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IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.

Identifieur interne : 000520 ( Main/Exploration ); précédent : 000519; suivant : 000521

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.

Auteurs : Sujin Kang [Japon] ; Toshio Tanaka [Japon] ; Hitomi Inoue [Japon] ; Chikako Ono [Japon] ; Shoji Hashimoto [Japon] ; Yoshiyuki Kioi [Japon] ; Hisatake Matsumoto [Japon] ; Hiroshi Matsuura [Japon] ; Tsunehiro Matsubara [Japon] ; Kentaro Shimizu [Japon] ; Hiroshi Ogura [Japon] ; Yoshiharu Matsuura [Japon] ; Tadamitsu Kishimoto [Japon]

Source :

RBID : pubmed:32826331

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English descriptors

Abstract

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.

DOI: 10.1073/pnas.2010229117
PubMed: 32826331
PubMed Central: PMC7486751


Affiliations:


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Le document en format XML

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<name sortKey="Tanaka, Toshio" sort="Tanaka, Toshio" uniqKey="Tanaka T" first="Toshio" last="Tanaka">Toshio Tanaka</name>
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<name sortKey="Inoue, Hitomi" sort="Inoue, Hitomi" uniqKey="Inoue H" first="Hitomi" last="Inoue">Hitomi Inoue</name>
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<name sortKey="Hashimoto, Shoji" sort="Hashimoto, Shoji" uniqKey="Hashimoto S" first="Shoji" last="Hashimoto">Shoji Hashimoto</name>
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<name sortKey="Kioi, Yoshiyuki" sort="Kioi, Yoshiyuki" uniqKey="Kioi Y" first="Yoshiyuki" last="Kioi">Yoshiyuki Kioi</name>
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<name sortKey="Matsumoto, Hisatake" sort="Matsumoto, Hisatake" uniqKey="Matsumoto H" first="Hisatake" last="Matsumoto">Hisatake Matsumoto</name>
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<nlm:affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871</wicri:regionArea>
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<name sortKey="Matsuura, Hiroshi" sort="Matsuura, Hiroshi" uniqKey="Matsuura H" first="Hiroshi" last="Matsuura">Hiroshi Matsuura</name>
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<nlm:affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871</wicri:regionArea>
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<name sortKey="Matsubara, Tsunehiro" sort="Matsubara, Tsunehiro" uniqKey="Matsubara T" first="Tsunehiro" last="Matsubara">Tsunehiro Matsubara</name>
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<nlm:affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871</wicri:regionArea>
<wicri:noRegion>Osaka 565-0871</wicri:noRegion>
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<name sortKey="Shimizu, Kentaro" sort="Shimizu, Kentaro" uniqKey="Shimizu K" first="Kentaro" last="Shimizu">Kentaro Shimizu</name>
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<nlm:affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871</wicri:regionArea>
<wicri:noRegion>Osaka 565-0871</wicri:noRegion>
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<name sortKey="Ogura, Hiroshi" sort="Ogura, Hiroshi" uniqKey="Ogura H" first="Hiroshi" last="Ogura">Hiroshi Ogura</name>
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<country xml:lang="fr">Japon</country>
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<name sortKey="Matsuura, Yoshiharu" sort="Matsuura, Yoshiharu" uniqKey="Matsuura Y" first="Yoshiharu" last="Matsuura">Yoshiharu Matsuura</name>
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<country xml:lang="fr">Japon</country>
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<name sortKey="Kishimoto, Tadamitsu" sort="Kishimoto, Tadamitsu" uniqKey="Kishimoto T" first="Tadamitsu" last="Kishimoto">Tadamitsu Kishimoto</name>
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<title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
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<imprint>
<date when="2020" type="published">2020</date>
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<term>Adult (MeSH)</term>
<term>Aged (MeSH)</term>
<term>Antibodies, Monoclonal, Humanized (therapeutic use)</term>
<term>Betacoronavirus (MeSH)</term>
<term>Burns (metabolism)</term>
<term>Burns (pathology)</term>
<term>Cells, Cultured (MeSH)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (metabolism)</term>
<term>Coronavirus Infections (pathology)</term>
<term>Cytokine Release Syndrome (drug therapy)</term>
<term>Cytokine Release Syndrome (metabolism)</term>
<term>Cytokine Release Syndrome (pathology)</term>
<term>Cytokines (blood)</term>
<term>Cytokines (metabolism)</term>
<term>Endothelial Cells (drug effects)</term>
<term>Endothelial Cells (metabolism)</term>
<term>Female (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Inflammation (MeSH)</term>
<term>Interleukin-6 (blood)</term>
<term>Interleukin-6 (metabolism)</term>
<term>Male (MeSH)</term>
<term>Middle Aged (MeSH)</term>
<term>Pandemics (MeSH)</term>
<term>Plasminogen Activator Inhibitor 1 (blood)</term>
<term>Plasminogen Activator Inhibitor 1 (metabolism)</term>
<term>Pneumonia, Viral (drug therapy)</term>
<term>Pneumonia, Viral (metabolism)</term>
<term>Pneumonia, Viral (pathology)</term>
<term>Receptors, Interleukin-6 (antagonists & inhibitors)</term>
<term>Receptors, Interleukin-6 (metabolism)</term>
<term>Respiratory Distress Syndrome, Adult (metabolism)</term>
