Re: Covid-19: European drugs agency to review safety of ibuprofen
Currently there are some concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin at conventional doses in the management of COVID-19 (coronavirus disease-19) in adult infected patients (1). We wish to briefly discuss the potential role of high doses of aspirin as a host direct strategy.
The main predictors of critical outcome in COVID-19 infections encompass age, the presence of underlying diseases, the presence of secondary infection and elevated inflammatory indicators in the blood (2). In fact, following COVID-19 infection a highly acute respiratory syndrome may be observed with release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6, and a strategy based on their signaling is currently under evaluation (3). In parallel, the recent awareness that COVID 2019 uses ACE2 (receptor Angiotensin converting enzyme 2) as its receptor (4) has led to a focus of attention in the use of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) as a strategy to counteract COVID infection. Considering the crosstalk between ACE2 signaling and inflammation, Kickbusch and Leung G hypothesized that ACE2 dysregulation of the renin angiotensin system (RAS) may have a central role in the pathophysiology of COVID-19 associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). They additionally speculated that the virus binding to ACE2 may attenuate residual ACE2 activity, further skewing the ACE/ACE2 balance to a state of predominant ACE/AngII/AT1 axis signaling (5).
On the other hand, several seminal studies have previously investigated in renal and cardiovascular apparatus the link between Ang II and nuclear factor κB (NF-κB) (6-7) showing that Angiotensin II activates NF-kB through AT1 and AT2 receptors (8). NF-kB is a ubiquitous master regulator of immunology/inflammatory response (9-10). Consequently, the inhibition of its activity could be a successfully strategy in controlling also AT2 signaling.
Aspirin and salicylates at higher doses with respect to those used to inhibit cycloxygenase (COX) activity have been shown to inhibit NF-kb activity also in lung cells (11-12). Interestingly, in a model of rats harboring human renin and angiotensinogen genes high doses of aspirin were able to inhibit NF-κB and to protect from angiotensin II induced renal and cardiovascular damage (13). It is worth noting that 5 to 8 g aspirin, in multiple daily doses of 1 g, were traditionally administered in the management of rheumatoid arthritis (14). That a substantial inhibition of NF-κB activity “in vivo” by high doses of aspirin and salicylate could be achievable in clinical practice has been previously recognized and discussed as a potential anticancer strategy (15).
In conclusion, in COVID-19 infection, targeting NF-kb with high doses of aspirin or salicylate could be part of a host directed therapeutic strategy to treat or prevent fatal “cytokine storms” in which the immune system is at the basis of organ failure.
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Competing interests: No competing interests