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Critical Care Medicine:
doi: 10.1097/CCM.0000000000000162
Online Laboratory Investigations

Combination Therapy of 15-Epi-Lipoxin A4 With Antibiotics Protects Mice From Escherichia coli–Induced Sepsis*

Ueda, Tomomi MD1; Fukunaga, Koichi MD, PhD2; Seki, Hiroyuki MD, PhD1; Miyata, Jun MD, PhD2; Arita, Makoto PhD3; Miyasho, Taku PhD4; Obata, Toru PhD5; Asano, Koichiro MD, PhD6; Betsuyaku, Tomoko MD, PhD2; Takeda, Junzo MD, PhD1

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Abstract

Objectives:

Inflammation occurs along with infection during sepsis. 15-Epi-lipoxin A4 has protective and resolving effects in experimental models of infection. In this study, we examined the effects of 15-epi-lipoxin A4 combined with antibiotics on Escherichia coli–induced peritonitis.

Design:

Prospective experimental study.

Setting:

University research laboratory.

Subjects:

Male C57BL/6 mice.

Interventions:

Mice were injected with E. coli to induce peritonitis and were given either 15-epi-lipoxin A4 (1 μg/mouse) or placebo (saline) with antibiotics (ceftazidime). The effects of 15-epi-lipoxin A4 on peritoneal cell populations, bacterial burden, and cytokine production were assessed. Survival rates were observed for up to 7 days. In addition, we examined the effects of 15-epi-lipoxin A4 on peritoneal macrophages stimulated with lipopolysaccharide, CpG DNA, or live E. coli.

Measurements and Main Results:

Treatment with 15-epi-lipoxin A4 significantly reduced the number of neutrophils in the peritoneum, inhibited production of cytokines and chemokines, and decreased bacterial load in the serum. Combined treatment of 15-epi-lipoxin A4 with antibiotics significantly improved survival in E. coli–infected mice. 15-Epi-lipoxin A4 also attenuated the production of interleukin-6 and tumor necrosis factor-α by lipopolysaccharide- or CpG DNA-stimulated peritoneal macrophages. Furthermore, 15-epi-lipoxin A4 combined with antibiotics synergistically reduced the production of interleukin-6 and tumor necrosis factor-α by peritoneal macrophages stimulated with live E. coli.

Conclusions:

15-Epi-lipoxin A4 combined with antibiotics attenuated systemic inflammation, inhibited bacteria dissemination, and improved survival in E. coli–infected mice. The reduced production of interleukin-6 and tumor necrosis factor-α by peritoneal macrophages suggested that 15-epi-lipoxin A4 blocked the initial proinflammatory response. Taken together, these data suggested that 15-epi-lipoxin A4 combined with antibiotics was beneficial in regulating the proinflammatory response in sepsis without exacerbating infection.

Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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