Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers.
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.
Zhu
Shu
S
Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, New York 11030, United States of America.
Ashok
Mala
M
Li
Jianhua
J
Li
Wei
W
Yang
Huan
H
Wang
Ping
P
Tracey
Kevin J
KJ
Sama
Andrew E
AE
Wang
Haichao
H
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013096:Spermine / Q000494:pharmacology*
D015415:Biomarkers; D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D013096:Spermine