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

{"title":"Differential effects of α7nAChR activation in a murine model of asthma.","authors":"Niyati A Borkar, Kenge K Lee, Michael A Thompson, Colleen M Bartman, Lisa L Nesbitt, Samantha K Hamrick, Yun Hua Fang, Y S Prakash, Christina M Pabelick","doi":"10.1152/ajplung.00119.2025","DOIUrl":"10.1152/ajplung.00119.2025","url":null,"abstract":"<p><p>Nicotine, a primary component of tobacco, cigarette smoke, and miscellaneous vaping products, can significantly impact respiratory health. Nicotine can exacerbate asthma through its actions on multiple cell types in airways. In this context, airway smooth muscle (ASM) is a key cell type for contractility and remodeling and could be a target of nicotine. We previously showed that ASM expresses functional nicotinic acetylcholine receptors (nAChRs) and that asthmatic ASM have higher α7 subunit of nAChR (α7nAChR) expression and function, which could make them more susceptible to deleterious effects of nicotine. We explore this paradigm in the current study by evaluating the effect of short term versus chronic nicotine exposure in regulating airway hyperreactivity (AHR) and remodeling in a mixed allergen (MA) model of asthma applied to wild-type (WT) versus global α7nAChR knockout (Glα7KO) versus smooth muscle-specific α7nAChR KO (smα7KO) mice. We hypothesized that the detrimental effect of nicotine occurs via α7nAChR in ASM, and that global α7nAChR KO has worsened impact of airway remodeling. Interestingly, we found that smα7KO improved lung function and AHR in MA-challenged alone, as well as in the presence of nicotine. In contrast, MA-challenged Glα7KO in the presence of nicotine showed worsened AHR. Lung histology of smα7KO mice showed reduced airway collagen deposition compared with WT and Glα7KO mice. Immunofluorescence analysis showed smα7KO reduced remodeling proteins. These data suggest that in vivo, α7nAChR has complex effects on AHR versus remodeling with worsening of ASM-mediated AHR or remodeling, but protective effects in non-ASM mediated AHR potentially involving epithelial cells and the immune system.<b>NEW & NOTEWORTHY</b> The studies demonstrate the differential effects of the nicotinic acetylcholine receptors (nAChRs) regulating airway hyperreactivity (AHR) and remodeling in a mixed allergen model of asthma. We compared wild-type (WT) versus global α7nAChR knockout (Glα7KO) versus smooth muscle-specific α7nAChR KO (smα7KO) mice. We found that smα7KO improved lung function and AHR in mice challenged with MA and in the presence of nicotine, whereas MA-challenged Glα7KO in the presence of nicotine showed worsened AHR.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L539-L556"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571936","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":"3-Mercaptopyruvate sulfurtransferase regulates mitochondrial metabolism and epithelial differentiation in neonatal patient-derived airway cells.","authors":"Abhrajit Ganguly, Cynthia M Carter, Aristides Rivera Negron, Paul T Pierce, Lynette K Rogers, Matthew S Walters, Y S Prakash, Trent E Tipple, Arlan Richardson","doi":"10.1152/ajplung.00418.2025","DOIUrl":"10.1152/ajplung.00418.2025","url":null,"abstract":"<p><p>Early-life airway epithelial development relies on tightly coordinated mitochondrial metabolic programs, yet the pathways that govern normal epithelial maturation during this vulnerable developmental window remain poorly defined. Hyperoxia disrupts airway epithelial maturation, contributing to lung injury and airway remodeling in infants with bronchopulmonary dysplasia (BPD), underscoring the need to identify mitochondrial pathways that regulate early epithelial differentiation. 3-Mercaptopyruvate sulfurtransferase (MPST), a mitochondrial sulfur metabolism enzyme, supports mitochondrial metabolic and bioenergetic function, but its role in human airway epithelial development is unknown. In this study, we used neonatal patient-derived tracheal airway epithelial cells (nTAECs) in a three-dimensional air-liquid interface (ALI) model to show that hyperoxia reduces MPST protein abundance. To determine how MPST loss alters early epithelial differentiation and metabolic homeostasis, we used RNAi to knock down MPST during ALI differentiation. MPST loss in nTAECs induced early (<i>ALI day 3</i>) transcriptomic shifts involving mitochondrial metabolic pathways, epithelial differentiation programs, and stress-response signature corresponding with decreased ciliated cell numbers during mid-differentiation phase (<i>ALI day 7</i>). Metabolic flux analysis revealed significantly reduced mitochondrial respiration without compensatory increase in glycolysis, indicative of disrupted metabolic flexibility. Together, these data show that MPST is essential for maintaining mitochondrial metabolic integrity necessary for normal airway epithelial development. Loss of MPST creates a developmental vulnerability that may contribute to hyperoxia-induced airway injury in neonates. Targeting MPST-dependent pathways could represent a new strategy to preserve airway health in infants at risk for BPD airway remodeling.