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.
Highlights
Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection
We found that administration of spermine conferred significant protection against lethal sepsis, and dramatically attenuated sepsis-induced local and systemic accumulation of several surrogate markers of sepsis
In light of our previous observation that spermine effectively attenuated carrageenan-induced paw edema only when given locally [27], we propose that spermine confers protection against lethal sepsis by modulating a local inflammatory response, which is partly sustained by HMGB1, either alone or in combination with other inflammatory stimuli [6,37]
Summary
Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. Upon recognition of various PAMPs (such as bacterial peptidoglycan, endotoxin, and/or CpG-deoxyribonucleic acid [DNA]) [3,4,5,6] or DAMPs (such as HMGB1) [7,8,9], macrophages release various cytokines (such as tumor necrosis factor [TNF], IL-1, IL-6, and IL-12) and chemokines (such as IL-8, MIP-1s, MIP-2, and MCP-1) [10,11,12]. An appropriate inflammatory response is required to defend against infection, an uncontrolled systemic inflammation may contribute to the pathogenesis of sepsis. In animal models of lethal systemic inflammation, TNF [13], IL-1 [14], interferon (IFN)-γ [15], macrophage migration inhibitory factor (MIF) [16,17], and HMGB1 [5,18], individually or in combi-
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call