Role of macrophages in atherosclerosis. Sequential observations of cholesterol-induced rabbit aortic lesion by the immunoperoxidase technique using monoclonal antimacrophage antibody.

To elucidate the role of macrophages in atherosclerosis, sequential observations were carried out on cholesterol-induced aortic lesions of the rabbit with the immunoperoxidase technique by use of monoclonal antimacrophage antibody. Animals on cholesterol diets for 8 weeks or longer showed increased accumulations of lipid-filled macrophages in the intima. At a very early stage, when no grossly visible alterations were observed, macrophages were seen clinging to the endothelial surface with apparent penetration of the endothelium. A single line of three or four vacuolated macrophages were found in otherwise normal subendothelial spaces. In flat lesions consisting of a few layers of foam cells, lipid-laden macrophages were the cells that predominated. In advanced plaque lesions, negatively staining, most presumably, smooth muscle foam cells became noticeable and increased in number. At this stage, macrophage foam cells predominated in the superficial layer of the lesion, whereas negatively staining foam cells were prevalent in deeper areas. Macrophages were also spotted within areas of necrosis, and they were occasionally observed near the necrotic core of the atheroma. During 24 to 74 weeks after termination of the cholesterol diet, the number of cells with specific macrophage staining markedly diminished. The results support the concept that circulating monocytes are the prime source of foam cells in the initial phase of atherogenesis. It seems likely that the major role of macrophages in atherogenesis is to remove lipids from areas of lesion formation. The failure of macrophages to perform their scavenger role successfully may be a major factor in the accumulation of lipid-rich debris in advanced lesions. Relative paucity of macrophages may also be an important factor explaining why regression of atherosclerosis occurs rarely in the rabbits.