<b>NEW & NOTEWORTHY</b> This study identifies 3-mercaptopyruvate sulfurtransferase (MPST) as a previously unrecognized regulator of neonatal airway epithelial development. In our neonatal patient-derived three-dimensional organotypic model, hyperoxia reduces MPST, and MPST loss alters mitochondrial metabolism and epithelial differentiation programs. These findings indicate that MPST deficiency contributes to mitochondrial dysfunction under hyperoxic conditions and highlight MPST-linked pathways as potential therapeutic targets to mitigate early-life airway injury and remodeling relevant to infants with bronchopulmonary dysplasia (BPD).</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L557-L566"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571906","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":"Altered lung function in mice is a sensitive indicator of lung damage following 6 months of electronic nicotine delivery system aerosol exposure.","authors":"Alexandra Noël, Trenton Johnson, Matthew Schexnayder, Rui Xiao, Ingeborg Langohr, Arthur Penn","doi":"10.1152/ajplung.00209.2025","DOIUrl":"10.1152/ajplung.00209.2025","url":null,"abstract":"<p><p>With the rising prevalence of vaping, there is a pressing need to identify biomarkers of toxicity related to chronic effects induced by the inhalation of electronic nicotine delivery system (ENDS) aerosols. In a mouse model, we investigated the long-term pulmonary effects associated with exposures to cinnamon-flavored ENDS aerosols for up to 6 mo. Following exposures and after 2 mo of recovery, pulmonary function testing and lung biochemical responses were assessed. Despite similar serum cotinine concentrations in male and female mice, males exposed for 6 mo to ENDS aerosols exhibited significant reductions in tidal and minute volumes, breathing frequency, and elevated respiratory elastance, while significantly increased tissue damping and respiratory resistance were observed in both sexes. All parameters, except minute volume and breathing frequency in males, returned to baseline following recovery. Although there were no significant changes in pulmonary inflammation in all groups, lung RNA sequencing revealed significant upregulation of <i>Cxcl5</i>, a neutrophil chemotactic chemokine, in all groups exposed to ENDS aerosols. In total, 69 genes in males and 63 genes in females, were dysregulated, including upregulated proinflammatory and oxidative stress-related genes. HIF-1α in lung tissue, and CXCL5 serum concentrations, were significantly elevated in the ENDS and recovery groups, respectively, compared with controls. Overall, this study showed that pulmonary inflammation is not a hallmark of long-term ENDS aerosol exposure, whereas altered lung function is a sensitive indicator of lung damage in mice.<b>NEW & NOTEWORTHY</b> In mice, inhalation of cinnamon-flavored electronic nicotine delivery system (ENDS) aerosols for 6 mo induced pulmonary effects, including hypoxia and molecular changes. Our data suggest that hypoxia may be linked to lung function deterioration, independent of pulmonary inflammation. Overall, our findings indicate that altered lung structure and function, rather than pulmonary inflammation, are sensitive indicators of lung damage in mice chronically exposed to ENDS aerosols.