HYPOTHERMIA ENHANCES THE BIOLOGICAL-ACTIVITY OF LIPOPOLYSACCHARIDE BYALTERING ITS FLUIDITY STATE

Lipopolysaccharides (LPS, endotoxin) of Gram-negative bacteria are amo ng the main causes of sepsis and septic shock. In the present study, t he influence of temperature on the biological activity of LPS was inve stigated. Lowering the temperature from 37 degrees C to 34.5 degrees C or to 30 degrees C significantly enhances in vitro tumor necrosis fac tor-alpha (TNF-alpha), interleukin (IL)-1 beta and IL-6 release induce d by different LPS chemotypes and heat-inactivated Escherichia coli. T his cytokine-increasing effect of lowering the temperature is highly m ediated by serum proteins, particularly by LPS-binding protein (LBP) a nd low-density lipoproteins (LDL). In contrast, cytokine production in duced by the superantigen toxic shock syndrome toxin-l (TSST-1) from G ram-positive Staphyloccoccus aureus decreases by around 70% at 30 degr ees C as compared with 37 degrees C, corresponding to the expected eff ect of change in temperature and regardless of the presence of serum p roteins. In order to explain the unexpected biological hypothermia eff ect with regard to LPS, the fluidity state of the lipid A portion of L PS as one important physico-chemical property possibly involved was in vestigated. The fluidity, determined by fluorescence polarization meas urements, was found to decrease with decreasing temperature. These dat a suggest that a low fluid LPS chemotype is biologically more active t han a more fluid one (and vice versa). Statistical analysis of the res ults shows a strong correlation between cytokine secretion and fluidit y state of a given LPS chemotype (0.71 < r < 0.89, all P < 0.01). As a clinical consequence, these data may be one possible explanation for the higher mortality rate of hypothermic Gram-negative sepsis.