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

{"title":"Corrigendum for Nwozor et al., volume 328, 2024, p. L724-L737.","authors":"","doi":"10.1152/ajplung.00223.2024_COR","DOIUrl":"https://doi.org/10.1152/ajplung.00223.2024_COR","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"329 3","pages":"L323"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938913","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":"High-fat diet obesity exacerbates acute lung injury-induced dysregulation of fatty acid oxidation in alveolar epithelial type 2 cells.","authors":"Eleni Kallinos, Kuei-Pin Chung, Lisa K Torres, Divya Bhatia, Baran Ersoy, Peter Carmeliet, William Zhang, Heather W Stout-Delgado, Augustine M K Choi, Maria Plataki","doi":"10.1152/ajplung.00406.2024","DOIUrl":"10.1152/ajplung.00406.2024","url":null,"abstract":"<p><p>Obesity is a risk factor for acute respiratory distress syndrome (ARDS). We previously showed that obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic model of ARDS. We sought to expand our understanding of this association and examined the effect of obesity on β-oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2s) in hyperoxia-induced ARDS. AEC2 were isolated from mice receiving 60% versus 10% fat diet. Carnitine palmitoyltransferase 1A (CPT1A) mediates the transport of fatty acids into mitochondria for subsequent FAO. <i>Cpt1a</i>^loxp/loxp<i>Sftpc</i>^CreERT2+/- mice were generated with AEC2-specific CPT1A downregulation. Obesity was associated with intracellular lipid accumulation and increased expression of CPT1A in AEC2 after hyperoxia. Mitochondrial FAO; however, was significantly transcriptionally downregulated in AEC2 of obese mice compared with lean mice after hyperoxia. AEC2 from obese mice exhibited more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared with lean mice. Consistent with earlier reports linking FAO perturbation to surfactant impairment, we also observed that high-fat diet was associated with reduced surfactant-related phospholipids in hyperoxic AEC2 and increased BALF surface tension, although obese <i>Cpt1a</i>^loxp/loxp<i>Sftpc</i>^CreERT2+/- mice were not protected from increased lung injury. In a reanalysis of a human single-cell lung atlas of COVID-19 ARDS, the downregulation of the FAO signature in AEC2 was significant only in obese, and not lean, patients with ARDS compared with controls. These findings demonstrate a previously underappreciated effect of diet on AEC2 function in acute lung injury.<b>NEW & NOTEWORTHY</b> High-fat diet obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic ARDS model. In the present study, obesity not only upregulated intracellular lipids and effectors of fatty acid mitochondrial import but also was associated with downregulated fatty acid oxidation and reduced ATP production in alveolar epithelial type 2 cells after injury. Hyperoxic AEC2 from obese mice had reduced phospholipids, and obese mice had increased BALF surface tension after injury.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L343-L356"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688646","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":"The pathophysiology of acute lung injury following intestinal ischemia-reperfusion.","authors":"Mickael Palmier, Sylvain Fraineau, Angela Sutton, Hanna Hlawaty, Jeremy Bellien, Didier Plissonnier","doi":"10.1152/ajplung.00052.2025","DOIUrl":"10.1152/ajplung.00052.2025","url":null,"abstract":"<p><p>Acute mesenteric ischemia (AMI) is a severe and life-threatening condition with a mortality rate of up to 50%. Its treatment, which depends on the etiology, focuses on preserving intestinal viability through prompt restoration of blood flow. Although it is well established that intestinal ischemia-reperfusion results in significant local tissue damage, it is less recognized that it can also lead to remote tissue injuries, particularly in the lungs. Acute lung injury following intestinal ischemia-reperfusion is a severe complication that affects nearly 30% of patients with acute mesenteric ischemia and significantly contributes to mortality. The underlying pathophysiology of this injury is complex and multifactorial, yet it remains poorly understood. Neutrophil-endothelial interactions, regulated by both systemic and local mediators, play a pivotal role. Among the contributing factors, the intestinal ischemia-reperfusion process itself appears to be the most significant. Reperfusion of the ischemic intestine allows the release of mediators generated during ischemia into the systemic circulation. This triggers a cascade of biological events, including elevated levels of proinflammatory cytokines, overproduction of reactive oxygen species (ROS), nitric oxide imbalance, neutrophil activation, mitochondrial damage, and the initiation of cell death pathways. Here, we review the current knowledge on the various pathophysiological pathways explored in clinical and animal models of acute lung injury induced by intestinal ischemia-reperfusion, with the aim of providing therapeutic insights.