Skip to main content
Top

Open Access 10-04-2024 | Septicemia | Original Paper

Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis

Authors: Carolin Christina Drost, Alexandros Rovas, Irina Osiaevi, Klaus Schughart, Alexander Lukasz, Wolfgang A. Linke, Hermann Pavenstädt, Philipp Kümpers

Published in: Angiogenesis

Login to get access

Abstract

Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81–0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.
Appendix
Available only for authorised users
Literature
1.
go back to reference Mulivor AW HHL (2002) Role of glycocalyx in leukocyte-endothelial cell adhesion. Am J Physiol Heart Circ Physiol 283(4):H1282–1291CrossRefPubMed Mulivor AW HHL (2002) Role of glycocalyx in leukocyte-endothelial cell adhesion. Am J Physiol Heart Circ Physiol 283(4):H1282–1291CrossRefPubMed
2.
go back to reference Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, Smith LP, Cheng SS, Overdier KH, Thompson KR, Geraci MW, Douglas IS, Pearse DB, Tuder RM (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18(8):1217–1223. https://doi.org/10.1038/nm.2843CrossRefPubMed Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, Smith LP, Cheng SS, Overdier KH, Thompson KR, Geraci MW, Douglas IS, Pearse DB, Tuder RM (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18(8):1217–1223. https://​doi.​org/​10.​1038/​nm.​2843CrossRefPubMed
12.
go back to reference Drost CC, Rovas A, Kusche-Vihrog K, Van Slyke P, Kim H, Hoang VC, Maynes JT, Wennmann DO, Pavenstadt H, Linke W, Lukasz A, Hesse B, Kumpers P (2019) Tie2 activation promotes Protection and reconstitution of the endothelial glycocalyx in human Sepsis. Thromb Haemost 119(11):1827–1838. https://doi.org/10.1055/s-0039-1695768CrossRefPubMed Drost CC, Rovas A, Kusche-Vihrog K, Van Slyke P, Kim H, Hoang VC, Maynes JT, Wennmann DO, Pavenstadt H, Linke W, Lukasz A, Hesse B, Kumpers P (2019) Tie2 activation promotes Protection and reconstitution of the endothelial glycocalyx in human Sepsis. Thromb Haemost 119(11):1827–1838. https://​doi.​org/​10.​1055/​s-0039-1695768CrossRefPubMed
13.
14.
16.
go back to reference Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810. https://doi.org/10.1001/jama.2016.0287CrossRefPubMedPubMedCentral Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810. https://​doi.​org/​10.​1001/​jama.​2016.​0287CrossRefPubMedPubMedCentral
22.
go back to reference Filbin MR, Mehta A, Schneider AM, Kays KR, Guess JR, Gentili M, Fenyves BG, Charland NC, Gonye ALK, Gushterova I, Khanna HK, LaSalle TJ, Lavin-Parsons KM, Lilley BM, Lodenstein CL, Manakongtreecheep K, Margolin JD, McKaig BN, Rojas-Lopez M, Russo BC, Sharma N, Tantivit J, Thomas MF, Gerszten RE, Heimberg GS, Hoover PJ, Lieb DJ, Lin B, Ngo D, Pelka K, Reyes M, Smillie CS, Waghray A, Wood TE, Zajac AS, Jennings LL, Grundberg I, Bhattacharyya RP, Parry BA, Villani AC, Sade-Feldman M, Hacohen N, Goldberg MB (2021) Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions. Cell Rep Med 2(5):100287. https://doi.org/10.1016/j.xcrm.2021.100287CrossRefPubMedPubMedCentral Filbin MR, Mehta A, Schneider AM, Kays KR, Guess JR, Gentili M, Fenyves BG, Charland NC, Gonye ALK, Gushterova I, Khanna HK, LaSalle TJ, Lavin-Parsons KM, Lilley BM, Lodenstein CL, Manakongtreecheep K, Margolin JD, McKaig BN, Rojas-Lopez M, Russo BC, Sharma N, Tantivit J, Thomas MF, Gerszten RE, Heimberg GS, Hoover PJ, Lieb DJ, Lin B, Ngo D, Pelka K, Reyes M, Smillie CS, Waghray A, Wood TE, Zajac AS, Jennings LL, Grundberg I, Bhattacharyya RP, Parry BA, Villani AC, Sade-Feldman M, Hacohen N, Goldberg MB (2021) Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions. Cell Rep Med 2(5):100287. https://​doi.​org/​10.​1016/​j.​xcrm.​2021.​100287CrossRefPubMedPubMedCentral
