American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Can ENaC \"TIP\" the Scales to Reduce Endothelial ROS and Vascular Leak During Pneumococcal Lung Injury?","authors":"Alison W Ha, Eleftheria Letsiou, Steven M Dudek","doi":"10.1165/rcmb.2024-0486ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0486ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602771","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":"Circulating mtNFPs Are Associated with ARDS after CPB and Regulate Endothelial Barrier through FPR2.","authors":"Peng Lu, Xiaopei Li, Jinqiang Wang, Xiangyu Li, Zihao Shen, Yuanpu Qi, Mingyu Chu, Xin Yao, Xiao Zhang, Yu Zheng, Faliang Zhan, Meijuan Song, Xiaowei Wang","doi":"10.1165/rcmb.2024-0076OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0076OC","url":null,"abstract":"<p><p>Cardiopulmonary bypass (CPB) increases the risk of acute respiratory distress syndrome (ARDS) due to endothelial cell (EC) barrier dysfunction. However, the specific role of mitochondrial N-formyl peptides (mtNFPs) in ARDS following CPB remains unexplored. Here, we investigated the differential expression of circulating mtNFPs in patients after CPB, focusing on the novel role of FPR2 in ECs. Levels of circulating mtNFPs were assessed using enzyme-linked immunosorbent assay (ELISA). Several mtNFPs (ND4, ND5, ND6, and Cox1) were significantly upregulated in patients with ARDS at day 1 post-CPB compared to patients without ARDS. Higher levels of ND6 were correlated with worst PaO₂/FiO₂ (r=-0.2219 and P<0.0001) and cardiac Troponin T (r=2.107 and P<0.0001). Utilizing patient-derived serum and a rat lung ischemia reperfusion injury (LIRI) model, we observed a positive correlation between serum ND6 concentration and ARDS, which is also associated with EC barrier dysfunction. In vitro experiments, using trans-endothelial electric resistance (TEER) measurements and fluorescence microscopy with FITC-labeled VE-cadherin, demonstrated that ND6 disrupts the EC barrier through FPR2. Furthermore, FPR2 controls the release of ND6 out of mitochondria and cytoplasm under hypoxia reoxygenation (HR). Activated FPR2 leads to upregulation of nuclear transcription factor-kappa B (NF-κB) by inducing IκBα phosphorylation, promoting ICAM1 and VCAM1 expression, thereby compromising EC barrier integrity. Circulating pro-inflammatory and barrier-disruptive mtNFPs, particularly ND6, are associated with ARDS in patients undergoing CPB. The novel ND6-FPR2 axis regulates inflammation and EC permeability through the NF-κB pathway.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602774","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":"https://doi.org/10.1165/rcmb.2024-0413MA","url":null,"abstract":"<p><p>Studies using human lung organoids (hLO) have focused on differentiation of lung epithelial subtypes into distal alveolar unit. A major question has been whether introducing endothelial cells (EC) and resultant vascularization alter development of hLO. We describe herein a method for vessel infiltration of hLO in which we determined differences of these hLOs with standard avascular hLOs. hLO are generated by combining hiPSC-derived lung progenitor cells (LP) with EC at different LP:EC ratios. This results in vascularization of hLO and enables comparisons with hLO generated without EC. We observe red blood-filled vessels in hLOs generated post-implantation into the kidney capsule of NOD/SCID mice. Both human and mouse EC conjoin in the capsule to form chimeric vessels in hLOs. Vessel-infiltrating hLOs show robust generation of alveolar type II epithelial cells (ATII) and alveolar type I cells (ATI), although there was no difference in the observed 1:1 ATII/ATI cell ratio. Electron microscopy revealed better-developed surfactant production apparatus in ATII of vascularized hLOs compared to avascular hLOs. We observed prominent primitive airway sacs with alveolar epithelial cells lining lumen in vascularized vs. avascular hLOs. The vessel-infiltrating hLOs also mounted a robust inflammatory response characterized by mouse PMN influx after challenging host mice with lipopolysaccharide. Thus, interaction of EC with LP generated vascularized hLOs and drive ATII and ATI differentiation and hLOs also mount a robust inflammatory response upon LPS challenge of hLO-transplanted recipient mice. Our results show usefulness of generating hLOs in studying human lung development and mechanisms underlying inflammatory lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-08","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":"Enhanced Gαq Signaling in <i>TSC2</i>-deficient Cells Is Required for Their Neoplastic Behavior.","authors":"Aurélie Tréfier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof","doi":"10.1165/rcmb.2024-0111OC","DOIUrl":"10.1165/rcmb.2024-0111OC","url":null,"abstract":"<p><p>Inherited or sporadic loss of the <i>TSC2</i> gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage ('LAM cells'). Their aberrant growth is attributed to increased activity of 'mechanistic target of rapamycin complex 1' (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM, but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G-protein coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in <i>TSC2</i>-deficient cells remained unknown. Using a human pluripotent stem cell-derived <i>in vitro</i> model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and pro-neoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking <i>TSC2</i> demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared to wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in <i>TSC2</i>-deleted cells was independent of mTOR activity, and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent pro-neoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602776","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":"Precision Cut Lung Slices: Emerging Tools for Preclinical and Translational Lung Research. An Official American Thoracic Society Workshop Report.","authors":"Mareike Lehmann, Ramaswamy Krishnan, Jennifer Sucre, Hrishikesh S Kulkarni, Ricardo H Pineda, Christopher Anderson, Nicholas E Banovich, Holger P Behrsing, Charlotte H Dean, Andrew Haak, Reinoud Gosens, Naftali Kaminski, Anna Zagorska, Cynthia Koziol-White, Jordan P Metcalf, Yong Ho Kim, Claudia Loebel, Enid Neptune, Alexandra Noel, Ganesh Raghu, Katherina Sewald, Ashish Sharma, Bela Suki, Anne Sperling, Amanda Tatler, Scott Turner, Ivan O Rosas, Pam van Ry, Timo Wille, Scott H Randell, Gloria Pryhuber, Mauricio Rojas, Jane Bourke, Melanie Königshoff","doi":"10.1165/rcmb.2024-0479ST","DOIUrl":"10.1165/rcmb.2024-0479ST","url":null,"abstract":"<p><p>The urgent need for effective treatments for acute and chronic lung diseases underscores the significance of developing innovative preclinical human research tools. The 2023 ATS Workshop on Precision Cut Lung Slices (PCLS) brought together 35 experts to discuss and address the role of human tissue-derived PCLS as a unique tool for target and drug discovery and validation in pulmonary medicine. With increasing interest and usage, along with advancements in methods and technology, there is a growing need for consensus on PCLS methodology and readouts. The current document recommends standard reporting criteria and emphasizes the requirement for careful collection and integration of clinical metadata. We further discuss current clinically relevant readouts that can be applied to PCLS and highlight recent developments and future steps for implementing novel technologies for PCLS modeling and analysis. The collection and correlation of clinical metadata and multiomic analysis will further advent the integration of this preclinical platform into patient endotyping and the development of tailored therapies for lung disease patients.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581622","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":"Novel Porcine Model Reveals Two Distinct LGR5 Cell Types During Lung Development and Homeostasis.","authors":"Kathryn M Polkoff, Ross Lampe, Nithin K Gupta, Yanet Murphy, Jaewook Chung, Amber Carter, Jeremy M Simon, Katherine Gleason, Adele Moatti, Preetish K Murthy, Laura Edwards, Alon Greenbaum, Aleksandra Tata, Purushothama Rao Tata, Jorge A Piedrahita","doi":"10.1165/rcmb.2024-0040OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0040OC","url":null,"abstract":"<p><p>Cells expressing LGR5 play a pivotal role in homeostasis, repair, and regeneration in multiple organs including skin and gastrointestinal tract, yet little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5⁺ cells in the lung that are conserved in human, but not mouse lungs. Using RNA sequencing, 3D imaging and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9⁺/ETV⁺/SFTPC⁺ progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung, but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5⁺ cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5⁺ cells include a subset of peribronchial fibroblasts (PBF) that express unique patterns of <i>SHH, FGF, WNT</i> and <i>TGF-β</i> signaling pathway genes. These results support distinct roles for LGR5⁺ cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581619","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":"Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.","authors":"Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk","doi":"10.1165/rcmb.2023-0249OC","DOIUrl":"10.1165/rcmb.2023-0249OC","url":null,"abstract":"<p><p>Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581617","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":"Endoplasmic Reticulum Oxidative Stress Promotes Glutathione-Dependent Oxidation of Collagen-1A1 and Promotes Lung Fibroblast Activation.","authors":"Joseph E Druso, Maximilian B MacPherson, Shi B Chia, Evan Elko, Reem Aboushousha, David J Seward, Hend Abdelhamid, Cuixia Erickson, Elizabeth Corteselli, Megan Tarte, Zhihua Peng, Daniel Bernier, Ester Zito, Matthew D Shoulders, Victor J Thannickal, Steven Huang, Albert van der Vliet, Vikas Anathy, Yvonne M W Janssen-Heininger","doi":"10.1165/rcmb.2023-0379OC","DOIUrl":"10.1165/rcmb.2023-0379OC","url":null,"abstract":"<p><p>Changes in the oxidative (redox) environment accompany idiopathic pulmonary fibrosis (IPF). S-glutathionylation of reactive protein cysteines is a post-translational event that transduces oxidant signals into biological responses. We recently demonstrated that increases in S-glutathionylation promote pulmonary fibrosis, which was mitigated by the deglutathionylating enzyme glutaredoxin (GLRX). However, the protein targets of S-glutathionylation that promote fibrogenesis remain unknown. In the present study we addressed whether the extracellular matrix is a target for S-glutathionylation. We discovered increases in COL1A1 (collagen 1A1) S-glutathionylation (COL1A1-SSG) in lung tissues from subjects with IPF compared with control subjects in association with increases in ERO1A (endoplasmic reticulum [ER] oxidoreductin 1) and enhanced oxidation of ER-localized PRDX4 (peroxiredoxin 4), reflecting an increased oxidative environment of the ER. Human lung fibroblasts exposed to TGFB1 (transforming growth factor-β1) show increased secretion of COL1A1-SSG. Pharmacologic inhibition of ERO1A diminished the oxidation of PRDX4, attenuated COL1A1-SSG and total COL1A1 concentrations, and dampened fibroblast activation. Absence of <i>Glrx</i> enhanced COL1A1-SSG and overall COL1A1 secretion and promoted the activation of mechanosensing pathways. Remarkably, COL1A1-SSG resulted in marked resistance to collagenase degradation. Compared with COL1, lung fibroblasts plated on COL1-SSG proliferated more rapidly and increased the expression of genes encoding extracellular matrix crosslinking enzymes and genes linked to mechanosensing pathways. Overall, these findings suggest that glutathione-dependent oxidation of COL1A1 occurs in settings of IPF in association with enhanced ER oxidative stress and may promote fibrotic remodeling because of increased resistance to collagenase-mediated degradation and fibroblast activation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"589-602"},"PeriodicalIF":8.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747232","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":"Iron Alters the Transcriptome and Volatile Organic Compounds in the BAL of Patients with Silicosis.","authors":"Christian Anthony Aloe, Nicole Soo Leng Goh, Hao Wang, Jonathan Luke McQualter, Sheik Nadeem Elahee Doomun, David De Souza, Reshma Pujari, Paris Claris Papagianis, Simon Hall Apte, Hayley Barnes, Ross Vlahos, Christine Faye McDonald, Ryan Francis Hoy, Daniel Charles Chambers, Tracy Li-Tsein Leong, Steven Bozinovski","doi":"10.1165/rcmb.2024-0181LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0181LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"71 5","pages":"617-621"},"PeriodicalIF":5.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556938","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":"Plasmacytoid Dendritic Cells: Bring a Glimmer of Hope for Patients with Lymphangioleiomyomatosis.","authors":"Heng Du, Heng-Jia Liu","doi":"10.1165/rcmb.2024-0266ED","DOIUrl":"10.1165/rcmb.2024-0266ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"503-504"},"PeriodicalIF":8.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625714","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}