Institutional members access full text with Ovid®

Share this article on:

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

doi: 10.1097/CCM.0000000000000162
Online Laboratory Investigations

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.

1Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.

2Pulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

3Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

4School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.

5Department of Surgery, Shiga University of Medical Science, Shiga, Japan.

6Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan.

* See also p. 1012.

Dr. Asano received grant support from Novartis and Merck Sharp and Dohme (MSD) and lectured for GlaxoSmithKline, MSD, and Astellas Pharma. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: k-fuku@jf7.so-net.ne.jp

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