Stables, M.J.; (2009) Immuno-stimulatory and anti-bacterial role for NSAIDs in mice and humans. Doctoral thesis , UCL (University College London).

Abstract

Antibiotic resistance arising from the selective pressure generated by excessive/inappropriate antibiotic use in human and veterinary practices poses major challenges to the management of infection, particularly with the scarcity of new antibacterial drugs. For this reason, there is considerable interest in developing strategies to counteract multidrug microbial resistance either as an independent pharmaceutical entity or as an adjunct to existing treatment regimes. Cyclooygenase (COX) metabolises phospholipase A2-liberated arachidonic acid to PGH2, which serves as a substrate for down-stream synthases to generate prostaglandins and thromboxane A2. Two isoforms of COX exist with constitutively expressed COX 1 suggested to make PGs to aid physiological processes while COX 2 is inducible at sites of inflammation believed to generate pathophysiological PGs. During inflammation in response to infection, PGs of the E/D series elevate cAMP by activating EP2/EP4 or DP1 receptors, respectively. Elevating cAMP inhibits two pivotal steps in NADPH oxidase-mediated bacterial killing, namely the phosphorylation as well as the translocation of the cytosolic p47phox subunit to cell membrane. Moreover, by signaling through EP2/4 PGE2 inhibits FcyR-mediated phagocytosis. As non-steroidal anti-inflammatory drug (NSAIDs) classically inhibit PG synthesis, it is not surprising that NSAlDs are increasingly recognised to facilitate leukocyte killing of bacteria. That notwithstanding, properties of COX 1 versus COX 2 inhibitors is unknown as is their respective roles in PG synthesis, cAMP expression and therefore cytokine balance during infection in both mouse and humans. Moreover, it is not known whether NSAlDs interfere with antibiotic-mediated bacterial killing. Finally, it is unknown whether priming the innate response by PG inhibition would enhance leukocyte killing of antibiotic-resistant bacteria by overcoming strategies drug-resistant bacteria have developed to parry antibiotic efficacy. To investigate this, we carried out a series or experiments in mouse and in humans finding that COX 1 is the predominant isoform active in PG synthesis during infection and that prophylactic as well as therapeutic inhibition of both COX isoforms kills bacteria to an equivalent extent by increasing phagocytic uptake and reactive oxygen intermediate-mediated killing. Moreover, we report that inhibition of PGs synthesis and signaling enhances bacterial killing in humans; that NSAlDs do not interfere with the mode of action of antibiotics but exert an additive effect when used in combination with penicillin, for instance. Finally, we show that priming the innate immune system with NSAIDs bypasses antibiotic resistance and kills drug-resistant bacteria. These data underlie the importance of lipid mediators in host responses to infection, the potential of inhibitors of PG signaling pathways as adjunctive therapies, particularly in the context of antibiotic resistance.

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