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IL-1 Mediates Tissue Specific Inflammation and Severe Respiratory Failure In Covid-19: Clinical And Experimental Evidence
Abstract . Background: Acute respiratory distress syndrome (ARDS) in COVID-19 has been associated with dysregulated immune responses leading to catastrophic inflammation. The activation pathways remain to be fully elucidated. We investigated the ability of circulating to induce dysregulated immune responses. Materials & Methods: Calprotectin and high mobility group box 1 (HMGB1) were associated with ARDS in 60 COVID-19 patients. In a second cohort of 40 COVID-19 patients calprotectin at hospital admission was associated with serum levels of soluble urokinase plasminogen activator receptor (suPAR). A COVID-19 animal model was developed by intravenous injection of plasma from healthy volunteers or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. In separate experiments, mice were treated with a) the IL-1 receptor antagonist Anakinra or vehicle and b) Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific anti-human IL-1α antibody XB2001, or isotype controls. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured. Results: Calprotectin, but not HMGB1, was elevated ARDS. Higher suPAR readouts indicated higher calprotectin levels. CHallenge of mice with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ and MPO. Anakinra treatment brought these levels down. Similar decrease was found in mice treated with Flo1-2a but not with XB2001. Conclusion: Circulating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1α mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or specific inhibition of IL-1α. Competing Interest Statement . J. Eugen-Olsen is a cofounder, shareholder and CSO of ViroGates A7S, Denmark and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark. He is granted by the Horizon 2020 European Grant RISKinCOVID. J. Simard is the CEO and founder of XBiotech. M.G. Netea is a scientific founder of TTxD, and received research grants from GSK and ViiV Healthcare. E.J. Giamarellos-Bourboulis has received honoraria from AbbVie USA, Abbott CH, InflaRx GmbH, MSD Greece, XBiotech Inc. and Angelini Italy; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMerieux Inc, InflaRx GmbH, and XBiotech Inc.; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). Clinical Trial . NCT04357366 Funding Statement . The study was funded in part by the Hellenic Institute for the Study of Sepsis and in part by the Horizon 2020 grant RISKinCOVID. The funders had no role in the design, collection, analysis and interpretation of data, writing, and decision to publish. Author Declarations . I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: National Ethics Committee of Greece and National Organization for Medicines of Greece All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Footnotes . 3 of the original co-authors Zhongli Xu, Katja Schubert, Marlen Hermann have been removed from the author list and are acknowledged in the respective section off the manuscript Data Availability . Data of this study are available after communication with the corresponding author. .
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