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

{"title":"Epigenetic age acceleration in idiopathic pulmonary fibrosis revealed by DNA methylation clocks.","authors":"Daniel B Kurbanov, Farida Ahangari, Taylor Adams, Ruben De Man, Jessica Tang, Marianne Carlon, Nebal Abu Hussein, Emmanuela Cortesi, Marta Zapata, Laurens De Sadelaar, Wim Wuyts, Bart Vanaudenaerde, Naftali Kaminski, John E McDonough","doi":"10.1152/ajplung.00171.2024","DOIUrl":"10.1152/ajplung.00171.2024","url":null,"abstract":"<p><p>In this research, we delve into the association between epigenetic aging and idiopathic pulmonary fibrosis (IPF), a debilitating lung disease that progresses over time. Utilizing the Illumina MethylationEPIC array, we assessed DNA methylation levels in donated human lung tissue from patients with IPF, categorizing the disease into mild, moderate, and severe stages based on clinical assessments. We used seven epigenetic clocks to determine age acceleration, which is the discrepancy between biological (epigenetic) and chronological age. Our findings revealed a notable acceleration of biological aging in IPF tissues compared with healthy controls, with four clocks-Horvath's, Hannum's, PhenoAge, and DunedinPACE-showing significant correlations. DunedinPACE, in particular, indicated a more rapid aging process in the more severe regions within the lungs of IPF cases. These results suggest that the biological aging process in IPF is expedited and closely tied to the severity of the disease. The study underscores the potential of DNA methylation as a biomarker for IPF, providing valuable insights into the underlying methylation patterns and the dynamics of epigenetic aging in affected lung tissue. This research supports the broader application of epigenetic clocks in clinical prognosis and highlights the critical role of biological age in the context of medical research and healthcare.<b>NEW & NOTEWORTHY</b> Using epigenetic clocks, we found a notable acceleration of biological aging in IPF tissues, particularly in DunedinPACE, suggesting that the biological aging process in IPF is accelerated and closely related to the severity of the disease. The study also underscores DNA methylation's potential as a biomarker for IPF, as well as the dynamics of epigenetic aging and the need to consider biological age in medical research and healthcare.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L456-L462"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456823","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 circulating renin-angiotensin system and mortality among patients hospitalized for COVID-19: a mechanistic substudy of the ACTIV-4 Host Tissue trials.","authors":"Christopher L Schaich, Mark C Chappell, Matthew S Shotwell, Meghan M Joly, Kevin W Gibbs, Aaron Barksdale, Ivor S Douglas, Peter Chen, Joseph E Levitt, Michael A Puskarich, Todd W Rice, Michelle S Harkins, Kristin M Hudock, Michael J Lanspa, Adit A Ginde, Wesley H Self, Sean P Collins, D Clark Files","doi":"10.1152/ajplung.00372.2024","DOIUrl":"10.1152/ajplung.00372.2024","url":null,"abstract":"<p><p>SARS-CoV-2 targets angiotensin-converting enzyme-2 (ACE2), a key peptidase of the renin-angiotensin system (RAS), which regulates the balance of the vasoconstrictor/inflammatory peptide Ang II and the vasodilator/anti-inflammatory peptide Ang-(1-7). Few studies have quantified the circulating elements of the RAS longitudinally in SARS-CoV-2 infection and their association with COVID-19 outcomes. Thus, we evaluated the association of circulating RAS enzymes and peptides with mortality among patients with COVID-19. Blood samples were collected from 111 patients with COVID-19 and new-onset hypoxemia during the delta and omicron waves at 19 hospitals in the United States. Circulating RAS components were quantified via radioimmunoassay or ELISA at 0 (baseline), 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal RAS concentrations with 90-day mortality. Participants were aged 18-90 (means [SD]: 55 [14]) yr and 62% were male. There were 22 (20%) deaths over 90 days of follow-up. ACE2 levels above the sample median (≥4.9 pM; adjusted HR [95% CI]: 0.10 [0.02, 0.43]) and ACE2/ACE ratio (≥6.0 × 10^-3; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log₂-normalized, time-varying predictors from <i>day 0</i> to <i>day 5</i>, twofold increments of ACE2 and ACE2/ACE ratio over this period were associated with lower mortality (adjusted HR: 0.79 [0.65, 0.97] and 0.78 [0.63, 0.97], respectively). Circulating Ang II, Ang-(1-7), and ACE levels were not associated with mortality. These results suggest higher circulating ACE2 protein in hospitalized patients with COVID-19 is associated with reduced mortality.