1. Inflammation in COVID-19

SARS-CoV-2 enters human cells mainly by binding the angiotensin-converting enzyme 2 (ACE2), which is highly expressed by alveolar lung cells, vascular endothelium, cardiac myocytes, and other cells ^[1]. Patients suffering from cardiovascular or cerebrovascular comorbidities have a higher risk of infection and worse outcomes ^[2][3][4]. The virus spreads not only by inhalation of viral particles but also through contaminated surfaces, where it can live for 24–72 h depending on the type of surface. In most cases, the incubation time is shorter than 14 days, with the patient being contagious even though asymptomatic ^[1]. Commonly identified symptoms include fever, dry cough, dyspnea, chest pain, fatigue, and myalgia. Other less frequent symptoms are headache, dizziness, abdominal pain, diarrhea, nausea, and vomiting ^[5]. The virus decreases the Type-I Interferon (IFN) response and increases T cell apoptosis, as well as natural killers (NK) cell abnormalities. The direct attack and resulting immune system weakness may explain some of the extreme complications seen in COVID-19 patients, such as hypoxemia, ARDS, arrhythmias, trauma, acute myocardial injury, and acute kidney injury ^[6][1][7]. In the vast majority of COVID-19 patients, the typical chest computed tomography scan presents bilateral pulmonary parenchymal ground-glass and consolidative opacities, which is even worse in ICU-admitted patients with bilateral multiple lobular and subsegmental areas of consolidation ^[2][3][8][9]. Laboratory findings are not pathognomonic, with lymphopenia, prolonged prothrombin time, and elevated lactate dehydrogenase being the most prominent. Some patients with extreme bilateral pneumonia have elevated levels of aspartate aminotransferase, creatine kinase, creatinine, C-reactive protein (CRP), D-dimers, and ferritin ^[10].

2. The Cytokine Storm in COVID-19

The spectrum of symptoms ranges from asymptomatic infections to mild respiratory symptoms to the lethal form of COVID-19, which is associated with severe pneumonia, acute respiratory distress, and fatality. In the early stages of the disease, initial symptoms such as fever, cough, diarrhea, myalgia, or fatigue are present. COVID-19 patients may develop profound hypoxemia early in their disease course. However, overt respiratory failure at these early stages is unusual. Rarely, a minority of patients develop aggravating symptoms leading to multiorgan dysfunction and serious ARDS due to an intense inflammatory response and cytokine overproduction—the cytokine storm. Cytokines are small cell-signaling protein molecules, which may have autocrine or paracrine actions, facilitating intracellular crosstalk ^[11][12]. The cytokine family consists of more than 100 members, sub-categorized into several smaller clusters such as interleukins (ILs), INFs, colony-stimulating factors (CSFs), tumor necrosis factors (TNFs), and chemokines ^[13]. A cytokine storm resembling the hyperinflammatory state of COVID-19 has previously been recognized in several critically ill adults, namely those suffering from macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (sHLH). MAS/sHLH has historically been classified based on the cause of the disease and is categorized into primary (genetic) and secondary (non-genetic) types, and further subdivided into viral, autoimmune, or neoplasia-related ^[14]. The classic MAS/sHLH is characterized by fever, adenopathy, hepatosplenomegaly, anemia, other cytopenias, liver function abnormalities, and triggered hypercoagulation secondary to inflammation, followed by pronounced hypercytokinemia ^[7].

In immunodeficient patients with severe COVID-19 pneumonia, primary HLH may be the potential underlying cause. After entering respiratory epithelial cells, SARS-CoV-2 provokes the activation of Th1 cells to secrete pro-inflammatory cytokines. It is pictured by the failure of perforin, NK, and CD8+ cytotoxic T cells, which lead to cell lysis initiating apoptosis of virally infected cells. Additionally, IFN-γ, which is produced by a large number of widespread T cells, causes excessive macrophage activation ^[15]. In COVID-19 patients, the incidence of cardiovascular symptoms is high due to the systemic inflammatory response and immune system disorders during disease progression ^[16]. The exact mechanism of cardiac involvement in COVID-19 remains unclear. One potential mechanism is a direct myocardial involvement mediated via ACE2 or a direct viral effect on the heart muscle called myocarditis. Other proposed mechanisms of myocardial injury include cytokine activity and respiratory insufficiency, all of which may result in myocardial cell apoptosis through a gradual decrease in oxygen provided to the heart muscle ^[16]. In most immunocompetent patients with severe COVID-19 pneumonia, MAS/sHLH is suspected as the triggering cause of hyper-inflammation. The potential association between SARS-CoV-2 and sHLH relies on its key feature to bind Toll-like receptors (TLRs) and activate inflammasomes (caspases) releasing IL-1β ^[17]. In vitro cell studies indicate that in the early stages of SARS-CoV infection, respiratory epithelial cells, dendritic cells (DCs), and macrophages exhibit a delayed release of cytokines and chemokines ^[18]. The induction of low levels of antiviral factor IFNs and high levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF) as well as specific chemokines (C-C motif chemokine ligand (CCL)-2, CCL-3, and CCL-5) describe this hyperinflammatory state ^[19][20]. Therefore, the severity of COVID-19 has been strongly associated with the volume of hypercytokinemia, referring to interleukins IL-1β, IL-2, IL-6, IL-7, IL-10, TNF-alpha, granulocyte colony-stimulating factor (G-CSF), IFN-γ-induced protein 10 kDa/CXCL10, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1-α, both in serum and affected tissues ^[7][15]. After the secretion of the pro-inflammatory cytokines IL-1, IL-6, and G-CSF, low levels of IFN-αβ and IFN-γ induce inflammatory cell infiltration through mechanisms involving the Fas–Fas ligand (FasL) or the TRAIL–death receptor 5 (DR5) and trigger the apoptosis of airway and alveolar epithelial cells. Endothelial and epithelial cell apoptosis damages the pulmonary microvascular and alveolar epithelial cell barriers, resulting in vascular leakage, alveolar edema, and gradually, hypoxia ^[21][22]. Finally, the accumulated mononuclear macrophages engage in phagocytic activity on the debris of dead cells and tissues, secreting more pro-inflammatory cytokines (TNF, IL-6, IL-1β, and inducible nitric oxide synthase (NOS)) and chemoattractants (such as CCL-2, CCL-3, CCL-5, CCL-7, and IFN-γ-induced protein 10) ^[21]. The pro-inflammatory feed-forward loop of cytokines on innate immune cells results in a cytokine storm, coagulopathy, and acute respiratory distress syndrome ^[23] (

