Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.

Abstract

SummaryHigh-density hpoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion ofproinflammatory cytokine inhibitors IL-lra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.T he systemic toxicity of Gram-negative sepsis is in large part mediated by endotoxin which induces an extensive inflammatory response characterized by cytokine release and activation of leukocytes. Once in the circulation, endotoxin is bound by lipopolysaccharide-binding protein (LBP) 1 which can transfer LPS to either cell-bound CD14 (causing activation of these cells), to soluble CD14 (facihtaring activation ofceUs not expressing CD14 on their surface), or to lipoproteins (1-7). Binding of LPS to lipoproteins results in inactivation of LPS (8-11). Preincubation of endotoxin with low-density lipoprotein (LDL), very-low density lipoprotein (VLDL) and chylomicrons reduced endotoxininduced lethality (12), whereas hypolipidemic animals were more sensitive to endotoxin (13). Further, transgenic mice with elevated apolipoprotein A-1 (apoA-1) and HDL levels are protected against LPS-induced mortality (14).The endotoxin-neutralizing capacity of lipoproteins is dependent on the lipid composition. Reconstituted human HDL (rHDL), containing purified apoA-1, phosphatidyl cho1Abbreviations used in this paper: apoA-1, apohpoprotein A-l; HDL, high-density hpoprotein; LBP, hpopolysaccharide-binding protein; LDL, low-density lipoprotein; rHDL, reconstituted human HDL; VLDL, very low-density lipoprotein.line and cholesterol, neutralized endotoxin in whole blood more effectively than LDL, VLDL, and natural HDL (15, 16). Pretreatment of animals with rHDL reduced endotoxininduced TNF production, leukopenia and lethality (17)(18)(19). The present study was designed to investigate the endotoxin-neutrahzing properties of rHDL (40 mg/kg) in humans in vivo. Materials and MethodsHuman Endotoxemia. Eight healthy male volunteers (mean age 24, range 20-28 yr) were enrolled in thi...

Low-density lipoprotein protects Vibrio vulnificus-induced lethality through blocking lipopolysaccharide action

“…V. vulnificus infection is characterized by the high fatality rates of 70% and the primary attack against people who are immunocompromised or have underlying diseases such as liver cirrhosis (Canturk et al, 2002). V. vulnificus cytolysin (VVC) has been incriminated as a virulence factors in V. vulnificus infection (Pajkrt et al, 1996). Indeed, antibodies against the cytolysin were detected in the blood of V. vulnificus infected mice or a human that survive V. vulnificus disease (Gray and Kreger, 1986).…”

“…Thus, scavengers of bacterial products are expected to protect against bacterial infection and sepsis, such as plasma lipoproteins (Canturk et al, 2002;Delgado-Rodriguez et al, 2002). Indeed, lipoproteins protect against the infection and inflammation by blocking endotoxin activity (Pajkrt et al, 1996;Netea et al, 1998). Furthermore, recently it has been known that total cholesterol, HDL and LDL levels on admission are inversely associated with the disease severity (Wu et al, 2004, Chien et al, 2005, Vermont et al, 2005.…”

HDL in Infectious Diseases and Sepsis

“…rHDL significantly reduced endotoxemia-induced inflammatory response, as it reduced clinical symptoms, reduced inflammatory cytokine (TNF-α, IL-6, IL-8) production, and attenuated LPS-induced leukocyte activation, in part due to the downregulation of the main LPS receptor monocyte-bound CD14 (Pajkrt et al 1996). In LPS-challenged macrophages, HDLs selectively inhibit the activation of type I IFN response genes (Suzuki et al 2010), which play a critical role in the antiviral response of cells, although emerging evidence also implicates this response in host defense during bacterial infection.…”

“…Administration of reconstituted HDL (rHDL) efficiently inhibits the LPS-induced cytokine release from the whole-blood system in vitro (Parker et al 1995); however, the first study that demonstrated the LPS-neutralizing ability of rHDL in humans was performed by intravenous infusion of rHDL before induction of endotoxemia in healthy volunteers (Pajkrt et al 1996). rHDL significantly reduced endotoxemia-induced inflammatory response, as it reduced clinical symptoms, reduced inflammatory cytokine (TNF-α, IL-6, IL-8) production, and attenuated LPS-induced leukocyte activation, in part due to the downregulation of the main LPS receptor monocyte-bound CD14 (Pajkrt et al 1996).…”

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

“…2,3 Then, infusions of ACh and SNP were repeated. In further 5 hypercholesterolemic patients, the effects of intravenous rHDL infusion on ACh-and SNP-induced vasodilation were assessed during intraarterial coinfusion of N G -monomethyl-L-arginine (L-NMMA, 4 mol/min; Clinalfa), an inhibitor of NO synthase.…”