Lipoxin A4 (
LXA4) is an endogenous
lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of
LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae.
LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (
LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h)
sepsis were studied.
Sepsis induced an early increase in
LXA4, FPR2/ALX lung expression, local and systemic
infection and
inflammation, and mortality. Treatment with BOC-2 in early
sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and
15-lipoxygenase in early
sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic
LXA4 or
BML-111 in early
sepsis decreased cell migration and worsened the
infection. In late
sepsis, treatment with BOC-2 had no effect, but
LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator
LXA4 and its receptor FPR2/ALX levels were increased in the early phase of
sepsis, contributing to the septic inflammatory dysregulation. In addition,
LXA4 has a dual role in
sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with
LXA4 system may be a new therapeutic avenue to treat
sepsis.