Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Keywords: COVID-19; NSAID; SARS-CoV-2; cytokine storm; inflammation; prostaglandin.

FIGURE 1

An overview of PG biosynthesis, receptors, and downstream signalling pathways. Arachidonic acid (AA) is released from membrane phospholipids via the actions of cytosolic PLA₂ (cPLA₂) following various stimuli and then metabolised to PGH₂ by COXs (COX‐1 and COX‐2). PGH₂ is unstable and subsequently converted into PGs, that is, PGD₂, PGE₂, PGF_2α, PGI₂, and TXA₂ by the actions of their synthases PGDS (LPGDS and HPGDS), PGES (mPGES‐1, mPGES‐2, and cPGES), PGFS (AKR1B1 and PGFS/ABR1C3), PGIS, and TXAS, respectively. PGs bind to their receptors and activate different downstream signalling pathways. PGD₂ receptors, DP1 and DP2, activate the cAMP and PI3K pathways, respectively, while DP2 also represses the cAMP pathway. PGE₂ receptors EP2 and EP4 activate both cAMP and PI3K pathways, EP1 activates PKC and Ca²⁺ pathways, and EP3 deactivates the cAMP pathway. Both PGF_2α receptor FP and TXA₂ receptor TP activate PKC and Ca²⁺ pathways, whereas PGI₂ receptor IP triggers activation of cAMP signalling. On the other hand, non‐steroidal anti‐inflammatory drugs (NSAIDs) inhibit AA biosynthesis of all PGs by targeting COX‐1 and/or COX‐2

FIGURE 2

Gene expression profiles of PG synthases and their receptors in human lung cells. Gene expression data from single‐cell RNA sequencing analysis of healthy lung cells from a young individual were retrieved from LungGENS (Lung Gene Expression iN Single‐cell, Du et al., 2017) and transformed to Z‐score. AT1, type 1 alveolar epithelial cell (pneumocyte); AT2, type 2 alveolar epithelial cell (pneumocyte). Words in Italic represent human gene symbols, while words in brackets represent human protein names

FIGURE 3

Possible mechanisms for PGE₂ modulation of immune cell functions in COVID‐19. PGE₂ is likely to modulate immune responses in various cell types during SARS‐CoV‐2 infection, influencing COVID‐19 pathogenesis. In epithelial cells, attachment of SARS‐CoV‐2 with ACE2 and TMPRSS2 leads to endocytosis, viral replication, and cell damage, activating RLR (RIG‐1 and MAD5)‐dependent production of type I and III IFNs and the TLR‐dependent NF‐κB pathway. The NF‐κB pathway induces expression of proinflammatory cytokines (e.g., IL‐1b, IL‐6, IL‐8, and GM‐CSF), chemokines (e.g., CCL2 and CXCL1), and other inflammatory mediators such as COX‐2 and mPGES‐1, resulting in PGE₂ secretion. Here, while it suppresses production of type I (and possibly type III) IFNs, PGE₂ further amplifies NF‐κB signalling and production of cytokines and chemokines in a positive feedback loop. PGE₂ may also directly modulate ACE2 and TMPRSS2 gene expression, endocytosis, and viral replication. In monocytes/macrophages, activation of NF‐κB and STAT3 mediates production of large amounts of inflammatory cytokines which contributes to development of cytokine secretion syndrome (the “cytokine storm”), chemokines that recruit monocytes and neutrophils, inflammatory biomarkers (e.g., SAAs, CPR, and D‐dimer), and PGE₂. Here, PGE₂ again represses IFN‐induced expression of ISGs, contributing to delay of viral clearance. Importantly, PGE₂ context‐dependently affects (either positively or negatively) not only NLRP3 inflammasome activation and related IL‐1β maturation but also NF‐κB‐dependent monocyte/macrophage cytokine production. PGE₂ differentially regulates platelet aggregation via different receptors and probably inhibits NETosis associated with inflammation and thrombosis. PGE₂ also down‐regulates IFN‐γ production and cytotoxicity of NK and CD8 T cells that kill cells infected with SARS‐CoV‐2 but promotes differentiation of proinflammatory Th17 and Th1 cells, the chief cellular sources of the cytokine storm at late stages of COVID‐19

FIGURE 4

Yin and Yang of NSAIDs in COVID‐19: potential effects. A diagram showing potentially positive and negative effects of NSAID use in COVID‐19 patients