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

{"title":"Low tidal volume ventilation facilitates spontaneous increase in bronchoconstriction and air trapping that can be resolved by deep inspiration and bronchodilator.","authors":"Yuto Yasuda, Geoffrey N Maksym, Lu Wang, Pasquale Chitano, Chun Y Seow","doi":"10.1152/ajplung.00085.2025","DOIUrl":"10.1152/ajplung.00085.2025","url":null,"abstract":"<p><p>Prolonged absence of deep inspiration (DI) increases airway resistance. The underlying mechanism is not entirely clear. We hypothesize that DI prohibition allows basal airway smooth muscle (ASM) tone to narrow and close airways over time, resulting in elevation of airway and lung resistance, as well as air trapping. We further hypothesize that DI or pharmacological bronchodilators can prevent or alleviate the resistance increase and air trapping. Physiological respiration was simulated in ex vivo sheep lungs. Lung resistance, elastance, and volume were measured using small tidal volume (120 mL), ventilation frequencies of 0.25 and 2 Hz, and transpulmonary pressure of 7.5 cmH₂O in the presence and absence of DI and bronchodilators. A DI maneuver, involving rapid inflation to total lung capacity followed by deflation to zero transpulmonary pressure, was used to resolve air trapping. Lung resistance and elastance were recorded pre- and post-DI. The experiments were also conducted in the presence of the bronchodilator salbutamol to assess the role of ASM. Ventilation without DI increased lung resistance and elastance, as well as air trapping. DI effectively resolved air trapping, restoring resistance and elastance to their initial values. Salbutamol also alleviated the increase in lung resistance, elastance, and air trapping. DI prevented air trapping and reduced lung resistance and elastance in ex vivo sheep lungs during tidal ventilation, playing a similar role as a pharmacological bronchodilator.<b>NEW & NOTEWORTHY</b> We showed that air trapping is a consistent feature in ex vivo sheep lungs possessing spontaneous bronchoconstriction, when the lungs are ventilated with small tidal volume without intermittent deep inspirations. We further demonstrated that in the presence of salbutamol, air trapping does not occur. This explains the importance of deep inspirations in normal breathing and indicates that airway smooth muscle tone could result in air trapping in the absence of deep inspiration.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L225-L233"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537769","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":"Lung-specific TGFβ overexpression increases airway fibrosis and airway contractility in transgenic mice.","authors":"Julia G Chitty, Maggie Lam, Weiyi Mao, Simon G Royce, Philip G Bardin, Jane E Bourke, Belinda J Thomas","doi":"10.1152/ajplung.00017.2025","DOIUrl":"10.1152/ajplung.00017.2025","url":null,"abstract":"<p><p>Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine implicated in the pathophysiology of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. Epithelial TGFβ1 is released in response to injury, inflammatory stimuli, and during bronchoconstriction to induce fibrosis. We hypothesized that elevated expression of endogenous TGFβ1, localized to the lung, would elicit autocrine effects to alter airway responsiveness. We utilized a transgenic mouse model of doxycycline (Dox)-induced, lung-specific overexpression of active TGFβ1 by giving Dox (0.25 mg/mL in drinking water, 8 wk), or normal water as a control. Comparing Dox with control groups, levels of TGFβ1 were ∼30-fold higher in bronchoalveolar lavage fluid (BALF), but not in serum, as measured by ELISA. BALF cells, predominantly macrophages, were ∼3.5-fold higher, with no evidence of tissue inflammation in hematoxylin and eosin (H&E)-stained sections from Dox mice. Higher collagen deposition was evident around the airways in Masson's trichrome-stained sections [subepithelial thickness (µm): control 10.4 ± 10.9, <i>n</i> = 9; Dox 25.8 ± 1.5, <i>n</i> = 13, <i>P</i> < 0.0001]. TGFβ1 overexpression increased baseline airway resistance and induced airway hyperresponsiveness (AHR) to methacholine (MCh) in vivo, as measured using in vivo plethysmography. Comparing precision-cut lung slices (PCLS) from separate Dox-treated and control mice, maximum contraction of intrapulmonary airways to MCh was increased ex vivo. Overall, elevated lung TGFβ1 levels resulted in localized airway fibrosis associated with increased airway contraction to MCh. These autocrine effects of endogenous TGFβ1 implicate its potential contribution to AHR, suggesting that targeting TGFβ1 may provide a novel approach to oppose excessive airway contraction in chronic lung diseases.