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L397-L418"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788024","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 value of deep inspirations.","authors":"Gary C Sieck","doi":"10.1152/ajplung.00249.2025","DOIUrl":"10.1152/ajplung.00249.2025","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L341-L342"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764371","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":"Functional modulation of retrotrapezoid neurons drives fentanyl-induced respiratory depression.","authors":"Thiago S Moreira, Nicholas J Burgraff, Ana C Takakura, Luiz M Oliveira, Emmanuel V de Araujo, Steven Guan, Jan-Marino Ramirez","doi":"10.1152/ajplung.00025.2025","DOIUrl":"10.1152/ajplung.00025.2025","url":null,"abstract":"<p><p>The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), characterized by severe suppression of respiratory rate, destabilized breathing patterns, hypercapnia, and heightened risk of apnea. The retrotrapezoid nucleus (RTN), a critical chemosensitive brainstem region in the rostral ventrolateral medullary reticular formation, contains Phox2b⁺/neuromedin-B (<i>Nmb</i>) propriobulbar neurons. These neurons, stimulated by CO₂/H⁺, regulate breathing to prevent respiratory acidosis. Since the RTN shows limited expression of opioid receptors, we expected that opioid-induced hypoventilation should activate these neurons to restore ventilation and stabilize arterial blood gases. However, the ability of the RTN to stimulate ventilation during OIRD has never been tested. We used optogenetic and pharmacogenetic approaches, to activate and inhibit RTN Phox2b⁺/<i>Nmb</i>⁺ neurons before and after fentanyl administration. As expected, fentanyl (500 µg/kg ip) suppressed respiratory rate and destabilized breathing. Before fentanyl, optogenetic stimulation of Phox2b⁺/<i>Nmb</i>⁺ or chemogenetic inhibition of <i>Nmb</i>⁺ cells increased and decreased breathing activity, respectively. Surprisingly, optogenetic stimulation after fentanyl administration caused a significantly greater increase in breathing activity compared with prefentanyl levels. In contrast, chemogenetic inhibition of RTN <i>Nmb</i> neurons caused profound hypoventilation and breathing instability after fentanyl. The results suggest that fentanyl does not inhibit the ability of Phox2b⁺/<i>Nmb</i>⁺ cells within the RTN region to stimulate breathing. Thus, this study highlights the potential of stimulating RTN neurons as a possible therapeutic approach to restore respiratory function in cases of opioid-induced respiratory depression (OIRD).<b>NEW & NOTEWORTHY</b> Opioid-induced respiratory depression (OIRD) suppresses breathing and destabilizes ventilation. Using optogenetic and chemogenetic tools, we demonstrated that stimulating retrotrapezoid nucleus (RTN) Phox2b⁺/<i>Nmb</i>⁺ neurons enhances breathing, even after fentanyl administration, whereas their inhibition exacerbates hypoventilation. These findings reveal that RTN neurons retain their ability to drive ventilation during OIRD, highlighting their potential as a therapeutic target to restore respiratory function in opioid overdose cases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L357-L375"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688645","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":"Opportunity knocks: the fourth cohort of the <i>American Journal of Physiology-Lung Cellular and Molecular Physiology</i> Early Career Editorial Fellowship Program.","authors":"Larissa A Shimoda, Cristina M Alvira, Julie A Bastarache, Rodney D Britt, Rachel S Knipe, Wolfgang M Kuebler, Thiago S Moreira, Eric P Schmidt","doi":"10.1152/ajplung.00238.2025","DOIUrl":"10.1152/ajplung.00238.2025","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L324-L326"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697384","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":"Bioenergetics and metabolism of the pulmonary endothelium. Scientific session I: ReSPIRE 2025.","authors":"Reece P Stevens, Justin T Roberts, Wolfgang M Kuebler, Ji Young Lee, Karthik Suresh, Rebecca F Hough","doi":"10.1152/ajplung.00222.2025","DOIUrl":"10.1152/ajplung.00222.2025","url":null,"abstract":"<p><p>Session I of the inaugural biennial Research Symposium on Pulmonary Injury and Repair of the Endothelium (ReSPIRE) highlighted