24.
go back to reference Rovas A, Neumann JK, Drost CC, Vollenberg R, Tholking G, Fobker M, Witzenrath M, Kumpers P, Agamotto Study G, Capnetz Study G (2023) Analysis of urinary glycosaminoglycans to Predict Outcome in COVID-19 and Community-Acquired Pneumonia-A Proof-of-Concept Study. J Clin Med 12(16). https://doi.org/10.3390/jcm12165269 Rovas A, Neumann JK, Drost CC, Vollenberg R, Tholking G, Fobker M, Witzenrath M, Kumpers P, Agamotto Study G, Capnetz Study G (2023) Analysis of urinary glycosaminoglycans to Predict Outcome in COVID-19 and Community-Acquired Pneumonia-A Proof-of-Concept Study. J Clin Med 12(16). https://​doi.​org/​10.​3390/​jcm12165269
39.
go back to reference Aletaha D, Kerschbaumer A, Kastrati K, Dejaco C, Dougados M, McInnes IB, Sattar N, Stamm TA, Takeuchi T, Trauner M, van der Heijde D, Voshaar M, Winthrop KL, Ravelli A, Betteridge N, Burmester GR, Bijlsma JW, Bykerk V, Caporali R, Choy EH, Codreanu C, Combe B, Crow MK, de Wit M, Emery P, Fleischmann RM, Gabay C, Hetland ML, Hyrich KL, Iagnocco A, Isaacs JD, Kremer JM, Mariette X, Merkel PA, Mysler EF, Nash P, Nurmohamed MT, Pavelka K, Poor G, Rubbert-Roth A, Schulze-Koops H, Strangfeld A, Tanaka Y, Smolen JS (2023) Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update. Ann Rheum Dis 82(6):773–787. https://doi.org/10.1136/ard-2022-222784CrossRefPubMed Aletaha D, Kerschbaumer A, Kastrati K, Dejaco C, Dougados M, McInnes IB, Sattar N, Stamm TA, Takeuchi T, Trauner M, van der Heijde D, Voshaar M, Winthrop KL, Ravelli A, Betteridge N, Burmester GR, Bijlsma JW, Bykerk V, Caporali R, Choy EH, Codreanu C, Combe B, Crow MK, de Wit M, Emery P, Fleischmann RM, Gabay C, Hetland ML, Hyrich KL, Iagnocco A, Isaacs JD, Kremer JM, Mariette X, Merkel PA, Mysler EF, Nash P, Nurmohamed MT, Pavelka K, Poor G, Rubbert-Roth A, Schulze-Koops H, Strangfeld A, Tanaka Y, Smolen JS (2023) Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update. Ann Rheum Dis 82(6):773–787. https://​doi.​org/​10.​1136/​ard-2022-222784CrossRefPubMed
40.
go back to reference Group WHOREAC-TW, Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, Savovic J, Tierney J, Baron G, Benbenishty JS, Berry LR, Broman N, Cavalcanti AB, Colman R, De Buyser SL, Derde LPG, Domingo P, Omar SF, Fernandez-Cruz A, Feuth T, Garcia F, Garcia-Vicuna R, Gonzalez-Alvaro I, Gordon AC, Haynes R, Hermine O, Horby PW, Horick NK, Kumar K, Lambrecht BN, Landray MJ, Leal L, Lederer DJ, Lorenzi E, Mariette X, Merchante N, Misnan NA, Mohan SV, Nivens MC, Oksi J, Perez-Molina JA, Pizov R, Porcher R, Postma S, Rajasuriar R, Ramanan AV, Ravaud P, Reid PD, Rutgers A, Sancho-Lopez A, Seto TB, Sivapalasingam S, Soin AS, Staplin N, Stone JH, Strohbehn GW, Sunden-Cullberg J, Torre-Cisneros J, Tsai LW, van Hoogstraten H, van Meerten T, Veiga VC, Westerweel PE, Murthy S, Diaz JV, Marshall JC, Sterne JAC (2021) Association between Administration of IL-6 Antagonists and mortality among patients hospitalized for COVID-19: a Meta-analysis. JAMA 326(6):499–518. https://doi.org/10.1001/jama.2021.11330CrossRef Group WHOREAC-TW, Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, Savovic J, Tierney J, Baron G, Benbenishty JS, Berry LR, Broman N, Cavalcanti AB, Colman R, De Buyser SL, Derde LPG, Domingo P, Omar SF, Fernandez-Cruz A, Feuth T, Garcia F, Garcia-Vicuna R, Gonzalez-Alvaro I, Gordon AC, Haynes R, Hermine O, Horby PW, Horick NK, Kumar K, Lambrecht BN, Landray MJ, Leal L, Lederer DJ, Lorenzi E, Mariette X, Merchante N, Misnan NA, Mohan SV, Nivens MC, Oksi J, Perez-Molina JA, Pizov R, Porcher R, Postma S, Rajasuriar R, Ramanan AV, Ravaud P, Reid PD, Rutgers A, Sancho-Lopez A, Seto TB, Sivapalasingam S, Soin AS, Staplin N, Stone JH, Strohbehn GW, Sunden-Cullberg J, Torre-Cisneros J, Tsai LW, van Hoogstraten H, van Meerten T, Veiga VC, Westerweel PE, Murthy S, Diaz JV, Marshall JC, Sterne JAC (2021) Association between Administration of IL-6 Antagonists and mortality among patients hospitalized for COVID-19: a Meta-analysis. JAMA 326(6):499–518. https://​doi.​org/​10.​1001/​jama.​2021.​11330CrossRef
