The purpose of the research is to define the role of cell types, in particular of macrophages, in the evolution of human and experimental atherosclerotic lesions. We have previously identified macrophages by means of morphologic and functional markers (Fc, C-3, mannose and acetylated LDL receptors; cell surface antigens; lysozyme; lectin binding; and acid lipase), and correlated lesion macrophage content with lipid related and connective tissue related activity in lesions. We found that macrophages varied in lesion involvement dependent on the species, time point in progression and regression, and presence of hypertension and that lesion macrophage volume was significantly related to lesion lipid-related enzyme activity. These findings have led us to pose the following hypotheses: 1) Each stage in lesion evolution (i.e., progression, stabilization, involution, or disruption) is associated with a particular configuration of macrophage number, location, and functional state. 2) Modification of the macrophage response can result in predictable modulation of the evolution of atherosclerotic lesions. We will test the first hypothesis by identifying and quantitating macrophages and assessing evidences of macrophage activity in human and experimental lesions. We will use macrophage markers (lectin binding and acid lipase histochemistry) and assay lipid related and connective tissue related functional states (acid lipase, cholesteryl esterase, ACAT, collagenase, elastase, cholesteryl ester formation, leukotriene production, and phagocytosis). We will then correlate these data with lesion topography, types and distribution of lesion cells, physical state of the lesion lipids, connective tissue composition and distribution, and evidence of lesion complication such as ulceration, hemorrhage, and thrombosis. To test the second hypothesis we will inhibit leukocyte functions by feeding rabbits fish oil-cholesterol containing diets (high in omega-3 fatty acids) and determine the adherence, ingress and distribution of arterial macrophages and lesion composition at multiple intervals during lesion progression and reversal. We will isolate macrophages and other artery wall cells and test the cells as well as lesion homogenates for metabolic and functional changes resulting from the fish oil diets. We will amplify the cellular response in similar experiments by means of a standard necrotizing ligation injury of the aorta. Identifyable profiles of lesion enzyme activity, lesion composition, and cell type should provide a basis for validation of clinical changes in lesions attributable to therapies designed to arrest or reverse atherosclerosis. The studies dealing with the modification of macrophage activity may reveal mechanisms by which these cells modulate atherogenesis and could provide model systems for the evaluation of inhibitors and stimulators of macrophage function(s) which may alter the evolution of atherosclerotic plaques.