Recombinant human macrophage colony-stimulating factor reduces plasma cholesterol and carrageenan granuloma foam cell formation in Watanabe heritable hyperlipidemic rabbits.

Abstract

Previous studies have demonstrated that short-term administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) reduces plasma cholesterol in rabbits, nonhuman primates, and human subjects. This study extended the dose schedule of rhM-CSF to 8 weeks of continuous intravenous infusion (CIV) in the Watanabe heritable hyperlipidemic (WHHL) rabbit and expanded the scope to include an assessment of macrophage-derived foam cell development. Ten male WHHL rabbits were injected subcutaneously with 1% carrageenan to promote formation of a macrophage-rich foam cell granuloma. Rabbits were infused with either vehicle or rhM-CSF at 100 micrograms/kg per day (weeks 1 through 5) followed by 300 micrograms/kg per day (weeks 6 through 8). rhM-CSF (100 micrograms/kg per day) decreased total plasma cholesterol by 45% at 2 weeks compared with controls. The gradual return of plasma cholesterol toward control concentrations over the subsequent 3 weeks correlated with the appearance of circulating antibodies specific to rhM-CSF. Granuloma weights at harvest (8 weeks after infusion) were significantly lower (2.8 +/- 0.7 g, mean +/- SEM) in rhM-CSF-treated rabbits relative to controls (7.1 +/- 1.5 g, P < .05). Granulomas from rabbits treated with rhM-CSF contained lower concentrations of cholesterol (2.0 +/- 0.7 versus 6.1 +/- 1.5 micrograms/mg, P < .03) and cholesteryl ester (0.7 +/- 0.4 versus 3.9 +/- 1.2 micrograms/mg, P < .03) than controls. Histological evaluation revealed that granulomas from the rhM-CSF-treated rabbits were more fibrous and contained fewer foam cells than those from controls.(ABSTRACT TRUNCATED AT 250 WORDS)