{"title":"Application of Metabolomics across the Spectrum of Pulmonary and Critical Care Medicine.","authors":"Catherine E Simpson, Julie G Ledford, Gang Liu","doi":"10.1165/rcmb.2024-0080PS","DOIUrl":"10.1165/rcmb.2024-0080PS","url":null,"abstract":"<p><p>In recent years, metabolomics, the systematic study of small-molecule metabolites in biological samples, has yielded fresh insights into the molecular determinants of pulmonary diseases and critical illness. The purpose of this article is to orient the reader to this emerging field by discussing the fundamental tenets underlying metabolomics research, the tools and techniques that serve as foundational methodologies, and the various statistical approaches to analysis of metabolomics datasets. We present several examples of metabolomics applied to pulmonary and critical care medicine to illustrate the potential of this avenue of research to deepen our understanding of pathophysiology. We conclude by reviewing recent advances in the field and future research directions that stand to further the goal of personalizing medicine to improve patient care.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317623","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}
Ya Wen, Xiang Zhang, Nicola Cacciani, Yvette Hedström, Yuji Ikeno, Jonas Bergquist, Lars Larsson
{"title":"Proteomics Panel of BAL Fluid Associated with Ventilator-induced Lung Injury.","authors":"Ya Wen, Xiang Zhang, Nicola Cacciani, Yvette Hedström, Yuji Ikeno, Jonas Bergquist, Lars Larsson","doi":"10.1165/rcmb.2023-0431LE","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0431LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465611","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":"July Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.71i1RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.71i1RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465609","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}
Rhianna F Baldi, Marissa W Koh, Chubicka Thomas, Tomasz Sabbat, Bincheng Wang, Stefania Tsatsari, Kieron Young, Alexander Wilson-Slomkowski, Sanooj Soni, Kieran P O'Dea, Brijesh V Patel, Masao Takata, Michael R Wilson
{"title":"Ventilator-induced Lung Injury Promotes Inflammation within the Pleural Cavity.","authors":"Rhianna F Baldi, Marissa W Koh, Chubicka Thomas, Tomasz Sabbat, Bincheng Wang, Stefania Tsatsari, Kieron Young, Alexander Wilson-Slomkowski, Sanooj Soni, Kieran P O'Dea, Brijesh V Patel, Masao Takata, Michael R Wilson","doi":"10.1165/rcmb.2023-0332OC","DOIUrl":"10.1165/rcmb.2023-0332OC","url":null,"abstract":"<p><p>Mechanical ventilation contributes to the morbidity and mortality of patients in intensive care, likely through the exacerbation and dissemination of inflammation. Despite the proximity of the pleural cavity to the lungs and exposure to physical forces, little attention has been paid to its potential as an inflammatory source during ventilation. Here, we investigate the pleural cavity as a novel site of inflammation during ventilator-induced lung injury. Mice were subjected to low or high tidal volume ventilation strategies for up to 3 hours. Ventilation with a high tidal volume significantly increased cytokine and total protein levels in BAL and pleural lavage fluid. In contrast, acid aspiration, explored as an alternative model of injury, only promoted intraalveolar inflammation, with no effect on the pleural space. Resident pleural macrophages demonstrated enhanced activation after injurious ventilation, including upregulated ICAM-1 and IL-1β expression, and the release of extracellular vesicles. <i>In vivo</i> ventilation and <i>in vitro</i> stretch of pleural mesothelial cells promoted ATP secretion, whereas purinergic receptor inhibition substantially attenuated extracellular vesicles and cytokine levels in the pleural space. Finally, labeled protein rapidly translocated from the pleural cavity into the circulation during high tidal volume ventilation, to a significantly greater extent than that of protein translocation from the alveolar space. Overall, we conclude that injurious ventilation induces pleural cavity inflammation mediated through purinergic pathway signaling and likely enhances the dissemination of mediators into the vasculature. This previously unidentified consequence of mechanical ventilation potentially implicates the pleural space as a focus of research and novel avenue for intervention in critical care.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064271","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}