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L487-L503"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13089630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484222","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":"Regenerative and repair roles of alveolar epithelial cells following lung injury.","authors":"Akira Yamagata, Anthea Weng","doi":"10.1152/ajplung.00421.2025","DOIUrl":"10.1152/ajplung.00421.2025","url":null,"abstract":"<p><p>The alveolar epithelium, composed of type 1 (AT1) and type 2 (AT2) cells, is central to gas exchange and the lung's response to injury. Historically viewed as a simple barrier, recent advances have unveiled the profound dynamics and plasticity of these cells in orchestrating tissue repair. This mini-review synthesizes recent breakthroughs in our understanding of the cellular and molecular mechanisms governing alveolar regeneration. We focus on the expanding diversity of progenitor cells, including resident AT2 cells and newly identified multipotent progenitors in the distal airways, and the complex signaling networks that dictate their fate. Furthermore, we explore the emergence of transitional cell states during repair and how aberrant cellular behaviors can drive pathological outcomes like fibrosis. A deeper comprehension of this dynamic cellular behavior is paramount for developing novel therapeutic strategies to promote effective lung repair and combat chronic lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L610-L614"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653521","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":"Assessment of pulmonary function in a mouse model of bronchopulmonary dysplasia by unrestrained whole body plethysmography and the forced oscillation technique.","authors":"David E Surate Solaligue, Claudio Nardiello, José Alberto Rodríguez-Castillo, Miša Gunjak, Ettore Lignelli, David Pérez Bravo, Francesco Palumbo, Ivana Mižik, Tilman Pfeffer, Despoina Myti, Jordi Ruiz-Camp, Heiko Steenbock, Balachandar Selvakumar, István Vadász, Susanne Herold, Sonja Genau, Lutz Naehrlich, Harald Ehrhardt, Anne Hilgendorff, Jürgen Brinckmann, John Morse, Annette Robichaud, Jason H T Bates, Werner Seeger, Rory E Morty","doi":"10.1152/ajplung.00277.2025","DOIUrl":"10.1152/ajplung.00277.2025","url":null,"abstract":"<p><p>Animal models of bronchopulmonary dysplasia (BPD) have allowed the discovery of pathological and disease-management pathways. The laboratory mouse is the go-to model for first-step experimental in vivo studies. BPD encompasses disturbances to lung structure and function, including breathing patterns and gas exchange. Despite advances in quantitative assessment of lung structure in mice, most mouse modeling studies continue to use disordered lung structure as the primary experimental endpoint. Technical challenges associated with lung function studies in neonatal mice have limited enthusiasm for drawing correlations between lung structure and lung function. As this represents a key limitation of mouse BPD models, methodologies were developed here to adapt two established techniques: unrestrained whole body plethysmography (WBP) and the forced oscillation technique (FOT), enabling reliable conscious and anesthetized assessments of lung function in mouse pups. Diseased mice presented with alveolar simplification as well as a reduced tidal volume and breathing frequency, as assessed by WBP. Changes in respiratory mechanics, namely reduced tissue damping and tissue elastance, were revealed by FOT. Alterations to pressure/volume loops suggested an obstructive pattern of disease. In a clinical cohort of 65 patients with BPD, decreased tidal volume but unchanged breathing frequency was noted. Thus, with some exceptions, disturbances to lung function in experimentally modeled elements of BPD in mice paralleled those of infants with BPD. This report serves the dual function of reporting an innovative methodology, describing protocols for using WBP and FOT in neonatal mice, while reporting functional respiratory mechanics outcomes in mice in which BPD was experimentally modeled.<b>NEW & NOTEWORTHY</b> Clinically, respiratory disease in newborns is diagnosed and managed using lung function tests; while in animal models of newborn lung disease, lung structure is the primary experimental endpoint. Here, a comprehensive experimental protocol for assessing lung function in newborn mice is provided. Observed disturbances in lung function were discussed in the context of parallel structural changes to the lung architecture, and comparisons were drawn with clinical lung function studies in infants with BPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L504-L529"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519671","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 S100A8/A9 in the pathogenesis of acute exacerbations of pulmonary fibrosis.","authors":"Naoki Nakamura, Hisao Higo, Satoru Senoo, Akihiko Taniguchi, Taichi Ozeki, Ryota Sunami, Yumi Inukai, Shusei Yamamoto, Junko Itano, Ayaka