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.