<b>NEW & NOTEWORTHY</b> TGFβ upregulation is common in respiratory diseases. Here, the authors have utilized for the first time a mouse model of lung-specific overexpression of active TGFβ to demonstrate the dual role of TGFβ1 in structural remodeling and dysregulation of airway contractility. Given these pathologies are common to asthma and COPD, this model provides a unique opportunity to identify essential novel therapeutics for the treatment of chronic lung diseases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L255-L265"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526033","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":"Combining innovative methodologies with deep personal connections to further physiology research: lessons from Joseph D. Brain, ScD.","authors":"Jeffrey J Fredberg, Joseph P Mizgerd","doi":"10.1152/ajplung.00281.2024","DOIUrl":"10.1152/ajplung.00281.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L197-L199"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198044","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":"Intrauterine inflammation-induced neonatal lung injury via succinic acid-mediated alveolar epithelial E-cadherin downregulation.","authors":"Baihe Li, Ze Chen, Dongting Yao, Wei Li, Qianqian Zhang, Meng Ni, Qianwen Shen, Zhenying Lin, Chunyu Cheng, Sudong Qi, Xiya Ding, Jiuru Zhao, Zhiwei Liu","doi":"10.1152/ajplung.00322.2024","DOIUrl":"10.1152/ajplung.00322.2024","url":null,"abstract":"<p><p>Intrauterine inflammation is associated with lung injury in offspring and long-term adverse pulmonary outcomes, but the underlying mechanism remains elusive. This study aimed to investigate the underlying molecular mechanism from the perspective of metabolites. Pregnant C57BL/6 mice received an intraperitoneal injection of LPS on <i>gestational day 12.5</i> to establish an intrauterine inflammation model. The results showed that prenatal LPS exposure induced bronchopulmonary dysplasia (BPD)-like alveolar simplification. Then, by LC/MS untargeted metabolomics analysis, succinic acid was found to be elevated in murine placentas and preterm human umbilical cord blood with intrauterine inflammation. Besides, the expression of succinate dehydrogenase B subunit (Sdhb), a key catalytic enzyme of succinic acid, was downregulated in the murine placentas with intrauterine inflammation. Tail intravenous administration of <i>Sdhb</i> siRNA led to the accumulation of succinic acid in the placenta and aggravated LPS-induced lung injury in the offspring. In offspring mice, intrauterine inflammation decreased E-cadherin levels in lung tissue, which were further reduced by <i>Sdhb</i> siRNA injection. Conversely, overexpression of E-cadherin alleviated inflammation-induced lung injury. In vitro experiments revealed that succinic acid downregulated E-cadherin expression in alveolar epithelial cells through the PI3K/Akt/Hif-1α pathway. Succinic acid also indirectly downregulated the E-cadherin expression in alveolar epithelial cells by inducing macrophage M2 polarization and the production of Tgf-β1. In conclusion, this study demonstrates that succinic acid is a critical mediator of intrauterine inflammation-induced lung injury in offspring.<b>NEW & NOTEWORTHY</b> Intrauterine inflammation induces the accumulation of succinic acid in the placenta, which subsequently downregulated E-cadherin expression in the alveolar epithelial cells, thereby contributing to lung injury.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L282-L295"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607156","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":"Sirtuin 3 deficiency exacerbates emphysema and lung inflammation in a murine model of chronic obstructive pulmonary disease.","authors":"Taro Ishimori, Minako Saito, Masaaki Yuki, Mototaka Hattori, Masahiro Shuzui, Saki Nagoshi, Shiho Kono, Hideaki Isago, Hiroyuki Tamiya, Naoya Miyashita, Takashi Ishii, Yu Mikami, Takahide Nagase, Yasuhiro Terasaki, Yoichi Shinozaki, Akihisa Mitani","doi":"10.1152/ajplung.00212.2024","DOIUrl":"10.1152/ajplung.00212.