Lipoxin A(4) promotes more complete inflammation resolution in sepsis compared to stable lipoxin A(4) analog

In sepsis, excessive inflammation may lead to organ injury or a paradoxical immunosuppressed state where the host is unable to clear preexisting infection. Resolution of inflammation is the process which restores tissue homeostasis and ensures that a chronic cycle of infection/inflammation does not occur. Lipoxin A4 (LXA4) is one of a family of lipid mediators with novel inflammation resolution activity. We compared the actions of LXA4 to the stable 15-epi-16-(para-fluorophenoxy)-lipoxin A4 methyl ester (LXA4 analog) in the cecal ligation and puncture (CLP) model of sepsis. Both LXA4 compounds (at 7 μg/kg; i.v.) reduced plasma TNFα and IL-6 concentrations compared to rats given vehicle saline. Neither treatment altered plasma IL-10 compared to CLP given saline, but LXA4 analog, increased plasma IL-10 concentrations compared to rats given LXA4. LXA4 reduced blood bacterial load but the LXA4 analog did not. LXA4 increased 8 day survival and the LXA4 analog did not have a significant effect. To examine possible mechanisms for the differences, we investigated peritoneal leukocyte gene expression of iNOS and macrophage phagocytic ability. Only LXA4 increased the percentage of phagocytic peritoneal macrophages. LXA4 reduced neutrophil gene expression of iNOS compared to CLP rats given vehicle, while the LXA4 analog did not. Our results suggest that at doses which reduced systemic inflammation, only LXA4 inhibited bacterial spread and increased survival. This difference may be due to the shorter-lived compound being able to increase macrophage phagocytosis and reduce neutrophil iNOS expression.