Investigation of biological responses to synthetic lipoxin mimetics

Lipoxins (LXs) are endogenously generated eicosanoids. Pharmacologic responses to LXs are consistent with promoting the resolution of aberrant inflammation and suppressing fibrosis. Exploiting the therapeutic potential of LXs has been challenging. To address this synthetic lipoxin mimetics (sLXms) been generated containing heteroaromatic substitutions of the triene core with imidazole or quinoxaline groups. In this thesis biologic responses to an imidazole and a quinoxaline containing sLXm have been characterised. These compounds are designated AT-01-KG and AT-02-CT respectively. AT-01-KG and AT-02-CT both inhibited NF-κB driven gene expression, activated the G protein coupled receptor FPR2, stimulated macrophage phagocytosis and demonstrated distinct effects on monocyte pro-inflammatory cytokine release. The activity of AT-01-KG and AT-02-CT in murine models of inflammation was explored i.e Zymosan-induced peritonitis. AT-01-KG showed greater potency and efficacy than AT-02-CT in this context and was therefore selected for further investigation in a more complex model of inflammation: polymicrobial sepsis. Caecal ligation and puncture was used to induce polymicrobial sepsis in a murine model. Treatment with AT-01-KG (2 ug/kg) was associated with significant protection relative to vehicle treatment reflected by aggregate clinical scores, reduced systemic inflammation and preserved cardiac function. These responses were underpinned by differential expression of cardiac and renal genes associated with inflammation and distinct patterns of serum and cardiac proteins. A pivotal role for FPR 2 in these responses is supported by data from mice where AT-01-KG was without any effects on the pathologies associated with the CLP induced sepsis. Remarkably, the protection observed in response to AT-01-KG was associated with reduced bacterial load locally (peritoneal) and systemically in wild type but not FPR 2/3 -/- suggesting an immune modulation effect of AT-01-KG on the host. In aggregate these data support the hypothesis that systemic LX mimetics may have therapeutic applications in the context of complex pathologies where an unmet need exists such as polymicrobial sepsis.