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a progressive lung disease caused mainly by cigarette smoke-mediated induction of oxidative stress. Sirtuin 3 (SIRT3) regulates reactive oxygen species levels, but there are no definitive reports on its role in COPD pathogenesis. We hypothesized that SIRT3 plays a protective role in COPD. First, we observed significantly reduced SIRT3 expression in COPD lungs and identified smoking as a suppressive factor for SIRT3 expression in the airway epithelium. Next, we analyzed the lung phenotypes of SIRT3 knockout (KO) mice and SIRT3-overexpressing transgenic (OE) mice, and induced a COPD model in these mice using elastase and lipopolysaccharide. We subsequently investigated the effects of SIRT3 on cytokine production, oxidative stress, and apoptosis in airway epithelial cells in vitro. SIRT3 knockout mice exhibited increased expression of apoptosis markers, and aged SIRT3 KO mice and SIRT3 KO COPD model mice exhibited a worsened emphysematous phenotype. By contrast, this effect was mitigated in SIRT3 OE COPD model mice. In vitro studies revealed that SIRT3 deficiency exacerbated inflammation, oxidative stress, and apoptosis in airway epithelial cells. We concluded that SIRT3 plays a vital role in COPD pathogenesis and could be a novel therapeutic target.<b>NEW & NOTEWORTHY</b> Our study is the first to elucidate the protective role of SIRT3 in the pathogenesis of COPD by modulating inflammatory responses and apoptosis. We have demonstrated that SIRT3 knockout mice spontaneously develop emphysema, and SIRT3 overexpression reduced elastase and LPS-induced emphysematous changes. In vitro studies have shown that SIRT3 deficiency leads to increased inflammation, oxidative stress, and apoptosis in airway and alveolar epithelium, contributing to the formation and exacerbation of emphysema.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L200-L213"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482793","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":"Carbonic anhydrase IX promotes acute lung injury and mortality in females during metabolic acidosis and pneumonia.","authors":"Reece P Stevens, Jacob Holston, Karam Maatouk, Chun Zhou, Madeline Stone, Viktoriya V Pastukh, C Michael Francis, Sagar Kumar, Meredith S Gwin, Sarah L Sayner, Troy Stevens, Ji Young Lee","doi":"10.1152/ajplung.00331.2024","DOIUrl":"10.1152/ajplung.00331.2024","url":null,"abstract":"<p><p>Carbonic anhydrase IX (CA IX) is a unique transmembrane CA isoform that is associated with chronic pulmonary vascular diseases and is upregulated in the lungs during infection. Whether CA IX contributes to alveolar-capillary dysfunction in the acute respiratory distress syndrome (ARDS) is unknown. Here, we tested the hypothesis that CA IX promotes acute lung injury during metabolic acidosis and pneumonia. Wild-type (WT) and CA IX knockout (KO) mice were fed 0.5% sucrose water (control) or 0.28 M NH₄Cl + 0.5% sucrose water for 7 days to induce metabolic acidosis, followed by intratracheal instillation of bacteria. Metabolic acidosis by itself did not cause pulmonary edema but modestly increased the lung wet-to-dry ratio in WT mice during pneumonia. A major sex difference in outcome was seen, where WT females had a higher filtration coefficient (<i>K</i>_f) in the isolated perfused lung and increased mortality compared with KO females. The <i>K</i>_f of WT and KO males did not differ; however, WT males had a 20% lower survival rate than KO males. In vitro expression of CA IX in pulmonary microvascular endothelial cells increased gap formation in the cell monolayer compared with KO cells during infection. No difference in lung bacterial clearance and plasma cytokines were seen between WT and KO mice regardless of sex. Thus, we report that CA IX promotes lung permeability and mortality but does not affect lung bacterial clearance, suggesting that CA IX may facilitate lung injury by directly affecting alveolar-capillary permeability and may serve as a therapeutic target in ARDS.