Tanaka, Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi, Yoshinobu Maeda, Nobuaki Miyahara","doi":"10.1152/ajplung.00162.2025","DOIUrl":"10.1152/ajplung.00162.2025","url":null,"abstract":"<p><p>Acute exacerbation of idiopathic pulmonary fibrosis is a life-threatening condition characterized by neutrophilic inflammation. S100A8/A9, an alarmin released by activated neutrophils and monocytes/macrophages, plays a pivotal role in regulating inflammatory responses. However, its specific involvement in acute exacerbations of pulmonary fibrosis remains unclear. This study evaluated the role of S100A8/A9 in the pathogenesis of acute exacerbations of pulmonary fibrosis. S100A8/A9 levels were measured in bronchoalveolar lavage fluid and serum from patients with idiopathic interstitial pneumonia, with and without acute exacerbations. To model acute exacerbations of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Subsequently, inflammatory cell infiltration, cytokine levels, morphological changes, and fibrosis marker levels in lung tissue and airways were analyzed. S100A8/A9 levels were significantly higher in the bronchoalveolar lavage fluid and serum of patients with idiopathic interstitial pneumonia experiencing acute exacerbations relative to those without; these levels were correlated with patient prognosis. In an experimental mouse model, intratracheal administration of bleomycin followed by lipopolysaccharide resulted in a significant increase in airway S100A8/A9 levels compared with bleomycin alone and control mice. Anti-S100A8/A9 neutralizing antibody Ab45 mitigated airway inflammation and lung fibrosis in mice with acute exacerbations of pulmonary fibrosis, reducing S100A8/A9 levels and neutrophil extracellular traps. In vitro, recombinant S100A8/A9 or lipopolysaccharide and neutrophils activated and differentiated fibroblasts; these effects were inhibited by anti-S100A8/A9 neutralizing antibody Ab45 and the humanized form of Ab45 (HuAb45). These findings highlight S100A8/A9 as a potential prognostic biomarker and therapeutic target for acute exacerbations of pulmonary fibrosis.<b>NEW & NOTEWORTHY</b> During acute exacerbation of idiopathic interstitial pneumonia, bronchoalveolar lavage fluid (BALF) and serum S100A8/A9 levels were elevated and associated with poor prognosis. In a mouse model of acute pulmonary fibrosis exacerbation, therapeutic targeting of S100A8/A9 attenuated lung inflammation and fibrosis, accompanied by reduced S100A8/A9 levels and neutrophil extracellular traps within airways. In vitro experiments demonstrated that neutrophil-derived S100A8/A9 promoted activation of lung fibroblasts and their differentiation into myofibroblasts, which was effectively inhibited by neutralizing antibodies.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L593-L609"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653615","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":"Modulation of alveolar macrophages by sex as a biological variable.","authors":"Shilpa Sonti, Connor Leek, Krithika Lingappan","doi":"10.1152/ajplung.00410.2025","DOIUrl":"10.1152/ajplung.00410.2025","url":null,"abstract":"<p><p>Alveolar macrophages (AMs) play a key role in the innate immune system and the pathogenesis of bronchopulmonary dysplasia (BPD), a condition with a significant sex bias. However, the influence of biological sex on AM immunometabolism remains poorly defined. We tested the hypothesis that female AMs would exhibit greater metabolic resilience (less impact on their mitochondrial function) compared with male AMs upon exposure to hyperoxia. We characterized bioenergetic profiles of male (MH-S) and female (AMJ2-C11) adult murine AM cell lines and primary neonatal AMs from C57BL/6 pups. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were quantified using Seahorse extracellular flux analysis at baseline and following 48 h of hyperoxia (85% O₂). Adult female AMs displayed an elevated basal and maximal respiration compared with males. Upon exposure to hyperoxia, female AMs showed decreased maximal OCR and spare respiratory capacity. Conversely, male AMs showed little change in oxidative phosphorylation. Uniquely, neonatal AMs of both sexes show a suppression in their mitochondrial function upon exposure to hyperoxia, but the decline is more significant in the male macrophages. In addition, the neonatal female macrophages also showed a higher glycolytic reserve compared with their baseline in room air, upon exposure to hyperoxia. Biological sex and developmental stage are fundamental determinants of AM bioenergetics. These intrinsic sex-specific mechanisms may underlie differential susceptibility to neonatal lung injury, underscoring the necessity of sex-specific therapeutic strategies.