American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.","authors":"Maritza J Romero, Qian Yue, Won Mo Ahn, Jürg Hamacher, Yusra Zaidi, Stephen Haigh, Supriya Sridhar, Joyce Gonzales, Martina Hudel, Yuqing Huo, Alexander D Verin, Betty S Pace, Brian K Stansfield, Mazharul Maishan, Enid R Neptune, Perenlei Enkhbaatar, Yunchao Su, Trinad Chakraborty, Graydon Gonsalvez, Edith Hummler, William B Davis, Vladimir Y Bogdanov, David J R Fulton, Gabor Csanyi, Michael A Matthay, Douglas C Eaton, Rudolf Lucas","doi":"10.1165/rcmb.2023-0440OC","DOIUrl":"10.1165/rcmb.2023-0440OC","url":null,"abstract":"<p><p>Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NOX2 (nicotinamide adenine dinucleotide phosphate hydrogen [NADPH] oxidase 2), involving the pneumococcal virulence factor PLY (pneumolysin). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of ENaC (epithelial sodium channel) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function-measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans blue dye incorporation in mouse lungs-after infection with pneumococci. PLY-induced hyperpermeability in human lung microvascular endothelial cell monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47^phox subunit (Western blotting) <i>in vitro</i> and by colocalization of CD31 and gp91^phox in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α knockout (enENaC-α knockout) mice develop increased capillary leak upon intratracheal instillation with PLY or pneumococci, compared with wild-type animals. TIP peptide diminishes capillary leak in <i>Streptococcus pneumoniae</i>-infected wild-type mice, without significantly increasing lung bacterial load. Lung slices from <i>S. pneumoniae</i>-infected enENaC-α knockout mice have significantly increased endothelial NOX2 expression, compared with infected cyclization recombination mice. In conclusion, enENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in acute respiratory distress syndrome, without impairing host defense.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"429-440"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455963","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":"Physiological Modeling of the Vascularized Human Lung Organoid.","authors":"Abdul S Qadir, Sukanta Das, Swathi Nedunchezian, Kaori Masuhara, Tushar J Desai, Jalees Rehman, Preetish Kadur Murthy, Yoshikazu Tsukasaki, Lijian Shao, Asrar B Malik","doi":"10.1165/rcmb.2024-0413MA","DOIUrl":"10.1165/rcmb.2024-0413MA","url":null,"abstract":"<p><p>Human lung organoids (hLOs) derived from induced pluripotent stem cells (iPSCs) are of great interest, as they inform lung development, such as differentiation of lung epithelial subtypes in the distal alveolar unit. An unaddressed question is whether introducing endothelial cells (ECs) and vascularization provides a better representation of hLOs. Here we describe a method in which vessels become integrated with hLOs. hLOs were generated by combining human iPSC-derived lung progenitor cells (LPs) with ECs at varying LP:EC ratios. At the optimal combination of both cells, we observed vessel infiltration of hLOs compared to without ECs. Red blood cells were seen in hLOs implanted into kidney capsules of NOD/SCID mice. Both human and mouse ECs conjoined to form chimeric vessels in hLOs. The vascularized hLOs showed alveolar type II epithelial (ATII) cells and ATI cells, although there was no difference in 1:1 ATII/ATI ratio. We observed primitive airway sacs with alveolar epithelial cells lining the lumen of vascularized hLOs. Electron microscopy revealed surfactant production in ATII cells of vascularized hLOs in contrast to absence of vessels. The vascularized hLOs also mounted a robust inflammatory response characterized by influx of mouse neutrophils after challenging mice with LPS. Thus, interactions of ECs with LPs generated vascularized hLOs that induced ATII and ATI differentiation, although not reaching to the ratio of 1:9 seen in mature human lungs. hLOs also showed the LPS induced inflammatory response upon transplantation into recipient mice. Our results show the potential of vascularized hLOs for studying human lung development and inflammatory lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"354-363"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602779","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":"ARF6 as a Novel Activator of HIF-2α in Pulmonary Arterial Hypertension.","authors":"Adam L Fellows, Chien-Nien Chen, Chongyang Xie, Nayana Iyer, Lukas Schmidt, Xiaoke Yin, Luke A Yates, Manuel Mayr, Andrew Cowburn, Lan Zhao, Beata Wojciak-Stothard","doi":"10.1165/rcmb.2024-0149OC","DOIUrl":"10.1165/rcmb.2024-0149OC","url":null,"abstract":"<p><p>ARF6 (ADP-ribosylation factor 6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wild-type, constitutively active, fast-cycling, and dominant-negative mutants of ARF6. The analysis revealed a novel link of ARF6 with HIF (hypoxia-inducible factor), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress, and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late-outgrowth endothelial colony-forming cells, and hypoxic mouse lungs <i>in vivo</i>. A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation, and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH endothelial colony-forming cells showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC, and oral CTC attenuated development of pulmonary hypertension in chronically hypoxic mice. We identify EGFR (epidermal growth factor receptor) as a direct interactor of ARF6 and EGFR signaling as a crucial mechanism linking ARF6 and HIF activation. In conclusion, we are the first to demonstrate a key role of ARF6 in the regulation of HIF-2α activation <i>in vitro</i> and <i>in vivo</i> and show that HIF-2α, a master regulator of vascular remodeling in PAH, can be targeted by a clinically approved antibiotic CTC.