INHIBITION OF MONONUCLEAR CELL RECRUITMENT IN AORTIC INTIMA BY TREATMENT WITH ANTI-ICAM-1 AND ANTI-LFA-1 MONOCLONAL-ANTIBODIES IN HYPERCHOLESTEROLEMIC RATS - IMPLICATIONS OF THE ICAM-1 AND LFA-1 PATHWAY IN ATHEROGENESIS
Q. Nie et al., INHIBITION OF MONONUCLEAR CELL RECRUITMENT IN AORTIC INTIMA BY TREATMENT WITH ANTI-ICAM-1 AND ANTI-LFA-1 MONOCLONAL-ANTIBODIES IN HYPERCHOLESTEROLEMIC RATS - IMPLICATIONS OF THE ICAM-1 AND LFA-1 PATHWAY IN ATHEROGENESIS, Laboratory investigation, 77(5), 1997, pp. 469-482
To investigate the mechanism(s) for mononuclear cell recruitment in th
e arterial wall during the development of atherosclerosis, we studied
intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-ass
ociated antigen-1 (LFA-1) expression in aortic intima from diet-induce
d hypercholesterolemic rats. ICAM-1 was barely found in the aortic wal
ls from rats fed a normal chow diet; however, in rats on a cholesterol
-rich diet for 4 weeks, ICAM-1 expression was markedly enhanced in the
intimal endothelial cells of aortas. Enhanced expression of ICAM-1 on
endothelial cells especially along the cellular borders in the abdomi
nal aorta was almost invariably associated with increased adherence of
mononuclear cells. Compared to control animals, in hypercholesterolem
ic rats, the numbers of intimal macrophages and T lymphocytes adhering
to the ''lesion-prone'' areas of the abdominal aorta were significant
ly increased by 5.9-fold (p < 0.001) and 2.2-fold (p < 0.001), respect
ively. More than 85% of adherent macrophages exhibited LFA-1 antigen o
n the cellular membrane surface as assessed by immunostaining. To exam
ine the participation of ICAM-1 and LFA-1 in adherence and migration o
f mononuclear cells, we administered monoclonal antibodies (mAb) again
st either ICAM-1 or LFA-1 into hypercholesterolemic rats after they we
re fed a cholesterol-rich diet for 2 weeks. Two weeks after the mAb tr
eatment, the number of macrophages adhering to the intima was signific
antly inhibited by 42% (p < 0.001) with anti-ICAM-1 mAb and by 31% (p
< 0.001) with anti-LFA-1 mAb compared to controls injected with mouse
IgG. Combined injection with these two mAb increased the reduction of
the number of macrophages in the intima to 58%. Furthermore, we found
that the decrease in the number of macrophages that adhered to the int
ima was almost exclusively due to the reduction of LFA-1-positive macr
ophages. These results suggest that the ICAM-1 and LFA-1 pathway is in
volved in mononuclear-endothelial cell interaction during cholesterol-
rich diet-induced atherogenesis.