<b>NEW & NOTEWORTHY</b> Sex-specific metabolic programming in alveolar macrophages reveals distinct vulnerability to oxidative stress. Sex-dependent metabolic dimorphism, evident in both adult cell lines and primary neonatal macrophages, suggests fundamental biological mechanisms underlying sexual dimorphism in lung disease susceptibility. These findings emphasize the critical importance of sex-specific analysis in immunometabolic research.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L530-L538"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13157820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502611","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":"<i>Pseudomonas aeruginosa</i> exoenzyme Y activity inhibits exoenzyme S-induced caspase activation in pulmonary microvascular endothelial cells.","authors":"Connor E Holm, Andrea Vavrinek, Sarah L Sayner, Madison Gray, Alana Smith-Gorcey, Katlyn Bouler, Magan Pittman, Hoa Tran, Jonathon P Audia, Terrence Ravine, Troy Stevens, Phoibe Renema","doi":"10.1152/ajplung.00373.2025","DOIUrl":"10.1152/ajplung.00373.2025","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is the most common cause of ventilator-associated pneumonia in intensive care unit (ICU) patients. Virulent <i>P. aeruginosa</i> strains utilize a type III secretion system that injects exoenzymes S, T, U, and/or Y (ExoS, T, U, and/or Y, respectively) into the host cell cytosol. Most clinically isolated <i>P. aeruginosa</i> strains encode ExoY, often in combination with ExoU and ExoT, or ExoS and ExoT. The effects of each individual exoenzyme on host cell signaling have been extensively studied, but how these signaling mechanisms are altered during co-intoxication is poorly understood. In this study, we sought to determine whether co-intoxication of ExoY with ExoS and/or ExoT modulated ExoS-induced caspase activation. Pulmonary microvascular endothelial cells (PMVECs) were infected with <i>P. aeruginosa</i> isogenic PAK strains expressing differing combinations of exoenzymes S, T, and Y. ExoS alone, but not ExoT or ExoY, induced significant caspase activation and cell death in PMVECs. Importantly, ExoY significantly decreased ExoS-induced caspase activation, but not cell death. To determine whether ExoY enzymatic activity was necessary to inhibit ExoS-induced caspase activation, ExoS-expressing <i>P. aeruginosa</i> strains were transformed with plasmids containing catalytically active or inactive ExoY. Enzymatically active ExoY inhibited ExoS-mediated caspase activation, whereas enzymatically inactive ExoY did not. The presence of ExoS did not significantly diminish ExoY-mediated cGMP production. Thus, we conclude that ExoY enzymatic activity inhibits ExoS-induced caspase activation in PMVECs.<b>NEW & NOTEWORTHY</b> <i>P. aeruginosa</i> strain PAK utilizes a type III secretion system to inject exoenzymes S, T, and Y directly into the host cell cytosol. In pulmonary microvascular endothelial cells, exoenzyme S (ExoS) alone, but not exoenzymes T or Y (ExoT or ExoY) alone, induces apoptotic caspase activation and cell death. When exoenzymes are coinjected, ExoY, but not ExoT, inhibits ExoS-induced caspase activation, but not cell death. ExoY must be catalytically active to prevent ExoS-induced caspase activation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L567-L575"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589314","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":"LncRNA HOTAIR contributes to cigarette smoke-induced pro-inflammatory responses in human airway epithelial cells.","authors":"Xinzi Zheng, Priscila P Villegas, Martijn C Nawijn, Irene H Heijink","doi":"10.1152/ajplung.00126.2025","DOIUrl":"10.1152/ajplung.00126.2025","url":null,"abstract":"<p><p>Inhalation of cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), inducing epigenetic changes in the airway epithelium, including dysregulation of long-noncoding RNAs (lncRNAs). LncRNA homeobox gene transcript antisense RNA (HOTAIR) regulates chromatin remodeling and has been implicated in CS-induced malignant transformation. We hypothesized that HOTAIR expression is altered in COPD, leading to airway epithelial abnormalities. HOTAIR expression and overall survival were studied in The Cancer Genome Atlas (TCGA) database. Airway epithelial