The cholesteryl-ester transfer protein isoform exclusively expressed in the small The C-terminus Domain of CETPI Defines its Function as a New Plasma Lipopolysaccharide-Binding Protein: Implications in septic shock.
The cholesteryl-ester transfer protein isoform exclusively expressed in the small intestine (CETPI) and present in human plasma, although described by our group a few years ago, it had been waiting for a functional description and a plausible role of physiological relevance. Now, the present study introduces CETPI as a new protein with the potential capability to recognize, bind and neutralize lipopolysaccharides (LPS) in circulation during septic shock. Employing several peptides derived from the C-terminus domain of CETPI containing an important density of positively charged residues and prolines, we demonstrate their property not only to interact with several LPS serotypes but also to displace LPS bound to the surface of cells. Peptide VSAK derived from the last 18 residues of CETPI protects against the cytotoxic effect of LPS upon macrophages, at high concentrations when macophages, hepatocytes and microglial cells are tested in culture, it does not show cytotoxicity by itself, and prevents against the expression of pro-inflammatory cytokines and the generation of oxidative stress. Employing a septic shock model in rabbits, we demonstrate that the infusion of peptide VSAK in vivo presents the ability to protect against the deleterious effects of LPS and the property of reducing the presence of TNFα in plasma. CETPI presents itself as a new protein that undoubtedly will advance the possibilities to better understand and treat the dangerous effects of LPS present during the treatment of sepsis caused by Gram-negative bacteria and its common consequence, a septic shock condition.
Peptide VSAK blockade of LPS action in a septic shock model established in rabbits. (A) Rectal temperature measurements throughout 90 min. Normalized values from temperatures that ranged from 37.5°C to 40.0 °C. Mean values are presented (n=5, X ± S.E.M.), *p˂0.05, **p˂0.01 obtained in the analysis of the LPS group with respect to the LPS plus peptide VSAK group. (B) Serum TNFα values obtained at the end of the 90 min experiment. Mean values are presented (n=5, X ± S.E.M.).