3.2 IL-6-induced endothelial dysfunction and coagulopathy in COVID-19
In addition to the direct role of SARS-CoV-2/ACE-2 interaction in inducing the endothelial dysfunction (Zhang et al., 2020b), IL-6 was also reported to interrupt the normal function of endothelial cells (ECs) through inactivating the endothelial nitric oxide synthase (eNOS) which in turn could decrease NO production with subsequent induction of an oxidative stress state leading to impairment in endothelial responses (Hung et al., 2010).
As a consequence, disrupting the endothelial cells function either by SARS-CoV-2 itself or IL-6 could activate the platelets and stimulate their adhesion and aggregation; resulting in a pulmonary specific vasculopathy termed Pulmonary Intravascular Coagulopathy (PIC) (Aird, 2003; Levi and van der Poll, 2017; McGonagle et al., 2020).
Most anatomical studies of COVID-19 victims demonstrate the formation of blood thrombus (fibrin clot) in their pulmonary vessels, in addition to deep vein thrombosis that increases the risk for developing pulmonary embolism (Cui et al., 2020; Klok et al., 2020). These clots result in a compensatory increase of plasminogen (fibrinolysin) but, with disease progression, it fails to break down these fibrin deposits reflected in elevated D-dimer (DD) levels, which is reported to be associated with the severity of COVID-19 infection and may be also correlated with activation of the pro-inflammatory cytokine cascade (Belen-Apak and Sarıalioğlu, 2020; Leonard-Lorant et al., 2020).
Emerging data suggest that COVID-19-associated endothelial dysfunction could induce several structural and functional changes resulting in leukocyte trafficking, which in turn, may shift the vascular equilibrium towards triggering more inflammation (Aird, 2003). Although leukocyte trafficking was known to play an essential part in the protective responses against any infection or injury, it may also lead to extensive tissue damage as shown in numerous inflammatory disorders (Chen et al., 2018). One of the most abundant leukocytes been assured in COVID-19 are neutrophils that represent the first line of defense in the innate immune system.