Baktybek Kojonazarov, Nils Kremer, Christina Pilz, Hossein Ardeschir Ghofrani, Norbert Weissmann, Robert Naeije, Werner Seeger, Ralph T Schermuly, Khodr Tello
{"title":"Single- versus Multiple-Beat Measurement of Right Ventricular Function in Rodents.","authors":"Baktybek Kojonazarov, Nils Kremer, Christina Pilz, Hossein Ardeschir Ghofrani, Norbert Weissmann, Robert Naeije, Werner Seeger, Ralph T Schermuly, Khodr Tello","doi":"10.1165/rcmb.2023-0407LE","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0407LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465612","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}
Eric D Morrell, Sarah E Holton, Alice Wiedeman, Susanna Kosamo, Mallorie A Mitchem, Victoria Dmyterko, Zoie Franklin, Ashley Garay, Ian B Stanaway, Ted Liu, Neha A Sathe, F Linzee Mabrey, Renee D Stapleton, Uma Malhotra, Cate Speake, Jessica A Hamerman, Sudhakar Pipavath, Laura Evans, Pavan K Bhatraju, S Alice Long, Mark M Wurfel, Carmen Mikacenic
{"title":"PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in ARDS.","authors":"Eric D Morrell, Sarah E Holton, Alice Wiedeman, Susanna Kosamo, Mallorie A Mitchem, Victoria Dmyterko, Zoie Franklin, Ashley Garay, Ian B Stanaway, Ted Liu, Neha A Sathe, F Linzee Mabrey, Renee D Stapleton, Uma Malhotra, Cate Speake, Jessica A Hamerman, Sudhakar Pipavath, Laura Evans, Pavan K Bhatraju, S Alice Long, Mark M Wurfel, Carmen Mikacenic","doi":"10.1165/rcmb.2024-0201OC","DOIUrl":"10.1165/rcmb.2024-0201OC","url":null,"abstract":"<p><p>The relationship between the Programmed Death-Ligand 1 (PD-L1)/Programmed Death-1 (PD-1) pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 (n = 59) and ARDS2 (n = 78)) or plasma samples alone (ARDS3 (n = 149)) collected from subjects with ARDS and tested for associations with mortality using multiple regression. We used mass cytometry to measure PD-L1/PD-1 expression and intracellular cytokine staining in cells isolated from bronchoalveolar lavage fluid (BALF) (n = 18) and blood (n = 16) from critically-ill subjects with or without ARDS enrolled from a fourth cohort. Higher plasma levels of sPD-L1 were associated with mortality in ARDS1, ARDS2, and ARDS3. In contrast, higher levels of sPD-L1 in the lung were either not associated with mortality (ARDS2) or were associated with survival (ARDS1). Alveolar PD-1<sup>POS</sup> T cells had more intracellular cytokine staining compared with PD-1<sup>NEG</sup> T cells. Subjects without ARDS had a higher ratio of PD-L1<sup>POS</sup> alveolar macrophages to PD-1<sup>POS</sup> T cells compared with subjects with ARDS. We conclude that sPD-L1 may have divergent cellular sources and/or functions in the alveolar vs. blood compartments given distinct associations with mortality. Alveolar leukocyte subsets defined by PD-L1/PD-1 cell-surface expression have distinct cytokine secretion profiles, and the relative proportions of these subsets are associated with ARDS.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475740","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}
Tahir Idris, Michael Bachmann, Marc Bacchetta, Bernhard Wehrle-Haller, Marc Chanson, Mehdi Badaoui
{"title":"Akt-driven TGF-β and DKK1 Secretion Impairs F508del Cystic Fibrosis Airway Epithelium Polarity.","authors":"Tahir Idris, Michael Bachmann, Marc Bacchetta, Bernhard Wehrle-Haller, Marc Chanson, Mehdi Badaoui","doi":"10.1165/rcmb.2023-0408OC","DOIUrl":"10.1165/rcmb.2023-0408OC","url":null,"abstract":"<p><p>Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is altered, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here, we evaluated the effect of highly effective modulator treatment (HEMT) on fibronectin apical deposition and investigated the intracellular mechanisms triggering the defect in polarity of the CF airway epithelium. To this end, primary cultures of CF (F508del variant) human airway epithelial cells (HAECs) and a HAEC