Discussion
COVID-19 is an ongoing pandemic with no vaccine or treatment. PEG
potentially exhibits clinically beneficial properties. Here, we
hypothesize that PEG could be a promising adjuvant treatment for
COVID-19-induced ARDS by multifactorial mechanism: PEG could inhibit
viral invasion, enhance performance of lung surfactant, prevent cytokine
storm syndrome and preserve endothelial integrity.
PEG could inhibit virus adhesion by immunocamouflage. The mechanism of
this protection is biophysical and depends on charge maskage and steric
hindrance induced by the polymer. Immunocamouflage depends on molecular
weight: high molecular weights PEG of 10 kDa to 35 kDa are better
absorbed and consequently they are more effective (Giraud et al., 2014,
Kyluik et al., 2011). It depends also on cell surface type: small
molecular weight PEG of 2 kDa were effective to bind to respiratory
Syncytial Virus (RSV) but they were completely ineffective in the host
cell (Kyluik et al., 2011). The efficacy of the immunocamouflage is also
concentration dependent (Eugene, 2004, Yu et al., 2004, Taeusch et al.,
2008).
For optimal immunocamouflage, PEG should be covalently grafted. This
could be challenging to realize in-vivo . In fact, intravenous
activated PEG will be covalently adsorbed to the vein wall and will not
reach the lung. Although less effective, PEG could also spontaneously
bind to cell and tissues surfaces and sterically stabilize the
underlying surface from interactions with other components. In a
clinical trials, PEG based gel applied to the lips (not covalently
bound) has shown an impressive reduction in herpes labialis relapses
(Senti et al., 2013).
Lung surfactant play a major role against pathogens including virus
(Glasser and Mallampalli, 2012). It prevents viral adhesion and destroy
free virus (Donovan et al., 2000, Glasser and Mallampalli, 2012).
Structural damage and destruction of endogenous surfactant is well known
features of ARDS. Surfactant replacement therapy substantially
contributes to lung compliance, minimizes fluid accumulation within the
alveoli, helps to maintain a uniform alveolar size during ventilation
and decrease pulmonary inflammation. This contributes to decrease
morbidity (need for mechanical ventilation and time on ventilator) and
mortality (Baudouin, 2004, Raghavendran et al., 2011). Unfortunately,
although surfactant replacement therapy is considered a life-saving
treatment for neonatal respiratory distress syndrome, the evidence of
therapeutic efficacy in adult ARDS is more limited (Baudouin, 2004).
Inadequate dosage, difficulty of effectively delivering surfactants to
injured lungs and inactivation of surfactant have been postulated for
its limited success. Here, the strategy proposed is enhancing endogenous
surfactant performance by PEG rather than surfactant replacement. This
could be achieved by PEG aerosolization or intravenous administration
which is much easier and less invasive than surfactant replacement.
SARS-CoV-2 infection induced exaggerated oxidative stress, severe immune
system overreaction and excessive pro-inflammatory cytokine production
characterized as cytokine storm which lead to subsequent progression to
ARDS and multiorgan failure (Ye et al., 2020). Interestingly, high
molecular weight PEGs have been shown to reduce cytokine production and
neutrophil activation in vitro and in vivo (Ferrero-Andres
et al., 2020, Ackland et al., 2010). The mechanism by which PEG reduces
inflammation is not elucidated. The decrease of leukocyte adhesion by
immunocamouflage could be implicated. Indeed, in a model of rat
peritoneal inflammation, the number of leukocytes decreased by 43% in
PEG treatment group (Nagelschmidt et al., 1998). Also, PEG probably
reduces inflammation by decreasing oxidative stress. In fact, although
PEG is not a radical scavenger, it likely prevents oxidative stress by
preserving membrane integrity. Here, membrane stabilization effect of
PEG has also been proposed as a mechanism of protecting against
COVID-19-induced ARDS.
In addition to the main mechanisms described above, PEG could protect
against COVID-19 by several other ways. In fact, ARDS impairs the lungs’
ability to exchange oxygen and carbon dioxide resulting in hypoxia.
Severe hypoxemia (PaO2/FiO2 < 100 mmHg) can be found in 20–30
% of COVID-19 patients and is associated with the highest mortality
rate (Chiumello and Brioni, 2016, Gattinoni et al., 2020).
Interestingly, PEG has been shown to decrease hypoxic injury and cell
death in cardiac myocytes (Malhotra et al., 2011). Moreover, Bejaoui et
al. have demonstrated that intravenous administration of PEG35 protect
rat liver against ischemia reperfusion injury in-vivo (Bejaoui et
al., 2016). The protective effects of PEG are associated with the
decreased formation of reactive oxygen species (ROS), prevention of
endothelial cell injury, decreased vascular permeability and
mitochondrial preservation (Lazar, 2015).
PEG could also protect against sepsis-induced-COVID-19. In fact, low
molecular weight PEG has been shown to decrease the mortality in both
lipopolysaccharide (LPS) and zymosan models of sepsis by greater than
50% (Ackland et al., 2010). Also, high molecular weight PEG prevented
lethal sepsis in a murine model of lethal sepsis induced by intestinal
Pseudomonas aeruginosa (Wu et al., 2004). Moreover, recent study has
demonstrated that administration of PEG20 protected myocardial and
neurological functions, ameliorates microcirculation, and improves
survival in a rat model of cardiopulmonary resuscitation (Yang et al.,
2018).
Last but not least, PEG could prevent acute platelet deposition on
damaged arteries (Deible et al., 1998), strongly reduced platelet
induced clot retraction (Bakaltcheva et al., 2000) and reduced leucocyte
adhesion (Bertuglia et al., 2006) which could reduce coagulopathy in
COVID-19 patients (Xiong et al., 2020).