Analysis of the participation of human cholesteryl ester transfer protein (CETP) on the inflammatory response in experimental model of polymicrobial sepsis

• Grant number: 10/50307-7
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2010
• End date: January 31, 2013
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Patricia Miralda Cazita
• Grantee: Patricia Miralda Cazita
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The cholesteryl ester transfer protein (CETP) is a glycoprotein secreted by many organs and is associated with HDL in the bloodstream. The plasma CETP activity is inversely correlated with plasma HDL-cholesterol concentration and despite numerous studies its role in atherosclerosis remains controversial. Recent studies from our laboratory indicate for the first time that CETP is involved in the inflammatory response because of a reduced mortality rate and plasma concentrations of cytokines (TNF-alpha and IL-6) after a lethal dose of lipopolysaccharide (LPS) in human CETP transgenic mice. CETP role in inflammation was raised because of the structural homology between CETP and LBP (lipopolysaccharide binding protein) which is the LPS carrier protein that is involved in the innate immune response. The current goal is to evaluate the involvement of CETP in polymicrobial sepsis. This will show whether the survival of CETP transgenic animals observed in the previous study is due to a LPS-specific response that is considered a TLR4 agonist, or common to sepsis. C57BL6/J male mice expressing or not the human huCETP gene, will be submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Animal mortality, release of inflammatory mediators, plasma lipoprotein profile (LP) and the migration of leukocytes into the peritoneal cavity will be determined. RT-qPCR of macrophage and liver mRNA of genes involved in the LPS metabolism, such as TLR4, SR-B1 and Acyloxyacyl hydrolase (AOAH)- that promotes the detoxification of LPS by deacylation - will be performed. Considering the need for therapeutic strategies to achieve the adequate control of sepsis, it is important to understand the interrelation among infection/inflammation, LP and CETP in order to help the development of new treatments for polymicrobial sepsis. (AU)