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. 2023 Sep 1;24(17):13574.
doi: 10.3390/ijms241713574.

Preliminary Comparison of Molecular Antioxidant and Inflammatory Mechanisms Determined in the Peripheral Blood Granulocytes of COVID-19 Patients

Elżbieta Skrzydlewska  1 , Wojciech Łuczaj  1 , Michał Biernacki  1 , Piotr Wójcik  1 , Iwona Jarocka-Karpowicz  1 , Biserka Orehovec  2 , Bruno Baršić  2 , Marko Tarle  2 , Marta Kmet  2 , Ivica Lukšić  2   3 , Zlatko Marušić  4 , Georg Bauer  5 , Neven Žarković  6
Affiliations

Preliminary Comparison of Molecular Antioxidant and Inflammatory Mechanisms Determined in the Peripheral Blood Granulocytes of COVID-19 Patients

Elżbieta Skrzydlewska et al. Int J Mol Sci. .

Abstract

The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC-MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.

Keywords: COVID-19; G protein-coupled receptors; antioxidants; eicosanoids; granulocytes; inflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Levels of Nrf2, phosphorylated Nrf2 (p-Nrf2), and its inhibitor, i.e., Kelch-like ECH-associated protein 1 (Keap1), as well as heme oxygenase-1 (HO-1) observed in the granulocytes of recovered (n = 15) and deceased COVID-19 patients (n = 15), as well as persons from the control group (n = 15). The data points represent individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
Figure 2
Figure 2
The activity of cytosolic superoxide dismutase (Cu,Zn-SOD) and mitochondrial superoxide dismutase (Mn-SOD) observed in the granulocytes obtained from recovered (n = 15) and deceased COVID-19 patients (n = 15), as well as from persons from the control group (n = 15). The data points represent individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
Figure 3
Figure 3
Levels of those proteins that play essential roles in the development of inflammation, such as two family members of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB p52 and NFκB p65), nuclear factor kappa-light-polypeptide-gene-enhancer of the B cells inhibitor, alpha gene (IκBα), and tumor necrosis factor alpha (TNFα) observed in the granulocytes obtained from recovered (n = 15) and deceased COVID-19 patients (n = 15), as well as from persons from the control group (n = 15). The data points represent the individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
Figure 4
Figure 4
The level of anti-inflammatory interleukin 10 (IL-10) and pro-inflammatory interleukins, 2 (IL-2) and 6 (IL-6), observed in the granulocytes of recovered (n = 15) and deceased patients with COVID-19 (n = 15), as well as in those of people from the control group (n = 15). The data points represent the individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
Figure 5
Figure 5
Levels of pro-inflammatory eicosanoids, thromboxane B2 (TXB2) and prostaglandin E2 (PGE2), and anti-inflammatory eicosanoids, 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and 5-hydroxyeicosatetraenoic acid (5-HETE), observed in the granulocytes obtained from recovered (n = 15) and deceased COVID-19 patients (n = 15), as well as from persons from the control group (n = 15). The data points represent the individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
Figure 6
Figure 6
Levels of receptors involved in oxidative and inflammatory processes—cannabinoid receptors 1 and 2 (CB1 and CB2); transient receptor potential cation channel subfamily V member 1 (TRPV1); and peroxisome proliferator-activated receptor gamma (PPARγ)—observed in the granulocytes obtained from recovered (n = 15) and deceased COVID-19 patients (n = 15), as well as from persons from the control group (n = 15). The data points represent the individual values per group: a—significantly different from control group, p < 0.05; x—significantly different from recovered COVID-19 patients, p < 0.05.
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