<term>Respiratory Distress Syndrome, Adult (pathology)</term>
<term>Sepsis (metabolism)</term>
<term>Sepsis (pathology)</term>
<term>Signal Transduction (MeSH)</term>
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<term>Adulte (MeSH)</term>
<term>Adulte d'âge moyen (MeSH)</term>
<term>Anticorps monoclonaux humanisés (usage thérapeutique)</term>
<term>Betacoronavirus (MeSH)</term>
<term>Brûlures (anatomopathologie)</term>
<term>Brûlures (métabolisme)</term>
<term>Cellules cultivées (MeSH)</term>
<term>Cellules endothéliales (effets des médicaments et des substances chimiques)</term>
<term>Cellules endothéliales (métabolisme)</term>
<term>Cytokines (métabolisme)</term>
<term>Cytokines (sang)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Infections à coronavirus (anatomopathologie)</term>
<term>Infections à coronavirus (métabolisme)</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Inflammation (MeSH)</term>
<term>Inhibiteur-1 d'activateur du plasminogène (métabolisme)</term>
<term>Inhibiteur-1 d'activateur du plasminogène (sang)</term>
<term>Interleukine-6 (métabolisme)</term>
<term>Interleukine-6 (sang)</term>
<term>Mâle (MeSH)</term>
<term>Pandémies (MeSH)</term>
<term>Pneumopathie virale (anatomopathologie)</term>
<term>Pneumopathie virale (métabolisme)</term>
<term>Pneumopathie virale (traitement médicamenteux)</term>
<term>Récepteurs à l'interleukine-6 (antagonistes et inhibiteurs)</term>
<term>Récepteurs à l'interleukine-6 (métabolisme)</term>
<term>Sepsie (anatomopathologie)</term>
<term>Sepsie (métabolisme)</term>
<term>Sujet âgé (MeSH)</term>
<term>Syndrome de détresse respiratoire de l'adulte (anatomopathologie)</term>
<term>Syndrome de détresse respiratoire de l'adulte (métabolisme)</term>
<term>Transduction du signal (MeSH)</term>
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<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Receptors, Interleukin-6</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en">
<term>Cytokines</term>
<term>Interleukin-6</term>
<term>Plasminogen Activator Inhibitor 1</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Cytokines</term>
<term>Interleukin-6</term>
<term>Plasminogen Activator Inhibitor 1</term>
<term>Receptors, Interleukin-6</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en">
<term>Antibodies, Monoclonal, Humanized</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Brûlures</term>
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
<term>Sepsie</term>
<term>Syndrome de détresse respiratoire de l'adulte</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Récepteurs à l'interleukine-6</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Endothelial Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Cytokine Release Syndrome</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Cellules endothéliales</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Burns</term>
<term>Coronavirus Infections</term>
<term>Cytokine Release Syndrome</term>
<term>Endothelial Cells</term>
<term>Pneumonia, Viral</term>
<term>Respiratory Distress Syndrome, Adult</term>
<term>Sepsis</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Brûlures</term>
<term>Cellules endothéliales</term>
<term>Cytokines</term>
<term>Infections à coronavirus</term>
<term>Inhibiteur-1 d'activateur du plasminogène</term>
<term>Interleukine-6</term>
<term>Pneumopathie virale</term>
<term>Récepteurs à l'interleukine-6</term>
<term>Sepsie</term>
<term>Syndrome de détresse respiratoire de l'adulte</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Burns</term>
<term>Coronavirus Infections</term>
<term>Cytokine Release Syndrome</term>
<term>Pneumonia, Viral</term>
<term>Respiratory Distress Syndrome, Adult</term>
<term>Sepsis</term>
</keywords>
<keywords scheme="MESH" qualifier="sang" xml:lang="fr">
<term>Cytokines</term>
<term>Inhibiteur-1 d'activateur du plasminogène</term>
<term>Interleukine-6</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr">
<term>Anticorps monoclonaux humanisés</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Adult</term>
<term>Aged</term>
<term>Betacoronavirus</term>
<term>Cells, Cultured</term>
<term>Female</term>
<term>Humans</term>
<term>Inflammation</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Pandemics</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Adulte</term>
<term>Adulte d'âge moyen</term>
<term>Betacoronavirus</term>
<term>Cellules cultivées</term>
<term>Femelle</term>
<term>Humains</term>
<term>Inflammation</term>
<term>Mâle</term>
<term>Pandémies</term>
<term>Sujet âgé</term>
<term>Transduction du signal</term>
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<front>
<div type="abstract" xml:lang="en">Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.</div>
</front>
</TEI>
<pubmed>
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<DateCompleted>
<Year>2020</Year>
<Month>09</Month>
<Day>17</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>09</Month>
<Day>24</Day>
</DateRevised>
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<Journal>
<ISSN IssnType="Electronic">1091-6490</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>117</Volume>
<Issue>36</Issue>
<PubDate>
<Year>2020</Year>
<Month>09</Month>
<Day>08</Day>
</PubDate>
</JournalIssue>
<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation>
</Journal>
<ArticleTitle>IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.</ArticleTitle>
<Pagination>
<MedlinePgn>22351-22356</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.2010229117</ELocationID>