<b>NEW & NOTEWORTHY</b> Acidosis is prevalent in patients with ARDS, yet the mechanisms involved in alveolar-capillary dysfunction during metabolic acidosis and lung injury remain poorly defined. Here, we report that carbonic anhydrase IX, a unique pH regulatory protein, promotes pulmonary edema and mortality but does not affect lung bacterial clearance during metabolic acidosis and pneumonia. Our findings suggest that carbonic anhydrase IX may serve as a therapeutic target to alleviate lung injury in patients with acidosis and ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L266-L281"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582829","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":"Degradation of oxidized phospholipids by lysosomal phospholipase A2 regulates pulmonary fibrosis.","authors":"Doyun Kwak, Song Ling, Natalya Subbotina, James A Shayman, Tomas H Sisson, Kevin K Kim","doi":"10.1152/ajplung.00038.2025","DOIUrl":"10.1152/ajplung.00038.2025","url":null,"abstract":"<p><p>Recent evidence suggests that oxidized phospholipids (oxPLs) play a critical role in the pathogenesis of pulmonary fibrosis. The precise mechanism by which oxPL contributes to fibrosis remains unknown and likely involves complex interactions between epithelial cell injury, phospholipid accumulation, and macrophage activation. We have previously identified lysosomal phospholipase A2 (LPLA2, PLAG15) as a critical enzyme involved in the catabolism of oxPL, especially within alveolar macrophages. We hypothesized that LPLA2 activity would mitigate the accumulation of oxPL within macrophages and thereby influence the development of pulmonary fibrosis. Using wild-type (WT) and LPLA2-null mice, we induced lung injury with bleomycin and assessed lung fibrosis severity, bronchoalveolar lavage (BAL) cell lipid accumulation, and monocyte/macrophage profibrotic activation. Our results show that LPLA2-null mice accumulated significantly more intracellular lipid within their alveolar cells, exhibited higher transforming growth factor-β (TGFβ) levels in their BAL fluid, and developed more severe fibrosis after bleomycin injury compared with WT mice. In vitro studies confirmed that LPLA2 expression in WT bone marrow-derived macrophages limits oxPL accumulation and thereby mitigates their profibrotic activation. Overexpression of LPLA2 in WT mice reduced alveolar cell lipid accumulation, decreased BAL fluid (BALF) TGFβ levels, and attenuated fibrosis. These findings underscore the critical role that LPLA2 plays in regulating lipid accumulation and suggest that enhancing LPLA2 activity within alveolar cells (or the alveolar compartment) could attenuate the fibrotic response following lung injury. By identifying LPLA2 as a key regulator in this pathway, we propose that targeting LPLA2 and related lipid metabolic processes offers a promising therapeutic strategy.<b>NEW & NOTEWORTHY</b> During lung injury and fibrosis, there is accumulation of oxidized phospholipid within macrophages in the alveolar space. This promotes profibrotic macrophage activation, resulting in pulmonary fibrosis. We find that degradation of oxidized phospholipid by lysosomal phospholipase A2 is important in preventing fibrosis. This offers a potential therapeutic target.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L214-L223"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493413","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":"Understanding and manipulating morphogenetic processes to generate in vitro models of airways.","authors":"Katharina Raasch, Pauline Henrot, Alice Hadchouel-Duvergé, Maeva Zysman, Isabelle Dupin","doi":"10.1152/ajplung.00015.2025","DOIUrl":"10.1152/ajplung.00015.2025","url":null,"abstract":"<p><p>Branching morphogenesis, the process by which cells and tissues organize into complex branched tubular structures, is fundamental to the development of functional organs, including the respiratory airways in mammalian lungs. Advances in understanding the molecular and cellular mechanisms driving morphogenetic processes have enabled the development of sophisticated in vitro models that mimic the structure and function of airways. This review recapitulates developmental principles guiding airway morphogenesis, including the key signaling pathways, cellular interactions, and the different biochemical and mechanical cues. We discuss how these principles have been harnessed to engineer in vitro models of airways, providing a comprehensive overview of current artificial lung culture systems. We consider fully morphogenetic-mimicking strategies such as organoid modeling to more reductionist strategies, such as airway-on-chip systems. By examining both the breakthroughs and current limitations, we highlight the potential of these models to reproduce airway physiology and diseases, such as congenital pulmonary airway malformation and chronic obstructive pulmonary disease. Furthermore, we consider future directions in the field, emphasizing the need for controlling complex environmental cues and integrating multiple cellular components to create increasingly accurate and functional airway models.