Combination therapy of 15-epi-lipoxin A4 with antibiotics protects mice from Escherichia coli-induced sepsis*.
OBJECTIVE
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.


METHODS
Prospective experimental study.


METHODS
University research laboratory.


METHODS
Male C57BL/6 mice.


METHODS
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.


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.
Tomomi
T
Ueda
Koichi
K
Fukunaga
Hiroyuki
H
Seki
Jun
J
Miyata
Makoto
M
Arita
Taku
T
Miyasho
Toru
T
Obata
Koichiro
K
Asano
Tomoko
T
Betsuyaku
Junzo
J
Takeda
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D002442:Ceftazidime / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000401:mortality; D018836:Inflammation Mediators / Q000378:metabolism; D044045:Lipoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000188:drug therapy / Q000401:mortality; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D044045:Lipoxins; C040527:lipoxin A4; D002442:Ceftazidime