Sex-related variations in the response of drug therapies targeting purinergic signaling pathways in sepsis

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Sex-related variations in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high morbidity and mortality. Current sepsis treatments are limited to supportive therapies, and specific pharmacologic treatments that could greatly improve patient outcomes have not yet been developed With hospital mortality rates of affected patients reportedly as high as 50%, there is a critical need for improved methods for treating sepsis. Sex differences in the morbidity and mortality of sepsis have been observed in various clinical studies and animal models. To date, females has shown less mortality and decreased organ failure in mice and humans compared to their male counterpart but the lack of studies comparing both genders limits our capacity to evaluate the extent of sex-related differences. However, the data obtained so far suggest that sex should be taken into account when identifying the optimal pharmacological intervention for sepsis. Our previous studies have shown that in male mice, anti-platelet therapy that targets the ADP-receptor P2Y12 improves the outcome of sepsis. However, targeting another platelet ADP-receptor, P2Y1 did not seem to alter sepsis. Previous data have shown that the signaling of the P2Y1 and P2Y12 activation and intracellular are complex and sex-specific in platelets, however the data are still unclear. We are lacking similar information in other cells of the immune system. No studies have investigated sex-related differences in targeting purinergic signaling during sepsis. Hence this project aims to investigate sex-related differences in how the purinergic signaling pathways of activated platelets respond to drug therapies used for treating sepsis. We will use a well-established murine model of sepsis such as cecal ligation and puncture in male and female P2Y12 knock-out (KO) and P2Y1 KO mice and compared them with wild-type. We will analyze the outcome of sepsis in terms of survival, organ dysfunction, plasma cytokine levels, as well as platelet functions, such as platelet-leukocyte interaction, platelet adhesion markers and platelet reactivity. The data obtained in this study will provide 1) a more comprehensive understanding of sex-related differences in platelet behavior during sepsis between male and female mice, 2) the efficacy and safety of anti-platelet drugs in male and female.