin Koloko Ngassie, Colleen M Bartman, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajplung.00027.2026","DOIUrl":"10.1152/ajplung.00027.2026","url":null,"abstract":"<p><p>Premature infants exposed to supplemental oxygen (O₂) are at increased risk of developing airway diseases such as asthma, hyperoxic lung injury (HLI), and bronchopulmonary dysplasia (BPD). Therefore, it is important to understand how O₂ detrimentally impacts developing airways. Previous studies found that severe (80%-90%) O₂ exposure increases reactive oxygen species (ROS) and lipid peroxidation, inducing ferroptosis in models of HLI. However, the impact of clinically relevant moderate (<60%) O₂ exposure is less understood. Recognizing the importance of smooth muscle in airway dysfunction, the present study uses human fetal airway smooth muscle (fASM) as a model to investigate whether hyperoxia contributes to the establishment of a ferroptotic phenotype. fASM pretreated with or without deferoxamine (DFO; 100 µM) or ferrostatin (Fer-1; 10 µM) was exposed for 48 h to normoxia (21% O₂) versus moderate to severe hyperoxia (50%, 70%, or 90% O₂). The effects of hyperoxia on antioxidant systems, iron metabolism, and lipid peroxidation, and the alleviating effect of DFO or Fer-1 were examined. Moderate hyperoxia impaired antioxidant systems involved in preventing ferroptosis and dysregulated iron metabolism. Interestingly, only severe hyperoxia (90% O₂) induced negative effects on downstream mechanisms involving early onset of ferroptosis such as increased labile iron and lipid peroxidation. DFO and Fer-1 showed no rescue effect on antioxidant systems. However, DFO decreased cytosolic iron, and Fer-1 decreased lipid peroxidation byproducts. Together, these data highlight the impact of supplemental oxygen on premature airways and introduce the concept of a dose-dependent effect of hyperoxia in the context of iron metabolism, lipid peroxidation, and ultimately ferroptosis.<b>NEW & NOTEWORTHY</b> Recognizing that antioxidant systems are impaired in the airways of premature infants, we used human fetal airway cells to explore the impact of oxygen on iron regulation and iron-mediated cell death (ferroptosis). We find moderate hyperoxia impairs antioxidant systems that prevent ferroptosis and dysregulates iron metabolism, while severe hyperoxia has a negative effect on mechanisms driving the early onset of ferroptosis. Inhibitors of ferroptosis decrease iron and lipid peroxidation, demonstrating links between oxygen and iron regulation in developing airways.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L144-L154"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269931","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":"Spatiotemporal calcium signaling to unlock the calcium paradox: location, location, location!","authors":"Amir A Zeki, John G Albeck","doi":"10.1152/ajplung.00262.2026","DOIUrl":"10.1152/ajplung.00262.2026","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L230-L232"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534733","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":"Inhibition of thrombospondin-1 signaling prevents experimental bronchopulmonary dysplasia.","authors":"Chantal Gaudet, Kathrine L Daniel, Sophie Holcik, Ali Hamraghani, Behzad Yeganeh, Robert P Jankov","doi":"10.1152/ajplung.00090.2026","DOIUrl":"10.1152/ajplung.00090.2026","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and proinflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. To gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting <i>1</i>) TSP-1-mediated TGF-β1 activation alone (LSKL) or <i>2</i>) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or H-IH (PND 1-7 85% O₂, PND 7-14 60% O₂, and PND 14-21 air with intermittent exposure to 10% O₂ for 10 min every 4 h) while either receiving daily subcutaneous LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1 and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology, and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.<b>NEW & NOTEWORTHY</b> Thrombospondin (TSP)-1, an angiostatic and proinflammatory protein recently implicated in bronchopulmonary dysplasia (BPD) pathogenesis, activates transforming growth factor (TGF)-β1 and suppresses nitric oxide signaling via separate receptor-mediated pathways. In a rat model of BPD, treatment with LSKL (targeting TSP-1-mediated TGF-β1 activation alone) had equivalent preventive effects on inhibited alveolarization, inflammation, and pulmonary hypertension to global inhibition of TSP-1 (soluble ligand trap). We conclude that limiting TSP-1-mediated activation of TGF-β1 appears sufficient to prevent experimental BPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L178-L190"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373700","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":"Pulmonary vascular tone competence: a framework for reversible arteriovenous malformations in hepatopulmonary syndrome and cavopulmonary shunt physiology.","authors":"Akio Ikai","doi":"10.1152/ajplung.00076.2026","DOIUrl":"10.1152/ajplung.00076.2026","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L191-L196"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417606","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":"The role of estrogen receptors and house dust mite-induced DNA methylation in a mouse model.","authors":"Sarah Commodore, Carolyn Damilola Ekpruke, Rachel Alford, Omar A Borges-Sosa, Dustin Rousselle, Maksat Babayev, Chukwudike Igwe, Christopher M Hemmerich, Douglas B Rusch, Patricia Silveyra","doi":"10.1152/ajplung.00102.2026","DOIUrl":"10.1152/ajplung.00102.2026","url":null,"abstract":"<p><p>Asthma is a chronic respiratory disease affecting over 230 million people worldwide, with higher prevalence in women. Environmental allergens such as house dust mite (HDM) trigger airway inflammation and hyperresponsiveness (AHR), yet the epigenetic mechanisms underlying these responses remain poorly understood. Furthermore, the role of estrogen receptors in the context of asthma is understudied. We aimed to investigate whether estrogen receptor-specific DNA methylation contributes to HDM-induced airway remodeling and hyperresponsiveness. Male and female C57BL/6J wild-type mice and estrogen receptor α and β knockout mice (<i>Esr1</i>^-/- and <i>Esr2</i>^-/-) were exposed to HDM or phosphate-buffered saline for 5 wk. DNA methylation and RNA sequencing data were obtained from snap-frozen whole lung tissues. HDM exposure resulted in widespread differential methylation of genes associated with inflammation and AHR, including <i>Itgal, Tmem267, Rap1b, Bmf, Mid1, Fgd1, Ddx4, Comtd1, Filip1l, Grb10</i>, and <i>Chst7</i>. Notably, the absence of estrogen receptor β (in <i>Esr2</i>^-/- mice) produced the most pronounced methylation patterns, particularly in females. Pathway enrichment analysis revealed asthma-relevant processes such as extracellular matrix remodeling, leukocyte adhesion and migration, airway smooth muscle contraction, and inflammatory signaling. Integration of methylation and gene expression data confirmed significant correlations (<i>P</i> < 0.05) for <i>Itgal</i>, <i>Rap1b</i>, and <i>Tmem267</i>, and a marginal correlation for Chst7 (<i>P</i> < 0.1), implicating these genes in allergic asthma pathogenesis. Our findings demonstrate that HDM exposure induces sex-specific epigenetic changes mediated by estrogen receptor status, highlighting a potential mechanism for increased asthma susceptibility in women. These results can inform estrogen receptor-targeted treatment strategies for allergic airway diseases.<b>NEW & NOTEWORTHY</b> Understanding estrogen receptor-mediated epigenetic regulation provides a foundation for developing sex-specific interventions for asthma, addressing the higher prevalence and severity observed in women. In this study, we demonstrate that exposure to house dust mite in the mouse lung is associated with epigenetic alterations in genes linked to airway hyperresponsiveness and lung inflammation. These alterations were dependent on the presence or absence of estrogen receptors.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L119-L143"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238544","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}