Abstract 13500: Human Cholesteryl Ester Transfer Protein Expression Enhances the Mouse Survival Rate by Lowering the Systemic Inflammatory Response in an Experimental Model of Polymicrobial Sepsis
Introduction: Recent study from our laboratory indicates that cholesteryl ester transfer protein (CETP) is involved in the inflammatory response due to a reduced mortality rate and plasma concentrations of cytokines after a lethal dose of lipopolysaccharide (LPS) to human CETP transgenic mice. The current goal was to evaluate the involvement of CETP in polymicrobial sepsis. We investigated whether the survival rate of CETP transgenic animals observed in the previous study was due to a LPS related specific TLR4 dependent agonist response or common to sepsis in general.
Methods: The animal protocol was approved by the University of São Paulo Medical School Ethics Committee (n°1107/09). C57BL6/J male littermates mice expressing (+) or not (-) the human CETP gene (huCETP), n= 8-15/group, 8-12 weeks of age, were submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Were determined the animal mortality, release of inflammatory mediators and the neutrophil migration into the peritoneal cavity, because the clearance of bacterial infection depends on efficient neutrophil migration into the infection site.
Results: Mortality rates were 6.7% in huCETP (+) and 40% in huCETP(-) mice (Log rank Test p=0.0267). After 48 h of CLP the plasma IL-6 concentration (pg/ml mean±SD) was lower in huCETP(+) as compared to huCETP (-) mice, respectively, 107.4 ± 38.61 and 274.9 ±114.9 (p=0.0087). The neutrophils migration to the peritoneal cavity (cells x 103 per cavity, mean±SD) was greater in huCETP (+) mice than huCETP(-), respectively: 14.43 ± 3.05 and 5.80 ± 1.85 (p=0.0095). In conclusion, our results indicate that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators in sepsis experimental. Considering the limitation of the mouse model to human physiology, more evidences are required to comprehend the interrelation between infection/inflammation and CETP to help the development of new treatment strategies for polymicrobial sepsis in humans. Our study provides a serious caveat to CETP inhibition in patients with severe sepsis.
- © 2011 by American Heart Association, Inc.