Abstract
SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications—including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)—have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.
Highlights
SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) for cell entry after spike protein priming by the transmembrane protease serine 2 (TMPRSS2) [1]
The theoretical relationship between SARS-CoV-2 infection, ACE2 levels and the RAAS is complex and incompletely understood: on the one hand it is hypothesized that up-regulating ACE2 can facilitate viral entry [1], but on the other hand it is proposed that SARS-CoV-2 itself downregulates ACE2 leading to unopposed RAAS activation which is associated with pro-inflammatory damage to lung and other tissue [9]
ACE2 mRNA and Protein Expression Is Not Regulated by non-steroidal anti-inflammatory drugs (NSAIDs) and Paracetamol
Summary
SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) for cell entry after spike protein priming by the transmembrane protease serine 2 (TMPRSS2) [1]. The theoretical relationship between SARS-CoV-2 infection, ACE2 levels and the RAAS is complex and incompletely understood: on the one hand it is hypothesized that up-regulating ACE2 can facilitate viral entry [1], but on the other hand it is proposed that SARS-CoV-2 itself downregulates ACE2 leading to unopposed RAAS activation which is associated with pro-inflammatory damage to lung and other tissue [9] If this second hypothesis is correct, drugs such as ACE-inhibitors, which inhibit the RAAS, could be protective in COVID-19 [10,11]. It has been theorized that because COVID-19 is a pro-inflammatory disease, complicated in its severe form by cytokine storms, modulation of the immune system by NSAIDs, which reduce inflammatory mediators by inhibiting cyclooxygenase (COX), may have a protective effect [11,12] This hypothesis is being tested with the LIBERATE trial
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