TY - JOUR
T1 - Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability
AU - Kovacs-Kasa, Anita
AU - Zaied, Abdelrahman A.
AU - Leanhart, Silvia
AU - Koseoglu, Murat
AU - Sridhar, Supriya
AU - Lucas, Rudolf
AU - Fulton, David J.
AU - Vazquez, Jose A.
AU - Annex, Brian H.
N1 - Funding Information:
B.H.A. is supported by R01HL150003, RO1148590, RO1HL141325, 3RO1HL101200 (Aleksander S. Popel, Johns Hopkins, PI), and RO1GM129074 (Feilim Mac Gabhann, Johns Hopkins, PI). R.L. is supported by R01HL138410A, and D.J.F. is supported by RO1HL147159. We declare no conflict of interest.
Publisher Copyright:
© 2022 American Society for Microbiology. All rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARSCoV- 2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-a), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-topatient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients.
AB - The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARSCoV- 2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-a), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-topatient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients.
KW - ACE-2 receptor
KW - Antiinflammatory cytokines
KW - Barrier dysfunction
KW - Complements factors
KW - Cytokine
KW - Endothelial injury
KW - Endothelial permeability
KW - Heat inactivation
KW - Neutralizing antibodies
KW - Plasma
KW - Proinflammatory cytokines
KW - SARS-CoV-2
KW - SARS-CoV-2 plasma
KW - Spike protein
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U2 - 10.1128/spectrum.01671-21
DO - 10.1128/spectrum.01671-21
M3 - Article
C2 - 35171047
AN - SCOPUS:85125212486
SN - 2165-0497
VL - 10
JO - Microbiology spectrum
JF - Microbiology spectrum
IS - 1
M1 - e01671-21
ER -