Abstract
Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.
Highlights
Sepsis brings on an uncontrolled inflammatory response and remains a significant cause of death despite the availability of the various therapeutic interventions [1, 2]
To investigate the cholesteryl ester transfer protein (CETP) relevance on sepsis, mice expressing the human CETP transgene and wild type (WT) mice were submitted to cecal ligation and puncture (CLP) and to sham-operation utilized as control for both groups
Human CETP expressing mice were more resistant to the CLP induced lethality, which is compatible with a beneficial role of the human CETP expression (Figure 1)
Summary
Sepsis brings on an uncontrolled inflammatory response and remains a significant cause of death despite the availability of the various therapeutic interventions [1, 2]. The bacterial lipopolysaccharide (LPS) is the primary cause of Gramnegative sepsis, and its interaction with lipopolysaccharide binding protein (LBP) catalyzes the binding of LPS to CD14. Several evidences indicate that the endotoxin LPS is removed from the bloodstream mainly by the liver, and yet the LPS hepatic uptake mechanisms remain uncertain [4,5,6]. Plasma LPS is transported in unbound (free) or bound forms. Bound LPS is found in aggregates belonging to bacterial membrane fragments, loosely linked to albumin, CD14, and other proteins. An important fraction of LPS is bound to Mediators of Inflammation lipoproteins. The lipoprotein-bound LPS is cleared mainly by hepatocytes [7, 8]
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