recent advances in endothelial bioenergetics and metabolism and their role in pulmonary vascular diseases. Emerging evidence suggests that the maladaptation of metabolic pathways in the lung endothelium contributes to the progression of the acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH). The conference highlighted several new aspects of endothelial metabolism, including the use of alternative fuel sources such as fructose and fatty acids, inflammatory signaling mediated by mitochondrial depolarization, bioenergetic reprogramming through isoform switching of genes during hypoxia, and feedback regulation of metabolism by hypercapnia. Ultimately, these findings point to future research directions aimed at identifying mechanisms of dysregulated endothelial metabolism, which could serve as therapeutic targets for pulmonary vascular diseases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L389-L396"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820292","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 spatial transcriptomic atlas of acute neonatal lung injury across development and disease severity.","authors":"Saahithi Mallapragada, Ruqian Lyu, Arianna L Williams-Katek, Brandon K Fischer, Annika Vannan, Niran Hadad, Evan D Mee, Shawyon P Shirazi, Christopher S Jetter, Nicholas M Negretti, Anne Hilgendorff, Laurie C Eldredge, Gail H Deutsch, Davis J McCarthy, Jonathan A Kropski, Jennifer M S Sucre, Nicholas E Banovich","doi":"10.1152/ajplung.00191.2025","DOIUrl":"10.1152/ajplung.00191.2025","url":null,"abstract":"<p><p>A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. Although the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of approximately 1.2 million cells. We applied computational clustering approaches to identify shared molecular patterns among this cohort, informing how tissue architecture and molecular spatial relationships are coordinated during development and disrupted in disease. Recognizing that all preterm birth represents an injury to the developing lung, we created a simplified classification scheme that relies upon the routinely collected objective measures of gestational age and lifespan. Within this framework, we have identified cell type patterns across gestational age and life span variables that would likely be overlooked when using the conventional \"disease versus control\" binary comparison. Together, these data represent an open resource for the lung research community, supporting discovery-based inquiry and identification of targetable molecular mechanisms in both normal and arrested human lung development.<b>NEW & NOTEWORTHY</b> Mapping the spatial and temporal transcriptional relationships during lung development is fundamental to understanding regeneration and chronic lung disease; however, the classification of samples as control or disease is especially challenging in the setting of preterm birth (itself a lung injury). Here, we report the largest neonatal lung transcriptomic atlas to date and an analysis framework based only on gestational age and lifespan, providing a new resource for hypothesis generation to the lung community.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L376-L388"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764370","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 H T Bates, Vikas Anathy, Matthew E Poynter, Jianmin Duan, Geneviève Gaucher, Glenn D Crater, Anne E Dixon","doi":"10.1152/ajplung.00049.2025","DOIUrl":"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 (HDM) extract 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.<b>NEW & NOTEWORTHY</b> Inhibition of the cannabinoid receptor 1, through a pharmacological inverse agonist, not only induces weight loss in a mouse model of obese asthma but also reduces airway hyperresponsiveness, particularly through decreasing elastance/increasing compliance.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L327-L340"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","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":"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 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.<b>NEW & NOTEWORTHY</b> Like human patients, adult mice get worse lung injury than juveniles. In pneumonia-induced lung injury, Yes-associated protein is more highly expressed in the endothelium of adult mice than juveniles, causing more NF-κB nuclear translocation and inflammation. This could partly explain better outcomes in kids with pediatric acute respiratory distress syndrome as compared with adults with ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L315-L322"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358178/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}