<b>NEW & NOTEWORTHY</b> We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L405-L412"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063094","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":"Cannabis vaping elicits transcriptomic and metabolomic changes involved in inflammatory, oxidative stress, and cancer pathways in human bronchial epithelial cells.","authors":"Maddison T Arlen, Stephanie J Patterson, Michelle K Page, Rui Liu, Vincenza Caruana, Emily T Wilson, Stéphane A Laporte, Maciej L Goniewicz, Cory S Harris, David H Eidelman, Carolyn J Baglole","doi":"10.1152/ajplung.00131.2024","DOIUrl":"10.1152/ajplung.00131.2024","url":null,"abstract":"<p><p>The increasing shift from cannabis smoking to cannabis vaping is largely driven by the perception that vaping to form an aerosol represents a safer alternative to smoking and is a form of consumption appealing to youth. Herein, we compared the chemical composition and receptor-mediated activity of cannabis smoke extract (CaSE) to cannabis vaping extract (CaVE) along with the biological response in human bronchial epithelial cells. Chemical analysis using HPLC and GC/MS revealed that cannabis vaping aerosol contained fewer toxicants than smoke; CaSE and CaVE contained teratogens, carcinogens, and respiratory toxicants. A bioluminescence resonance energy transfer (BRET)-based biosensor detected the receptor-mediated activity of the extracts, primarily driven by Δ⁹-tetrahydrocannabinol (Δ⁹-THC) concentration. RNA-sequencing showed both CaSE and CaVE induced similar transcriptional responses, significantly upregulating genes within pathways related to inflammation, cancer, and cellular stress. This was paralleled by downregulation of pathways related to lipid synthesis and metabolism from both CaSE and CaVE. Targeted metabolomics revealed significant changes in metabolites involved in lipid and membrane metabolism, energy production, nucleotide/DNA/RNA pathways, and oxidative stress response, suggesting potential impairment of lung epithelial cell repair and function. In addition, the upregulation of 5-hydroxymethylcytosine (5hmC) indicates epigenetic changes potentially contributing to inflammation, oxidative stress, and an increased risk of cancer. These findings challenge the notion that cannabis vaping is risk-free, highlighting an urgent need for comprehensive research into its respiratory health effects. This comparison of cannabis consumption methods offers insights that could inform public health policies and raise consumer awareness regarding the potential risks of inhaling cannabis aerosol.<b>NEW & NOTEWORTHY</b> Cannabis use is increasing worldwide amid broad acceptance and legalization. The prevalence of traditional smoking is diminishing in favor of vaping dry flower. This is the first study to provide initial evidence that cannabis aerosol contains carcinogenic, teratogenic, and respiratory toxicants that induce transcriptional responses in epithelial cells analogous to those from cannabis smoke, suggesting potential adverse pulmonary effects.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L478-L496"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998436","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":"Distinct single-cell transcriptional profile in CD4+ T-lymphocytes among obese children with asthma.","authors":"Vickram Tejwani, Rulin Wang, Andres Villabona-Rueda, Karthik Suresh, Tianshi David Wu, Ian M Adcock, Nazanin Z Kermani, Joe Zein, Nadia N Hansel, Srinivasan Yegnasubramanian, Meredith C McCormack, Franco R D'Alessio","doi":"10.1152/ajplung.00270.2024","DOIUrl":"10.1152/ajplung.00270.2024","url":null,"abstract":"<p><p>Obesity is a risk factor for asthma morbidity, associated with less responsiveness to inhaled corticosteroids. CD4+ T cells are central to the immunology of asthma and may contribute to the unique obese asthma phenotype. We sought to characterize the single-cell CD4+ transcriptional profile differences in obese children with asthma compared with normal-weight children with asthma. Eight normal-weight and obese participants with asthma were clinically phenotyped and matched based on asthma control. Peripheral blood (PB) CD4+ T cells were sorted, and single-cell RNA sequencing was conducted. Cell clusters were identified by canonical gene expression and differential gene expression and reactome pathway analysis was applied. The obese PB bulk transcriptomic signature from the U-BIOPRED pediatric cohort was assessed in our cohort as well. Obese children with asthma have a distinct CD4+ transcriptional profile with differential gene expression. There were more activated protein tyrosine phosphate receptor type C (PTPRC)^high cells and less PTPRC^low in children with obesity. Children with obesity had higher enrichment of the neutrophil degranulation, interleukin-7 (IL-7) receptor, and IL-7-related janus kinase-signal transducer and activator of transcription signaling pathways. Genes previously associated with more severe asthma, <i>IL-32</i>, <i>FKBP5</i> gene expression, <i>IL-6</i>, and Rho transcriptional signaling, were also enriched in obese children with asthma. Our findings shed insight into the molecular mechanisms underpinning more severe and steroid-resistant asthma among children with obesity. Further investigation is needed to identify potential new therapeutic targets for this group.