Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19

Abstract

IntroductionResistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis.Materials and MethodsFirst, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis.ResultsIn the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules.ConclusionResistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Chemerin as a Potential Marker of Resolution of Inflammation in COVID-19 Infection

“…The data on the role of resistin and adiponectin in COVID-19 are scarce. In line with our results, resistin was elevated in COVID-19 patients, and associated with cytokines and endothelial cell adhesion molecules, while also being related to a worse clinical course in patients with COVID-19 [ 15 ]. Perpiñan et al have reported that resistin was an early predictor for requiring invasive ventilation in COVID-19 pneumonia, irrespective of the presence of obesity and metabolic syndrome [ 37 ].…”

“…There is a paucity of data regarding the kinetics of biomarkers during acute COVID-19 infection, including adipokines. The results of the existing studies are often inconsistent, with some studies reporting higher levels of chemerin [ 14 ], resistin [ 15 ], adiponectin [ 16 ], while others show lower levels of chemerin [ 17 ], and similar concentrations of adiponectin in COVID-19 patients as compared with non-COVID-19 patients [ 18 ].…”

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

“…Resistin is peptide hormone derived from adipose tissue which is associated with endothelial injury and inflammatory response. Plasma level of resistin is increased in COVID-19 patients and associated with disease severity as well as the expression of inflammatory cytokines (IL-6, IL-8 and MCP-1) and adhesion molecules (ICAM1 and VCAM1) [ 80 ]. One universal mechanism of endothelial inflammation in COVID-19 patients is plausibly associated with the downregulation of KLF2 [ 81 ], a master regulator of vascular homeostasis.…”

“…It has been reported that the secretion of multiple markers of endothelial activation/dysfunction is elevated in COVID-19 patients, such as D-dimer (marker of coagulopathy and systemic thrombosis), vWF (a primary component of coagulation pathway and mediator of vascular inflammation and thrombo-inflammation released from Weibel-Palade bodies), factor VIII (marker of coagulation), PAI-1 (a marker of endothelial damage and senescence), soluble thrombomodulin (sTM), soluble P-selectin (marker of platelet and endothelial activation), soluble ICAM1 (sICAM1, marker of endothelial inflammation), soluble VCAM1 (sVCAM1, marker of endothelial inflammation), angiopoietin-2 (Ang-2, marker of angiogenesis and thrombosis), soluble E-selectin (sE-selectin, marker of endothelial inflammation), ET1 (a potent vasoconstrictor), VEGF-A (marker of angiogenesis and endothelial hyperpermeability), IL-6 and IL-8 (markers of endothelial inflammation), MCP-1 (marker of endothelial inflammation), resistin (an adipokine associated with endothelial damage and vasoconstriction), nitrosylhemoglobin (HbNO), lactate, and syndecan-1 (marker of endothelial glycocalyx damage) [ 19 , 23 , 80 , 102 – 106 ]. In addition, the levels of these endothelial markers are elevated in intensive care units (ICU) non-survivors compared to survivors.…”

Graphene Oxide Decreases Pro-Inflammatory Proteins Production in Skeletal Muscle Cells Exposed to SARS-CoV-2 Spike Protein

“… 55 Activation of oxidative stress can be a step in the development of a cytokine storm. Analysis of the level of cytokines and the found increased synthesis of IL-8, MCP-1 and ICAM-1 - characteristic of COVID-19 infection, 56 induced in human skeletal muscle cells by the presence of the spike protein, clearly indicated the activation of the cytokine storm.…”