LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients

Isabelle Fournel,Randa Bittar,Hélène Choubley,Auguste Dargent,Laurent Lagrost,Jean-Pierre Quenot,Jean-Paul Pais De Barros,Alain Carrié,Thomas Gautier,David Masson,Wilfried Le Goff,Samir Saheb,Anne Laure Rerole

doi:10.1194/jlr.ra120001132

Abstract

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.

Highlights

Supplementary key words lipoproteins low density lipoprotein tandem mass spectroscopy human and clinical research inflammation sepsis septic shock polymyxin hemoperfusion low density lipoprotein apheresis lipopolysaccharide
Efficiency of DALI microbeads was considerably reduced in lipoprotein-deficient plasma (11% reduction versus 27% in whole plasma), the 3-hydroxy myristate (3HM) decrease remained significant in this matrix (Fig. 2)
We demonstrated for the first time that LDL apheresis is a viable alternative to PMX adsorption for the removal of LPS from plasma

Summary

Introduction

LPS is first bound to HDL particles in the circulation, but its elimination requires first a transfer to LDLs mediated by proteins such as LPS binding protein (LBP) or phospholipid transfer protein (PLTP) [14], and second internalization and degradation by hepatocytes via LDLR [20]. We have termed this pathway reverse LPS transport [21] by analogy with cholesterol, and it may bear a critical role during human sepsis.

Methods

Results

Conclusion