Recent studies of the atherogenic process in hypercholesterolemic animals suggest that the macrophage plays a role in the initiation and possibly the progression of atherosclerotic lesions. Although much is known about macrophage biology in general, very little is known about the properties of the macrophage while resident within the developing lesion other than its capacity for accumulating large amounts of lipid. The objectives of this study are to further elaborate how macrophages are involved in the atherogenic process, and specifically to determine whether the arterial macrophage is functionally and antigenically different from macrophages resident within other tissues. Initially, macrophage- derived foam cells will be isolated from atherosclerotic rabbit arteries using an enzyme digestion procedure, and purified using rate zonal gradient centrifugation, both under sterile conditions. The isolated foam cells will be placed in culture and the capacity of the cells to secrete mitogens, chemotactic factors, lipoprotein lipase, and Apo E will be assayed. In addition, the capacity of the foam cells to bind, degrade, and modify lipoproteins and proliferate will be determined. Subset of the foam cells, defined on the basis of size and buoyant density, type of lesion or location within a lesion will be purified and placed in culture. The functional assays listed above will be performed in order to determine whether there is any functional differences in the subsets of these cells. The purified foam cells, as well as crude homogenates of atherosclerotic lesions, and lipid-laden cultured macrophages will be used as immunogens to generate specific monoclonal antibodies that recognize the subsets of foam cells. In this fashion, we hope to demonstrate a correlation between the functional and antigenic properties of these cells. Knowledge of phenotypic heterogeneity of arterial macrophages should help define the natural history of the atherosclerotic lesion and aid in the design of therapeutic strategies.
| Rosenfeld, M E; Butler, S; Ord, V A et al. (1993) Abundant expression of apoprotein E by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb 13:1382-9 |
| Rosenfeld, M E; Yla-Herttuala, S; Lipton, B A et al. (1992) Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol 140:291-300 |
| Rosenfeld, M E; Khoo, J C; Miller, E et al. (1991) Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest 87:90-9 |
