Antioxidant amplifies antibiotic protection in the cecal ligation and puncture model of microbial sepsis through interleukin-10 production.

Abstract

Preadministration of antioxidants such as pyrrolidine dithiocarbamate (PDTC) and phenyl N-tert-butyl nitrone (PBN) protects animals from lethality in sepsis models. However, the requirement of preadministration greatly diminishes the clinical significance of these studies. Although the synthetic antioxidant PBN has been shown to effectively protect rodents from lethality in endotoxemia (lipopolysaccharide [LPS] model), preliminary screening indicates that pre- or postadministration of PBN does not protect in the rat cecal ligation and puncture (CLP) model. We show in this report that in a rat CLP model, the administration of PBN (150 mg/kg, 30 min after CLP) followed by the antibiotic imipenem (IMP; 10 mg/kg, 1 h after CLP) significantly increased survival compared with other single treatment groups. Previously, we have shown that PBN's protection in a rat LPS model is mediated by the overproduction of the anti-inflammatory cytokine interleukin (IL)-10. We show in this study that the increase in survival found in the PBN + IMP-treated group was abrogated by immunoneutralization with anti-IL-10 antibody, indicating that endogenous IL-10 is an effective protective factor. Plasma LPS levels were shown to be elevated after imipenem treatment, and the increased LPS level could have assisted to overproduce endogenous IL-10, as in the case of the PBN-treated LPS model. Statistical analysis indicated that the increase of IL-10 in PBN + IMP-treated group at early time period has significant association to the improvement of survival.

• Authors: Yashige Kotake, Danny R Moore, Angelica Vasquez-Walden, Tahereh Tabatabaie, Hong Sang
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 19 Issue 3 Pg. 252-6 (Mar 2003) ISSN: 1073-2322 [Print] United States
• PMID: 12630525 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Antioxidants
• Cyclic N-Oxides
• Interleukin-6
• Lipopolysaccharides
• Nitrogen Oxides
• Thiocarbamates
• Tumor Necrosis Factor-alpha
• Interleukin-10
• prolinedithiocarbamate
• phenyl-N-tert-butylnitrone
• Proline

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Antioxidants (therapeutic use)
• Bacterial Infections (prevention & control)
• Cecum (physiology)
• Cyclic N-Oxides
• Disease Models, Animal
• Drug Synergism
• Interleukin-10 (blood)
• Interleukin-6 (blood)
• Kinetics
• Lipopolysaccharides (blood, toxicity)
• Male
• Nitrogen Oxides (therapeutic use)
• Proline (analogs & derivatives, therapeutic use)
• Punctures
• Rats
• Rats, Wistar
• Sepsis (prevention & control)
• Thiocarbamates (therapeutic use)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)