line, Calu-3, knocked down for <i>CFTR</i> (CF transmembrane conductance regulator) were compared with control counterparts. We show that <i>CFTR</i> mutation in primary HAECs and <i>CFTR</i> knockdown cells promote the overexpression and oversecretion of TGF-β1 and DKK1 when cultured at an air-liquid interface. These dynamic changes result in hyperactivation of the TGF-β pathway and inhibition of the Wnt pathway through degradation of β-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-β and Wnt signaling pathways is reinforced by aberrant Akt signaling. Pharmacological manipulation of TGF-β, Wnt, and Akt pathways restored polarization of the F508del CF epithelium, a correction that was not achieved by HEMT. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization in primary airway epithelial cells and may provide an explanation to the mitigated efficacy of HEMT on lung infection in people with CF.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292428","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}
Nadia Milad, Sophie Aubin, Christine Racine, François Maltais, Yohan Bossé, Mathieu C Morissette
{"title":"Lung Tissue Transcriptomics Reveal Associations between Thymic Stromal Lymphopoietin Signaling, Mast Cells, and Airway Obstruction in Active Smokers.","authors":"Nadia Milad, Sophie Aubin, Christine Racine, François Maltais, Yohan Bossé, Mathieu C Morissette","doi":"10.1165/rcmb.2023-0416LE","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0416LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141465610","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}
Hélène Le Ribeuz, Anaïs Saint-Martin Willer, Benoit Chevalier, Maria Sancho, Bastien Masson, Mélanie Eyries, Vincent Jung, Ida Chiara Guerrera, Mary Dutheil, Kristelle El Jekmek, Loann Laubry, Gilles Carpentier, Francisco Perez-Vizcaino, Ly Tu, Christophe Guignabert, Marie-Camille Chaumais, Christine Péchoux, Marc Humbert, Alexandre Hinzpeter, Olaf Mercier, Véronique Capuano, David Montani, Fabrice Antigny
{"title":"Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction.","authors":"Hélène Le Ribeuz, Anaïs Saint-Martin Willer, Benoit Chevalier, Maria Sancho, Bastien Masson, Mélanie Eyries, Vincent Jung, Ida Chiara Guerrera, Mary Dutheil, Kristelle El Jekmek, Loann Laubry, Gilles Carpentier, Francisco Perez-Vizcaino, Ly Tu, Christophe Guignabert, Marie-Camille Chaumais, Christine Péchoux, Marc Humbert, Alexandre Hinzpeter, Olaf Mercier, Véronique Capuano, David Montani, Fabrice Antigny","doi":"10.1165/rcmb.2023-0185OC","DOIUrl":"10.1165/rcmb.2023-0185OC","url":null,"abstract":"<p><p>Pulmonary arterial (PA) hypertension (PAH) is a severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a <i>KCNK3</i> gene (Potassium channel subfamily K member 3; coding for outward K<sup>+</sup> channel) variant in a patient with dasatinib-associated PAH and investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control human PA smooth muscle cells (hPASMCs) and human pulmonary endothelial cells (hPECs), we evaluated the consequences of <i>KCNK3</i> knockdown on cell migration, mitochondrial membrane potential, ATP production, and <i>in vitro</i> tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp experiments revealed that the <i>KCNK3</i> variant represents a loss-of-function variant. Dasatinib contributed to PA constriction by decreasing KCNK3 function and expression. In control hPASMCs, <i>KCNK3</i> knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or <i>KCNK3</i> knockdown reduced the number of caveolae in hPECs. Moreover, <i>KCNK3</i> knockdown in control hPECs reduced migration, proliferation, and <i>in vitro</i> tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in <i>KCNK3</i> and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that a loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317624","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 Tale of Two Cytokines: IL-10 Blocks IFN-γ in Influenza A Virus-<i>Staphylococcus aureus</i> Coinfection.","authors":"Christina Sul, Eva Nozik, Christina Malainou","doi":"10.1165/rcmb.2024-0154ED","DOIUrl":"10.1165/rcmb.2024-0154ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849779","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}