<Abstract>
<AbstractText>Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.</AbstractText>
<CopyrightInformation>Copyright © 2020 the Author(s). Published by PNAS.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y">
<Author ValidYN="Y">
<LastName>Kang</LastName>
<ForeName>Sujin</ForeName>
<Initials>S</Initials>
<Identifier Source="ORCID">0000-0001-5086-1405</Identifier>
<AffiliationInfo>
<Affiliation>Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Tanaka</LastName>
<ForeName>Toshio</ForeName>
<Initials>T</Initials>
<Identifier Source="ORCID">0000-0002-0590-2893</Identifier>
<AffiliationInfo>
<Affiliation>Medical Affairs Bureau, Osaka Habikino Medical Center, Osaka 583-8588, Japan.</Affiliation>
</AffiliationInfo>
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<LastName>Inoue</LastName>
<ForeName>Hitomi</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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</Author>
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<LastName>Ono</LastName>
<ForeName>Chikako</ForeName>
<Initials>C</Initials>
<AffiliationInfo>
<Affiliation>Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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<Author ValidYN="Y">
<LastName>Hashimoto</LastName>
<ForeName>Shoji</ForeName>
<Initials>S</Initials>
<AffiliationInfo>
<Affiliation>Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka 583-8588, Japan.</Affiliation>
</AffiliationInfo>
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<LastName>Kioi</LastName>
<ForeName>Yoshiyuki</ForeName>
<Initials>Y</Initials>
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<Affiliation>Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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</Author>
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<LastName>Matsumoto</LastName>
<ForeName>Hisatake</ForeName>
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<Identifier Source="ORCID">0000-0001-5771-570X</Identifier>
<AffiliationInfo>
<Affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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</Author>
<Author ValidYN="Y">
<LastName>Matsuura</LastName>
<ForeName>Hiroshi</ForeName>
<Initials>H</Initials>
<Identifier Source="ORCID">0000-0002-8618-0385</Identifier>
<AffiliationInfo>
<Affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Matsubara</LastName>
<ForeName>Tsunehiro</ForeName>
<Initials>T</Initials>
<Identifier Source="ORCID">0000-0002-0910-3124</Identifier>
<AffiliationInfo>
<Affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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</Author>
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<LastName>Shimizu</LastName>
<ForeName>Kentaro</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y">
<LastName>Ogura</LastName>
<ForeName>Hiroshi</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Matsuura</LastName>
<ForeName>Yoshiharu</ForeName>
<Initials>Y</Initials>
<Identifier Source="ORCID">0000-0001-9091-8285</Identifier>
<AffiliationInfo>
<Affiliation>Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.</Affiliation>
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</Author>
<Author ValidYN="Y">
<LastName>Kishimoto</LastName>
<ForeName>Tadamitsu</ForeName>
<Initials>T</Initials>
<AffiliationInfo>
<Affiliation>Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; kishimoto@ifrec.osaka-u.ac.jp.</Affiliation>
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<Month>08</Month>
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<MeshHeading>
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<MeshHeading>
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<MeshHeading>
<DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName>
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<MeshHeading>
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<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
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<MeshHeading>
<DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName>
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<MeshHeading>
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<QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
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<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D007249" MajorTopicYN="N">Inflammation</DescriptorName>
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<DescriptorName UI="D015850" MajorTopicYN="N">Interleukin-6</DescriptorName>
<QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D017395" MajorTopicYN="N">Plasminogen Activator Inhibitor 1</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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<DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D019947" MajorTopicYN="N">Receptors, Interleukin-6</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D012128" MajorTopicYN="N">Respiratory Distress Syndrome, Adult</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
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<Keyword MajorTopicYN="Y">endothelial cell</Keyword>
<Keyword MajorTopicYN="Y">tocilizumab</Keyword>
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<CoiStatement>Competing interest statement: T.K. holds a patent for tocilizumab and receives royalties from Actemra.</CoiStatement>
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