Investigations into low-dose aspirin as an adjunct therapy for sepsis and device-related biofilm infections

Sepsis is a deadly condition that develops when the host immune system is ill equipped to respond to infection. Delays in the appropriate identification and management of sepsis in health care facilities can lead to organ failure, which is associated with high mortality rates (40-70%). Current therapies of sepsis provide support and target the source of infection, but do not address the inflammatory pathways that have shown to contribute to increased disease severity. As such, there is an urgent need for an effective adjunct therapy for sepsis. Aspirin offers a cost-effective alternative to other adjunct therapies currently under investigation, and at low-doses the proposed mechanism of action includes the production of specialised pro-resolving mediators; including aspirin-triggered lipoxins (ATL), that mediate the resolution of inflammation by inhibiting the activation of NFκB, which was shown to improve outcomes in other inflammatory conditions. The purpose of this study was therefore to investigate the anti-inflammatory effects of aspirin in clinical sepsis, as well as experimentally in mouse models of gram-positive sepsis, using ATL and NFκB as primary read out parameters.<br><br>Chapter 3 of this thesis investigated of the mechanisms of aspirin-therapy in participants with sepsis enrolled into the Mechanism of Aspirin Therapy in Sepsis (MATHS) randomised control trial. Low-dose aspirin therapy (100 mg/day) increased production of ATL in plasma, and inhibition of NFκB in PBMC. In order to address this question, a mouse model of systemic bloodstream infection was established. Chapter 4 of this thesis investigated the effect of aspirin therapy in a wild-type mouse model of staphylococcal-induced sepsis. Unlike the participants in the trial, aspirin at an equivalent low-dose (1 mg/kg/day) over two days did not significantly impact ATL and NFκB in mice. Nevertheless, low-dose aspirin-treated mice did demonstrate a complete clearance of bacteria from all target organs within 24 h of the second aspirin dose, and showed considerable improvements in clinical outcomes, in the absence of supportive antibiotic therapy. Chapter 5 investigated the mechanisms of salicylic acid (SA) inhibition on growing staphylococcal biofilms, both in vitro and in an in vivo mouse model of device-related biofilm infection. SA treatment significantly diminished two key mechanisms of biofilm formation including: biomass production and extracellular DNA (eDNA) release, reducing the structural integrity of biofilm. Low-dose aspirin (1 mg/kg/day) over five days lead to the reduction of surface biofilm in stainless steel implanted mice. Aspirin-treated mice, regardless of implant type had accelerated wound healing, shown by reduced epithelial thickness.<br><br>In summary, this thesis has contributed to the understanding of immunological pathways activated following localised and systemic infection, leading to the early development of sepsis. Further, this study has elucidated a potential role for low-dose aspirin (100 mg/day or equivalent in animal studies) as an adjunct pro-resolution therapy in both device-related biofilm infection and sepsis. Completion of the MATHs clinical trial will be required to provide definitive evidence to support advancing to a prospective trial in septic patients. Further research is required in to develop animal models that will more accurately represent human disease.