Reconstituted High-Density Lipoprotein Attenuates Organ Injury and Adhesion Molecule Expression in a Rodent Model of Endotoxic Shock

Abstract

The salutary effects of high-density lipoproteins (HDLs) in animal and human models of endotoxic shock have in the past been attributed to the ability of this lipoprotein to bind to lipopolysaccharide. However, the precise mechanisms for the protective effect of HDL are unclear. The first objective of this study was to determine the effects of HDLs on the organ injury and dysfunction associated with acute severe endotoxemia. Second, to gain insight into the mechanism of action of HDL, we also investigated the effect of HDLs on 1) the expression of P-selectin and intercellular adhesion molecule-1 in the kidneys of rats treated with endotoxin and 2) the rise in the plasma levels of tumor necrosis factor-alpha (TNF-alpha). Rats were given Escherichia coli lipopolysaccharide (6 mg/kg i.v.), pretreated with either vehicle (n = 9) or reconstituted HDL (rHDL; apolipoprotein A-I/phosphatidylcholine proteoliposomes, n = 10), and were monitored for 6 h. Here we report that rHDL attenuates the renal injury and dysfunction caused by endotoxin in the rat. In addition, rHDL reduced the degree of histological tissue injury in the lung, liver and intestine and attenuated the expression of P-selectin and intercellular adhesion molecule-1 in the renal glomerulus. Interestingly, pretreatment of rats with rHDL did not prevent the hypotension nor the rise in plasma levels of TNF-alpha (at 90 min) caused by endotoxin. Thus, rHDL reduces the organ injury/dysfunction, but does not affect the circulatory failure, nor the rise in plasma levels of TNF-alpha caused by endotoxin in the rat. We propose that the mechanisms of these beneficial effects of HDL may be related to direct inhibition of adhesion molecule expression.

Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice

“…Pretreatment with rHDL was shown to have a significant effect in inhibiting endotoxin-induced organ damage, such as the lowered neutrophil infiltration in lung seen in histological examination (23,24). Hubsch, Casas, and Doran (25) found that both prophylactic and therapeutic rHDL administration could improve clinical outcome, with a significant attenuation of acidosis in the rabbit Gram-negative bacteremia model.…”

High-density lipoproteins: an emerging target in the prevention of cardiovascular disease

“…Reports that HDL improves reactivity of vascular rings in organ bath studies [42,43] was extended to the human setting where infusion of rHDL restores endothelial function in subjects with hypercholesterolaemia [44] or low levels of HDLC in the setting of heterozygous ABCA1 deficiency [45]. Reduced tissue injury in models of ischaemia-reperfusion [46,47] and shock in the setting of both hypovolemia [48] and sepsis [49] is likely to result from the combination of antioxidant, antiinflammatory and NOenhancing activities of HDL. HDLs have also been reported to possess antiapoptotic activity [50][51][52][53], although the underlying mechanism for this property remains unresolved.…”

Papel protector de las lipoproteínas de alta densidad en sepsis: aspectos básicos e implicancias clínicas

“…Adicionalmente, se han evaluado los efectos en daño orgánico múltiple con el uso de rHDL en modelos animales de endotoxemia. En estos estudios se ha observado que el pre-tratamiento con rHDL reduce el daño estructural renal, hepático, pulmonar e intestinal producido por LPS 41 . Aunque en este estudio no se detectó una disminución de la elevación de los niveles de FNT-α inducidos por LPS, la rHDL disminuyó la expresión glomerular renal de P-selectina e ICAM, sugiriendo que en este modelo el mecanismo protector de las rHDL sería mediante la inhibición de las moléculas de adhesión presentes en la superficie celular.…”