Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers.

Abstract

The pathogenesis of sepsis is partly attributable to dysregulated inflammatory response mediated by pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and damage-associated molecular patterns (DAMPs) (for example, high-mobility group box 1 [HMGB1]). An endogenous ubiquitous polyamine, spermine, inhibits endotoxin-induced cytokine release in vitro, but its capacities to attenuate sepsis- and HMGB1-induced inflammatory responses was previously unknown. We thus tested the hypothesis that spermine protects mice against lethal sepsis by attenuating sepsis-induced local and systemic inflammatory responses. Intraperitoneal (i.p.) administration of spermine (10 mg/kg, twice daily, for 3 d) conferred a significant protection against lethal sepsis. The protective effects were associated with a significant reduction in peritoneal and serum levels of several surrogate markers of sepsis (for example, Interleukin-6 [IL-6], keratinocyte-derived chemokine [KC], monocytes chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-2 [MIP-2], tissue inhibitor of metalloproteinase-1 [TIMP-1], soluble tumor necrosis factor-alpha receptor I [sTNFRI], and soluble tumor necrosis factor-alpha receptor II [sTNFRII]) during a late stage of sepsis. In vitro, spermine effectively inhibited HMGB1-induced release of the above surrogate markers in peritoneal macrophages. Thus, spermine confers protection against lethal sepsis partly by attenuating sepsis- and HMGB1-induced inflammatory responses.

• Authors: Shu Zhu, Mala Ashok, Jianhua Li, Wei Li, Huan Yang, Ping Wang, Kevin J Tracey, Andrew E Sama, Haichao Wang
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) 2009 Jul-Aug Vol. 15 Issue 7-8 Pg. 275-82 ISSN: 1528-3658 [Electronic] England
• PMID: 19593412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cytokines
• HMGB1 Protein
• Hbp1 protein, rat
• Inflammation Mediators
• Lipopolysaccharides
• lipopolysaccharide, Escherichia coli O111 B4
• Spermine

Topics

• Analysis of Variance
• Animals
• Biomarkers (metabolism)
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• HMGB1 Protein (pharmacology)
• Inflammation (drug therapy, metabolism, pathology)
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Injections, Intraperitoneal
• Lipopolysaccharides (pharmacology)
• Macrophages, Peritoneal (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Rats
• Sepsis (drug therapy, metabolism, pathology)
• Spermine (pharmacology)