Hyperlipoproteinemic low-density lipoprotein receptor-deficient mice are more susceptible to sepsis than corresponding wild-type mice

Abstract

High circulating concentrations of lipoproteins have been shown to modify the cytokine response and reduce mortality after endotoxin or live bacterial challenge. Sepsis, however, is more complex than endotoxemia, and it is not clear whether elevated plasma lipoproteins will be protective. Previous studies have shown that the low-density-lipoprotein receptor deficient (LDLR^—/— ) mice with increased circulating LDL are protected against the lethal effects of endotoxemia and Gram-negative infection. We evaluated whether the LDLR^—/— mice would be protected against the effects of sepsis induced by cecal ligation and puncture (CLP). Mortality was greater in LDLR^{—/ —} mice than in control C57Bl/6J mice. At 120 h after inducing sepsis, 20% of the control mice survived whereas none of the LDLR^—/— mice were alive. Prior to inducing sepsis, serum concentrations of amyloid A protein and lipopolysaccharide binding protein (LBP) were significantly elevated in the LDLR^—/— mice in comparison to the C57Bl/6J mice. Protein expression of sCD14 was also greater in the serum from the LDLR^{—/ —} mice than the C57Bl/6J mice. The elevated serum concentrations of LBP and CD14 were not associated with increases in the levels of liver CD14 mRNA and LBP mRNA. After inducing sepsis, serum concentration of interleukin (IL)-1β was also significantly higher in LDLR^{— /—} mice than in the control C57Bl/6J mice. These findings indicate that the LDLR^{— /—} mice were more susceptible to the lethal effects of sepsis induced by CLP. The LDLR^{— /—} mice also had higher serum concentrations of baseline, acute phase response proteins, SAA and LBP, and increased production of IL-1β in response to CLP.

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