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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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

Fingerprint

Sepsis
Escherichia coli
Anti-Bacterial Agents
Peritoneal Macrophages
Therapeutics
Interleukin-6
Tumor Necrosis Factor-alpha
Peritonitis
Lipopolysaccharides
lipoxin A4
Infection
Cytokines
Inflammation
Ceftazidime
Bacterial Load
Peritoneum
DNA
Inbred C57BL Mouse
Chemokines
Neutrophils

Keywords

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

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Combination therapy of 15-epi-lipoxin a4 with antibiotics protects mice from escherichia coli-induced sepsis. / Ueda, Tomomi; Fukunaga, Koichi; Seki, Hiroyuki; Miyata, Jun; Arita, Makoto; Miyasho, Taku; Obata, Toru; Asano, Koichiro; Betsuyaku, Tomoko; Takeda, Junzo.

In: Critical Care Medicine, Vol. 42, No. 4, 2014.

Research output: Contribution to journalArticle

Ueda, Tomomi ; Fukunaga, Koichi ; Seki, Hiroyuki ; Miyata, Jun ; Arita, Makoto ; Miyasho, Taku ; Obata, Toru ; Asano, Koichiro ; Betsuyaku, Tomoko ; Takeda, Junzo. / Combination therapy of 15-epi-lipoxin a4 with antibiotics protects mice from escherichia coli-induced sepsis. In: Critical Care Medicine. 2014 ; Vol. 42, No. 4.
@article{4cdcae8b7a814b709599d9ac98e2f062,
title = "Combination therapy of 15-epi-lipoxin a4 with antibiotics protects mice from escherichia coli-induced sepsis",
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.",
keywords = "anti-inflammatory lipid mediators, combination drug therapy, lipoxin A4, mortality, peritonitis, sepsis",
author = "Tomomi Ueda and Koichi Fukunaga and Hiroyuki Seki and Jun Miyata and Makoto Arita and Taku Miyasho and Toru Obata and Koichiro Asano and Tomoko Betsuyaku and Junzo Takeda",
year = "2014",
doi = "10.1097/CCM.0000000000000162",
language = "English",
volume = "42",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Combination therapy of 15-epi-lipoxin a4 with antibiotics protects mice from escherichia coli-induced sepsis

AU - Ueda, Tomomi

AU - Fukunaga, Koichi

AU - Seki, Hiroyuki

AU - Miyata, Jun

AU - Arita, Makoto

AU - Miyasho, Taku

AU - Obata, Toru

AU - Asano, Koichiro

AU - Betsuyaku, Tomoko

AU - Takeda, Junzo

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - anti-inflammatory lipid mediators

KW - combination drug therapy

KW - lipoxin A4

KW - mortality

KW - peritonitis

KW - sepsis

UR - http://www.scopus.com/inward/record.url?scp=84897083849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897083849&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000000162

DO - 10.1097/CCM.0000000000000162

M3 - Article

C2 - 24463858

AN - SCOPUS:84897083849

VL - 42

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 4

ER -