45.
go back to reference Murugesan H, Cs G, Nasreen HS, Santhanam S, M G, Ravi S, Es SS (2022) An evaluation of efficacy and safety of Tofacitinib, a JAK inhibitor in the management of hospitalized patients with mild to moderate COVID-19 - an open-label Randomized Controlled Study. J Assoc Physicians India 69(12):11–12PubMed Murugesan H, Cs G, Nasreen HS, Santhanam S, M G, Ravi S, Es SS (2022) An evaluation of efficacy and safety of Tofacitinib, a JAK inhibitor in the management of hospitalized patients with mild to moderate COVID-19 - an open-label Randomized Controlled Study. J Assoc Physicians India 69(12):11–12PubMed
46.
go back to reference Guimaraes PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, Kalil Filho R, Junior VM, Soeiro AM, Tognon AP, Veiga VC, Martins PA, Moia DDF, Sampaio BS, Assis SRL, Soares RVP, Piano LPA, Castilho K, Momesso R, Monfardini F, Guimaraes HP, de Ponce D, Dulcine M, Pinheiro MRT, Gunay LM, Deuring JJ, Rizzo LV, Koncz T, Berwanger O, Investigators S-CT (2021) Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med 385(5):406–415. https://doi.org/10.1056/NEJMoa2101643CrossRefPubMed Guimaraes PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, Kalil Filho R, Junior VM, Soeiro AM, Tognon AP, Veiga VC, Martins PA, Moia DDF, Sampaio BS, Assis SRL, Soares RVP, Piano LPA, Castilho K, Momesso R, Monfardini F, Guimaraes HP, de Ponce D, Dulcine M, Pinheiro MRT, Gunay LM, Deuring JJ, Rizzo LV, Koncz T, Berwanger O, Investigators S-CT (2021) Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med 385(5):406–415. https://​doi.​org/​10.​1056/​NEJMoa2101643CrossRefPubMed
49.
go back to reference Barkhausen T, Tschernig T, Rosenstiel P, van Griensven M, Vonberg RP, Dorsch M, Mueller-Heine A, Chalaris A, Scheller J, Rose-John S, Seegert D, Krettek C, Waetzig GH (2011) Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med 39(6):1407–1413. https://doi.org/10.1097/CCM.0b013e318211ff56CrossRefPubMed Barkhausen T, Tschernig T, Rosenstiel P, van Griensven M, Vonberg RP, Dorsch M, Mueller-Heine A, Chalaris A, Scheller J, Rose-John S, Seegert D, Krettek C, Waetzig GH (2011) Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med 39(6):1407–1413. https://​doi.​org/​10.​1097/​CCM.​0b013e318211ff56​CrossRefPubMed
51.
go back to reference Kang S, Onishi S, Ling Z, Inoue H, Zhang Y, Chang H, Zhao H, Wang T, Okuzaki D, Matsuura H, Takamatsu H, Oda J, Kishimoto T (2024) Gp130-HIF1alpha axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling. Proc Natl Acad Sci U S A 121(2):e2315898120. https://doi.org/10.1073/pnas.2315898120CrossRefPubMed Kang S, Onishi S, Ling Z, Inoue H, Zhang Y, Chang H, Zhao H, Wang T, Okuzaki D, Matsuura H, Takamatsu H, Oda J, Kishimoto T (2024) Gp130-HIF1alpha axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling. Proc Natl Acad Sci U S A 121(2):e2315898120. https://​doi.​org/​10.​1073/​pnas.​2315898120CrossRefPubMed
Metadata
Title
Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis
Authors
Carolin Christina Drost
Alexandros Rovas
Irina Osiaevi
Klaus Schughart
Alexander Lukasz
Wolfgang A. Linke
Hermann Pavenstädt
Philipp Kümpers
Publication date
10-04-2024
Publisher
Springer Netherlands
Published in
Angiogenesis
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-024-09916-w
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare