Combination therapy of 15-epi-lipoxin a4 with antibiotics protects mice from escherichia coli-induced sepsis

Tomomi Ueda, Koichi Fukunaga, Hiroyuki Seki, Jun Miyata, Makoto Arita, Taku Miyasho, Toru Obata, Koichiro Asano, Tomoko Betsuyaku, Junzo Takeda

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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.

Original languageEnglish
JournalCritical Care Medicine
Volume42
Issue number4
DOIs
Publication statusPublished - 2014

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Keywords

  • anti-inflammatory lipid mediators
  • combination drug therapy
  • lipoxin A4
  • mortality
  • peritonitis
  • sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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