Table 1

3. Inflammation and Pro-Inflammatory Cytokines in Atherosclerosis

Atherosclerosis is characterized by the formation of plaques in the vessel wall. These develop through complex pathophysiological pathways that involve pro- and anti-inflammatory cytokines, secreted by vascular endothelial cells, leukocytes, platelets, and mast cells ^[13][11]. Endothelial injury, impaired lipid metabolism, and hemodynamic disruption, followed by flow-mediated inflammatory changes in the endothelium, are the main steps in plaque formation and atherosclerosis progression ^[2]. Inflammation begins when the endothelial cells become activated and secrete adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin) and other inflammatory factors while the smooth muscle cells secrete chemokines and chemoattractants (monocyte chemoattractant protein-1 (MCP-1)), which jointly draw monocytes, lymphocytes, mast cells, and neutrophils into the arterial wall, followed by their migration to the sub-endothelial space ^[13][30]. The effect of two pro-inflammatory cytokines, TNF-alpha and IL-1, which promote the expression of cytokines, adhesion molecules as well as the migration and mitogenesis of vascular smooth muscle and endothelial cells, is of particular interest ^[31]. TNF-alpha and IFN-γ have also been associated with the disruption of endothelial cell junctions, leading to leukocyte transmigration, vascular permeability, and matrix degradation, all of which facilitate atherosclerosis development ^{[13][30][31][32]}.

With regards to human monocytes, three subsets exist owing to differences in functions ^[33]. CD14

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⁻ monocytes, which are similar to murine Ly6C high monocytes, differentiate to macrophages and engulf a large number of chemically modified (by reactive oxygen species) low-density lipoprotein (LDL) particles known as oxidized LDL (oxLDL), which are prone to phagocytosis ^[13][34]. The accumulation of oxLDL in the macrophages transforms them into foam cells, contributing in this way to atherosclerotic plaques ^[35]. T cells, B cells, neutrophils, dendritic cells, and myeloid cell proliferation are types of resistant chemoattracted cells found in atherosclerotic lesions ^[36].

Selectins and platelet endothelial cell adhesion molecule (PECAM-1) assist the accumulation of leukocytes into the sub-endothelial space, inducing the inflammation and volume of the lipid core ^[37]. Fibrous tissue is added to form a fibrous cap over the lipid-rich necrotic cores and just under the endothelium at the blood interface. With aging, the persistent unregulated action of proteolytic enzymes dissolves the fibrous tissue; the fibrous cap becomes thinner and weakens. This thin cap is prone to rupture, exposing the thrombogenic material of the internal arterial wall leading to thrombus formation. As far as the vulnerability of plaque is concerned, studies have focused on the collagenolytic action of matrix metalloproteinases and cysteine proteases in the plaque ^[38]. The expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) increases the risk of plaque rupture, bleeding, and thrombosis ^[39][40]. Recent studies have shown that IL-1, as well as TNF-alpha and its superfamily of CD40/CD40L ligand, disrupt the fibrinolytic and anti-thrombotic actions triggering thrombotic events ^[41]. It has also been described that in later stages of atherosclerosis, cytokines such as TNF-alpha, INF-γ, IL-1, and IL-6 act differently, inducing smooth muscle cell apoptosis and matrix degradation, leading to plaque destabilization ^[42][43]. Similar effects have been noted following the increase of acute-phase proteins, the proliferation of foam cells, and the reduced secretion of NO. CRP has also been linked to a pro-thrombotic function, as it is associated with TF upregulation, decreased levels of prostaglandins (PGI2) and endothelial NOS, and the impairment of coagulation balance, as measured by the thromboxane A2/PGI2 ratio ^{[44][45][46][47]}. Finally, the triple activity of INF-γ has been found to destabilize the plaque (as it prevents smooth muscle differentiation), the procollagen-I gene expression, and the collagen crosslinking enzyme, lysyl oxidase ^[48][49][50].