<b>NEW & NOTEWORTHY</b> This study identified unique contributors to asthma in children with obesity and found novel pathways. Increased expression of IL-7R, IL-32, PARP-1, <i>FKBP5</i> gene, IL-6, and Rho transcriptional signaling were observed in obese individuals with asthma.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L372-L378"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045562","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":"Effects of maternal edible THC consumption on offspring lung growth and function in a rhesus macaque model.","authors":"Lyndsey E Shorey-Kendrick, B Adam Crosland, Matthias C Schabel, Ilhem Messaoudi, Minzhe Guo, Matthew G Drake, Zhenying Nie, R Clayton Edenfield, Issac Cinco, Michael H Davies, Jason A Graham, Olivia L Hagen, Owen J T McCarty, Cindy T McEvoy, Eliot R Spindel, Jamie O Lo","doi":"10.1152/ajplung.00360.2024","DOIUrl":"10.1152/ajplung.00360.2024","url":null,"abstract":"<p><p>Prenatal cannabis use is rising, in part due to legalization and perceptions of safety. The impact of prenatal cannabis exposure on offspring development, especially respiratory health, remains largely unknown. The objective of this study was to determine whether in utero exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, is deleterious to offspring lung development and function using a rhesus macaque model. Female rhesus macaques received a daily edible containing either THC (2.5 mg/7 kg/day, equivalent to a heavy medical cannabis dose) or placebo during gestation and postnatally. Serial in utero magnetic resonance imaging (MRI) was performed during pregnancy at approximately gestational days (G)110 and G150. At 6 mo of age, infants underwent pulmonary function testing, followed by tissue collection for molecular analysis (bulk RNAseq, whole genome bisulfite sequencing, and spatial RNAseq). THC-exposed infants displayed significantly reduced forced residual capacity, which correlated with nonsignificant decreases in total lung capacity, lung diffusion capacity and lower fetal lung perfusion, oxygen availability, and lung volume measured by MRI. Consistent with these decreases in volume indices, levels of pulmonary growth factors were decreased in bronchial alveolar lavage at 6 mo. Molecular analysis of infant lungs revealed altered epigenetic regulation of gene expression, including at genes involved in extracellular matrix organization and lung development, and activation of immune signaling. Our study suggests that exposure to prenatal edible THC alters epigenetic regulation of lung gene expression and may negatively affect offspring lung development and function. Data from this study will help guide healthcare provider counseling on cannabis use in pregnancy.<b>NEW & NOTEWORTHY</b> In a translational rhesus macaque model, chronic prenatal delta-9-tetrahydrocannabinol exposure resulted in decreased lung volumes in offspring measured at 6 mo of age. These decreases correlated with altered DNA methylation in the lung, including at genes involved in extracellular matrix organization, lung development, and activation of immune signaling, and changes in lung cell composition as measured by spatial transcriptomics. These findings add to the growing evidence that prenatal cannabis exposure may adversely affect offspring development.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L463-L477"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187682","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":"Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.","authors":"Anna Birnhuber, Valentina Biasin, Pritesh P Jain, Grzegorz Kwiatkowski, Ekaterina Boiarina, Jochen Wilhelm, Katharina Ahrens, Chandran Nagaraj, Andrea Olschewski, Martin Witzenrath, Stefan Chlopicki, Leigh M Marsh, Christoph Tabeling, Grazyna Kwapiszewska","doi":"10.1152/ajplung.00274.2024","DOIUrl":"10.1152/ajplung.00274.2024","url":null,"abstract":"<p><p>Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused, and ventilated lungs of Fra-2 TG mice compared with wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary arterial smooth muscle cells (PASMCs) with elevated intracellular calcium levels after interleukin (IL)-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH.<b>NEW & NOTEWORTHY</b> In patients suffering from systemic sclerosis (SSc), pulmonary arterial hypertension (PAH) is a life-threatening complication linked to immune dysregulation. Preclinical analyses in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH, identify type 2 inflammation as a key driver of vascular remodeling. Anti-inflammatory treatment targeting type 2 inflammation via IL-13 neutralizing antibodies improved pulmonary vascular remodeling. Thus, type 2-specific anti-inflammatory treatment may be a promising therapeutic approach in SSc-PAH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L413-L429"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187746","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":"Surfactant protein levels and genetic variants as biomarkers for COVID-19 severity in children.","authors":"Natalie Sicher, Brycen Aldrich, Shaoyi Zhang, Lauren Mazur, Susan Juarez, Erik Lehman, Dajiang Liu, Chintan K Gandhi","doi":"10.1152/ajplung.00318.2024","DOIUrl":"10.1152/ajplung.00318.2024","url":null,"abstract":"<p><p>Since its outbreak, the novel coronavirus (COVID-19) has significantly impacted the pediatric population. Pulmonary surfactant dysfunction has been linked to other respiratory diseases in children and COVID-19 in adults, but its role in COVID-19 severity remains unclear. We hypothesized that elevated surfactant protein (SP) levels and single nucleotide polymorphisms (SNPs) of SP genes are associated with severe COVID-19 in children. We enrolled 325 COVID-19 positive children and categorized them as having mild or severe disease. Plasma SP-A, SP-B, and SP-D levels were measured. DNA was extracted and genotyped for SNPs in five SP genes, <i>SFTPA1</i>, <i>SFTPA2</i>, <i>SFTPB</i>, <i>SFTPC</i>, and <i>SFTPD</i>. Quantile regression was used to compare SP levels between groups, and receiver operating curve analysis determined an optimal cutoff value of SP level for predicting severe COVID-19. Logistic regression evaluated the odds ratio (OR) for severe disease and associations between SNPs and COVID-19 severity. We found that increased plasma SP-A levels, but not SP-B or SP-D, were significantly associated with severe COVID-19. No significant correlation was observed between age and SP levels. A plasma SP-A level of 10 ng/mL was identified as the optimal cutoff for predicting severe COVID-19, with an OR of 5.9, indicating that children with SP-A levels above this threshold are nearly six times more likely to develop severe COVID-19 disease. In addition, the rs8192340 of <i>SFTPC</i> was associated with decreased risk of severe COVID-19 before, but not after, Bonferroni correction. These findings suggest that plasma SP-A may serve as a potential biomarker for severe COVID-19 in children.<b>NEW & NOTEWORTHY</b> Surfactant dysfunction is linked to other pulmonary diseases, but its role in pediatric coronavirus (COVID-19) is unclear. We found elevated plasma surfactant protein (SP)-A levels, but not SP-B or SP-D, significantly associated with severe COVID-19. A plasma SP-A threshold of 10 ng/mL predicted severe COVID-19. The rs8192340 of <i>SFTPC</i> was associated with decreased risk of severe COVID-19 before, but not after, Bonferroni correction. These findings suggest plasma SP-A may serve as a potential biomarker for pediatric COVID-19 severity.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L350-L356"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998497","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":"Every breath you take: exploring macrophages and environmental exposures in the lung-a tribute to Dr. Joseph Brain's legacy.","authors":"Larissa A Shimoda, Julie A Bastarache, Rodney D Britt, Wolfgang M Kuebler","doi":"10.1152/ajplung.00407.2024","DOIUrl":"10.1152/ajplung.00407.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L321-L323"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998421","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":"Shear stress-induced restoration of pulmonary microvascular endothelial barrier function following ischemia reperfusion injury requires VEGFR2 signaling.","authors":"Don Walsh, Daria S Kostyunina, Aoife Blake, John Boylan, Paul McLoughlin","doi":"10.1152/ajplung.00200.2024","DOIUrl":"10.1152/ajplung.00200.2024","url":null,"abstract":"<p><p>Normal shear stress produced by blood flow is sensed by the vascular endothelium and required for maintenance of the homeostatic functions of the endothelium in systemic conduit and resistance vessels. Many critical illnesses are characterized by periods of abnormally reduced or absent shear stress in the lung (e.g., hemorrhagic shock, embolism, ischemia reperfusion injury, and lung transplantation) and are complicated by pulmonary edema following reperfusion due to microvascular leak. The role of shear stress