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"380-392"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646690","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":"Red Blood Cell Metabolic Responses during Acute Hypoxic Exercise in Healthy Adults.","authors":"Lindsay M Forbes, Francesca I Cendali, Travis Nemkov, Todd M Bull, Angelo D'Alessandro, Karen E Rawlinson, Robert C Roach, Andrew W Subudhi, Tim Lahm, William K Cornwell","doi":"10.1165/rcmb.2024-0178LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0178LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 4","pages":"456-459"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750720","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":"Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza.","authors":"Nurbek Mambetsariev, Manuel A Torres Acosta, Qianli Liu, Carla P Reyes Flores, Anthony M Joudi, Kathryn A Helmin, Jonathan K Gurkan, Elizabeth M Steinert, Luisa Morales-Nebreda, Benjamin D Singer","doi":"10.1165/rcmb.2024-0254LE","DOIUrl":"10.1165/rcmb.2024-0254LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 4","pages":"453-456"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750721","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":"April Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.72i4RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.72i4RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 4","pages":"iii-iv"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750718","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":"Guarding the Endothelium: SOX17's Crucial Role in Pulmonary Hypertension.","authors":"Xinyi Zhang, Zhiyu Dai","doi":"10.1165/rcmb.2024-0490ED","DOIUrl":"10.1165/rcmb.2024-0490ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"343-345"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543056","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":"Cracking the Code of the Jugular Vagal Sensory Neurons in Allergic Airway Responsiveness.","authors":"Aung Aung Kywe Moe","doi":"10.1165/rcmb.2024-0445ED","DOIUrl":"10.1165/rcmb.2024-0445ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"346-348"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543055","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":"Chronic Hypoxia in an EXTrauterine Environment for Neonatal Development Impairs Lung Development.","authors":"Maureen Peers de Nieuwburgh, Mallory Hunt, Prashant Chandrasekaran, Tiffany L Vincent, Kevin B Hayes, Isabel R Randazzo, Meredith Gunder, Felix R De Bie, Arthur Colson, Minqi Lu, Hongbo Wen, Sylvia N Michki, Jack Rychik, Fréderic Debiève, Jeremy Katzen, Lisa R Young, Marcus G Davey, Alan W Flake, J William Gaynor, David B Frank","doi":"10.1165/rcmb.2024-0012OC","DOIUrl":"10.1165/rcmb.2024-0012OC","url":null,"abstract":"<p><p>Severe fetal hypoxia poses a significant risk to lung development, resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development, we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 d gestational age) delivered by cesarean section was reduced, and animals were supported using the Extrauterine Environment for Neonatal Development through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared with their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions, with decreased macrovessel numbers and microvascular endothelial cell numbers and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB (surfactant protein B) and processed SFTPC protein expression concomitant with a decrease in alveolar type 2 cell number. These findings demonstrate that maternally independent fetal hypoxia predominantly affects distal airway development, alveolar type 2 cell number, and surfactant production, with mild effects on the vasculature.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"441-452"},"PeriodicalIF":5.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493007","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":"Esrrg Inhibition Protects Against PM2.5-induced Asthma Aggravation by Reducing Pde3b.","authors":"Zhihua Zhang, Tao Cai, Xin Zhang, Xingbin Li, Xin Wang","doi":"10.1165/rcmb.2024-0461OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0461OC","url":null,"abstract":"<p><p>PM2.5 exposure is closely linked to the exacerbation of asthma. Estrogen related receptor gamma (Esrrg), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM2.5 to establish a mouse model of asthma aggravation by PM2.5. In view of mRNA sequencing, <i>Esrrg</i> was the only member of nuclear receptor superfamily in the up-regulated differentially expressed genes in OVA compared with Naive groups as well as OVA+PM2.5 compared with OVA groups (|log₂ (fold change)|>1 and p<0.05). <i>In vivo</i>, adeno-associated virus carrying <i>Esrrg</i> shRNA (AAV-shEsrrg) was applied to silencing Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist GSK5182. Either AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM2.5-aggravated asthmatic mice. <i>In vitro</i>, isolated mouse primary tracheobronchial epithelial cells (MTEC) from mice were identified by detecting cytokeratin 7-positive cells. The treatment of adenovirus vector with shEsrrg or GSK5182 mitigated the cell damage induced by PM2.5. Notably, phosphodiesterase 3B (Pde3b) expression was declined by Esrrg inhibition <i>in vivo</i> and <i>in vitro</i>. Dual luciferase reporter and ChIP-PCR assays showed the binding of Esrrg to the Pde3b promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM2.5-deteriorated asthmatic mouse model and prevented PM2.5-driven MTEC injury through binding to the <i>Pde3b</i> promoter, which might contribute to further study the therapy of PM2.5-aggravated asthma.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735540","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}