Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis

In sepsis, hyperactivation of neutrophils can lead to tissue injury. Later, neutrophil dysregulation with reduced levels of migration, decreased apoptosis and inadequate phagocytosis may impair the host׳s ability to clear infection. Lipoxin A4 (LXA4) is a pro-resolution lipid mediator which reduces neutrophil migration and inflammatory mediator expression. As neutrophil migration and activation are important in bacterial clearance, the role of LXA4 in regulating neutrophil function for bacterial clearance is unclear. Using the cecal ligation and puncture (CLP) rat model of sepsis, LXA4 given after 1h reduced blood bacterial load at 24h. LXA4 treatment decreased neutrophil migration to the peritoneum but augmented blood neutrophil phagocytic ability and promoted apoptosis without affecting free radical production. In contrast, LXA4 increased peritoneal neutrophil phagocytic ability without affecting apoptosis or free radical production suggesting that in vivo effects of LXA4 were compartment specific. To investigate if LXA4 acted directly on neutrophils, blood and peritoneal leukocytes were taken from CLP rats 1h after surgery and incubated ex vivo with and without LXA4. LXA4 (1nM) increased phagocytosis in blood neutrophils without affecting apoptosis or free radical production. Ex vivo LXA4 had no effect on peritoneal neutrophils which suggests that LXA4 enhanced peritoneal neutrophil phagocytic ability in vivo by an indirect mechanism. The results suggest that LXA4 reduced neutrophil migration, but increased neutrophil bacteria clearing function without excessive free radical production. This phenotype was associated with reduced blood bacteria load.