cells (AECs) were isolated from transplanted lungs of 11 patients with COPD, tracheobronchial tissue of 9 non-COPD donors, and bronchial brushings of ex-smokers with/without COPD (<i>n</i> = 6/group). HOTAIR expression, histone modifications, and production of proinflammatory cytokines (CXCL8 and GM-CSF) were assessed in the absence/presence of CS extract (CSE) and HOTAIR-polycomb inhibitor AQB. High HOTAIR expression correlated with poor overall survival in cancer patients with COPD, but not those without. Although HOTAIR expression was not significantly different between AECs from controls and subjects with COPD at baseline, it was significantly increased by 20% CSE only in COPD-derived AECs. CSE significantly decreased H3K4me3 levels in COPD-derived AECs, but not those from controls. AQB reduced baseline H3K27me3 levels in both groups, with a stronger effect in control-derived AECs. In addition, it reduced H3K4me3 levels in the presence of CSE in both groups. Finally, although AQB significantly suppressed CSE-induced production of GM-CSF and CXCL8 in control AECs, it failed to do so in COPD. Together, these findings suggest that COPD-derived AECs are more susceptible to CSE-induced HOTAIR upregulation, which may have a proinflammatory effect that cannot be inhibited by AQB.<b>NEW & NOTEWORTHY</b> COPD-derived AECs exhibit higher susceptibility to CSE-induced HOTAIR upregulation. CSE induces distinct histone modification patterns (H3K4me3) specifically in COPD-derived AECs. HOTAIR is essential for mediating CSE-induced proinflammatory responses in AECs.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L446-L456"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353436","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 impact of estrogen replacement during perimenopause on lung function and airway inflammation in the VCD mouse model.","authors":"William P Pederson, Laurie Michelle Ellerman, Riley D Hellinger, Joselyn Joanna Rojas Quintero, Francesca Polverino, John P Konhilas, Julie G Ledford","doi":"10.1152/ajplung.00295.2025","DOIUrl":"10.1152/ajplung.00295.2025","url":null,"abstract":"<p><p>Menopause associated asthma impacts a subset of women and is less responsive to current treatments. Mechanisms driving this late-onset asthma are unknown. We recently developed a mouse model of menopause associated asthma using a combination of 4-vinylcyclohexene diepoxide (VCD) and house dust mite (HDM) exposures. The goal of this study was to determine how hormone replacement therapy during perimenopause impacts lung function and inflammation. The experimental groups included menopausal mice (VCD) with and without exposure to HDM (to model allergic airways disease) and menopausal mice with and without hormone replacement therapy (HRT; via estrogen pellet implantation). Lung function during methacholine challenge was assessed by flexiVent. Serum, bronchoalveolar lavage fluid (BALF), and histological samples were collected for assessment. Mice that received HRT during perimenopause had enhanced airway hyperresponsiveness (AHR) detected by total airway resistance (<i>R</i>_rs), tissue damping (<i>G</i>), and downward shifts in pressure-volume (PV) curves compared with controls, independent of HDM challenge. Although HRT in perimenopause resulted in decreased eosinophils in the HDM model, neutrophil levels and mucus production were unchanged. Mice receiving HRT in perimenopause also had significantly increased collagen production and inflammation associated with large and small airways, independent of HDM challenge. HRT given during perimenopause may be detrimental to lung responses, including increased AHR and decreased lung function, as well as increased tissue inflammation and airway remodeling.<b>NEW & NOTEWORTHY</b> Menopause-associated asthma is a subtype of asthma that is still largely unexplored and difficult to manage. Women experiencing menopause-associated asthma often have more severe exacerbations, higher rates of exacerbation, and most importantly, poor response to standard treatments. This study examined the impact of estrogen replacement given during the perimenopause phase on lung inflammation and function after menopause. While decreasing eosinophil recruitment, estrogen replacement actually led to worse lung function and more airway remodeling.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L379-L389"},"PeriodicalIF":3.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275455","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}