Recombinant human macrophage colony-stimulating factor reduces plasma cholesterol and carrageenan granuloma foam cell formation in Watanabe heritable hyperlipidemic rabbits.
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)
Schaub
R G
RG
Genetics Institute, Inc, Cambridge, Mass.
Bree
M P
MP
Hayes
L L
LL
Rudd
M A
MA
Rabbani
L
L
Loscalzo
J
J
Clinton
S K
SK
D000818:Animals; D000906:Antibodies / Q000097:blood; D002351:Carrageenan; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D006099:Granuloma / Q000139:chemically induced / Q000473:pathology*; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D007958:Leukocyte Count; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000473:pathology; D008297:Male; D010976:Platelet Count; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
D000906:Antibodies; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D002351:Carrageenan; D002784:Cholesterol