Lipoxin A4 Increases Survival by Decreasing Systemic Inflammation and Bacterial Load in Sepsis

Abstract

Sepsis is characterized by systemic inflammation with release of a large amount of inflammatory mediators. If sustained, this inflammatory response can lead to multiple organ failure and/or immunoparalysis. In the latter condition, the host may be susceptible to opportunistic infections or be unable to clear existing infections. Therefore, it is potentially beneficial to resolve inflammation by reducing inflammation without compromising host defense. We examined the effect of lipoxin A4 (LXA4), a compound with inflammatory resolution properties, in the cecal ligation and puncture (CLP) model of sepsis. Cecal ligation and puncture rats were given either saline or LXA4 (40 μg/kg, i.p.) 5 h after surgery. Lipoxin A4 administration increased 8-day survival of CLP rats, which lived longer than 48 h, and attenuated tissue injury after 8 days. Therefore, we investigated the effects of LXA4 on systemic inflammation and bacterial load 48 h after CLP sepsis. Plasma IL-6, monocyte chemotactic protein 1, and IL-10 levels were reduced in LXA4-treated rats compared with CLP rats given saline vehicle. Lipoxin A4 reduced phosphorylation of the p65 subunit of nuclear factor κB (NF-κB) at serines 536 and 468 in peritoneal macrophages, suggesting that LXA4 reduced production of proinflammatory mediators through an NF-κB-mediated mechanism. Lipoxin A4 reduced blood bacterial load and increased peritoneal macrophage number without affecting phagocytic ability, suggesting that LXA4 reduced blood bacterial load by enhancing macrophage recruitment. It also suggests that LXA4 reduced systemic inflammation and NF-κB activation without compromising host defense. Increased macrophage recruitment was in part due to a direct effect of LXA4 as LXA4 increased peritoneal macrophage recruitment in sham controls and partly due to reduced production of IL-10 as LXA4 decreased macrophage IL-10 release (a known inhibitor of macrophage migration) after CLP. The results suggest that LXA4 increased survival in sepsis by simultaneously reducing systemic inflammation as well as bacterial spread.

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

“…The omega-6 derivative LXA 4, administered to CLP rats increases survival rates and attenuates tissue injury (9). The omega-3 derivative resolvin D 1 improves the outcome of sepsis (28).…”

“…Proresolving mediators share a set of properties that are emerging as paradigmatic (6); these include modulation of immune cell recruitment [inhibition of polymorphonuclear (PMN) migration and promotion of monocyte influx], augmentation of phagocytosis (leading to bacteria containment), promotion of apoptosis and efferocytosis, and eventually tissue/ organ repair with restoration of physiological function (6,7). It is perhaps for these organic and multifactorial biological actions that proresolving mediators like the protein annexin A1 (AnxA1) and the bioactive lipids lipoxin A 4 (LXA 4 ) and resolvin D 2 exert protection in models of experimental sepsis (8)(9)(10). Of relevance, the receptor target for AnxA1 and LXA 4 is a G protein-coupled receptor that belongs to the formyl-peptide receptor (FPR) family, termed FPR2/ALX.…”

Simvastatin and a Plant Galactolipid Protect Animals from Septic Shock by Regulating Oxylipin Mediator Dynamics through the MAPK-cPLA2 Signaling Pathway

“…The inhibition of cPLA 2 , 5-LOX, and sEH expressions remains unclear, especially in sepsis. LXA 4 has been extensively reported to have antiinflammatory and proresolution activities and has been associated with decreased systemic inflammation and reduced septic bacterial load (39). Other HETE species, for example, 20-HETE and 11-HETE, were not affected significantly by any of the treatments, but it seems likely that dLGG and simvastatin divert the fate of AA and LA oxidation, and shunt them toward production of antiinflammatory and proresolution species highlighted by the increase in 11(12)-EET for high-dose dLGG pretreatment and 5(6)-EET for simvastatin.…”

Lipid Mediators in the Resolution of Inflammation

“…3) and its AT-RvD3 (4S,11R, 17R-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z- (Walker et al 2011) Apop PMN (Godson et al 2000;Schwab et al 2007) Serum-treated zymosan (Schwab et al 2007) Latex beads (Schwab et al 2007 Apop PMN (Schwab et al 2007;Oh et al 2011) Serum-treated zymosan (Schwab et al 2007;Ohira et al 2010;Oh et al 2011) Latex beads (Schwab et al 2007) E. coli 18S-RvE1…”