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).