in regulating the pulmonary microvascular endothelial barrier in the intact vascular bed has not been previously examined. We tested the hypothesis that, in lungs injured by a period of ischemia and reperfusion (IRI), reduced shear stress contributes to increased pulmonary microvascular endothelial barrier permeability and edema formation. Furthermore, we examined the role of vascular endothelial-derived growth factor receptor 2 (VEGFR2) as a mechanosensor mediating the endothelial response to this altered shear stress. Following IRI, we perfused isolated ventilated mouse lungs with a low viscosity solution (LVS) or a higher, physiological viscosity solution (PVS) at constant flow to produce differing endothelial shear stresses in the intact microcirculation. Lungs perfused with LVS developed pulmonary edema due to increased endothelial permeability whereas those perfused with PVS were protected from edema formation by reduced endothelial permeability. This effect of PVS required normal VEGFR2 mechanoreceptor function. These data show for the first time that shear stress has an important role in restoring endothelial barrier function in the intact pulmonary microcirculation following injury and have important implications for the treatment of pulmonary edema in critically ill patients.<b>NEW & NOTEWORTHY</b> Critical illnesses are frequently complicated by noncardiogenic pulmonary edema. Many such illnesses include periods of reduced blood flow, often accompanied by hemodilution, which together reduce endothelial shear stress. We report that in ischemia-reperfusion injury reduced shear stress contributes to increased permeability of the in situ pulmonary microvascular endothelium and worsens alveolar edema. Restoring shear stress toward normal reduces endothelial permeability and edema formation, an effect that requires the normal mechanoreceptor function of VEGFR2.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L389-L404"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863000","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 mysterious case of missing lymphocytes: a cautionary tale of interinstitutional variability in outcomes of lung dissociation protocols.","authors":"Olivia S Harlow, Vijay Raaj Ravi, Fang Ke, Nathan L Sanders, Elise Armstrong, Joseph P Mizgerd, Anukul T Shenoy","doi":"10.1152/ajplung.00323.2024","DOIUrl":"10.1152/ajplung.00323.2024","url":null,"abstract":"<p><p>Rigor and reproducibility are vital to scientific advancement. It is unclear whether a protocol optimized for tissue dissociation in one institution performs well universally. Here, we share our brand-new lab's experience with interinstitutional variability that led to the discovery that a protocol optimized for murine lung dissociation at Boston University (BU) fails to reproduce similar CD4⁺ T cell, CD8⁺ T cell, and B cell outcomes at the University of Michigan at Ann Arbor (U-M). We report that the type 2 collagenase-based protocol from BU yields reduced numbers of lung lymphocytes at U-M, and this appeared to be a result of harsher collagenase activity despite using identical protocols, reagents, and vendors at both institutions. This variability could not be explained by higher Ca²⁺ levels in Ann Arbor water (which we posited may heighten the collagenase activity) but instead appeared to be due to technical details within the protocol that led to the protocols behaving in an institution-specific manner. Indeed, we find that merely switching between the protocol from BU and a newly optimized protocol at U-M was sufficient to improve (or worsen) lymphocyte yields from murine lungs when synchronously performed at both institutions. Taken together, although the reason(s) for the interinstitutional variability in lymphocyte outcomes remains unknown, this report serves as a cautionary tale against directly adopting lung dissociation protocols across institutions without reoptimization, and calls for careful inspection of cross-institutional reproducibility of previously described protocols.<b>NEW & NOTEWORTHY</b> Rigor and reproducibility are vital to scientific advancement. It is unclear whether a protocol optimized for tissue dissociation in one institution performs well universally. Here, the authors share their experience with interinstitutional variability that led to the discovery that a protocol optimized for murine lung dissociation in one institution failed to reproduce similar lymphocyte outcomes elsewhere. This report, thus, serves as a cautionary tale against directly adopting tissue dissociation protocols across institutions without reoptimization.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L260-L266"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941552","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}