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.