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L234-L254"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511426","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":"A cannabinoid receptor 1 inverse agonist induces weight loss and reduces airway hyperresponsiveness in a mouse model of obese asthma.","authors":"Carolyn R Morris, Ravishankar Chandrasekaran, Isabella M Butzirus, Nirav Daphtary, Minara Aliyeva, Allison M Manuel, William G Tharp, Jason Bates, Vikas Anathy, Matthew E Poynter, Jianmin Duan, Geneviève Gaucher, Glenn D Crater, Anne E Dixon","doi":"10.1152/ajplung.00049.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00049.2025","url":null,"abstract":"<p><p>Most people with severe asthma have obesity. Metabolic dysfunction, often associated with obesity, is particularly associated with severe asthma. Mechanisms linking metabolic dysfunction with asthma, and whether improving metabolic function can affect asthma, are not known. The endocannabinoid system plays a significant role in metabolism; inhibition of cannabinoid receptor 1 (CB₁R) induces weight loss and improves serum lipid profiles. We used a CB₁R inverse agonist, INV-202, in a mouse model of obese asthma and investigated changes in weight, inflammation, airway reactivity, and surfactant lipids. Mice were fed low or high fat diets (LFD, HFD), and house dust mite extract (HDM) was delivered intranasally to induce allergic airway inflammation. Mice received INV-202 by oral gavage. Airway hyperresponsiveness was measured by flexivent and lung tissue cytokines were measured by ELISA. Leukocytes and lipids in the bronchoalveolar lavage fluid (BALF) were analyzed by flow cytometry and mass spectroscopy, respectively. LFD and HFD mice lost an average of 11% and 27% of their body weight, respectively. LFD mice had a 33% decrease in CCL20 in lung tissue and a 55% decrease in neutrophils in BALF. LFD and HFD mice had improvements in airway hyperresponsiveness, particularly as measured by reduced elastance. Phosphatidylglycerol in BALF increased with INV-202, which significantly correlated with compliance in LFD mice. This study supports a significant contribution of metabolic factors related to the endocannabinoid system in lung compliance and airway reactivity, in part through effects on surfactant lipid composition, and demonstrates the potential of CB₁R inverse agonists to treat obese asthma.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706044","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":"Yes-associated Protein Induces Age-dependent Inflammatory Signaling in the Pulmonary Endothelium.","authors":"Memet T Emin, Alexandra M Dubuisson, Prisha Sujin Kumar, Carsten Knutsen, Cristina M Alvira, Rebecca F Hough","doi":"10.1152/ajplung.00178.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00178.2025","url":null,"abstract":"<p><p>Acute Lung Injury (ALI) causes the highly lethal Acute Respiratory Distress Syndrome (ARDS) in children and adults, for which therapy is lacking. Children with Pediatric ARDS (PARDS) have a mortality rate that is about half of adults with ARDS. Improved ALI measures can be reproduced in rodent models with juvenile animals, suggesting that physiologic differences may underlie these outcomes. Here, we show that pneumonia-induced ALI caused inflammatory signaling in the endothelium of adult mice which depended on Yes-associated protein (YAP). This signaling was not present in 21-day-old weanling mice. Transcriptomic analysis of lung endothelial responses revealed nuclear factor kappa-B (NF-κB) as significantly increased with ALI in adult versus weanling mice. Blockade of YAP signaling protected against inflammatory response, hypoxemia, and NF-κB nuclear translocation in response to <i>Pseudomonas aeruginosa</i> pneumonia in adult mice. Our results demonstrate an important signaling cascade in the lung endothelium of adult mice that is not present in weanlings. We suggest other pathways may also exhibit age-dependent signaling, which would have important implications for ARDS therapeutics in the adult and pediatric age groups.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706045","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}