Activation and cholesterol accumulation of macrophages induced by hypercholesterolemia. A study using a rat peritoneal macrophage model for extravascular in vivo generation of foam cells.
Intimal infiltration of lipid-filled macrophages (M psi s) is an important event in the pathogenesis of atherosclerosis. To better understand M psi functions, a model for the extravascular in vivo generation of foam cells in rat peritoneal cavities was utilized. Morphologic alterations, intracellular cholesterol accumulation, subpopulation, activation and proliferative properties of M psi from hypercholesterolemic rats (HM psi s) were compared with M psi s from normal rats (NM psi s). HM psi s revealed a significant increase of cholesterol mass in the cytoplasm; 65% of HM psi s were loaded with various amounts of oil-red-O-stainable lipid droplets which were barely identified in NM psi s. Ultrastructurally, accumulated lipid droplets in HM psi s were either membrane-bound or membrane-free in the cytoplasm. Further biochemical analysis revealed that cellular levels of total cholesterol, free cholesterol, and cholesteryl esters in HM psi s were increased 6-, 8-, and 4-fold, respectively. As to the M psi subpopulation, there was a significant increase of Ia-antigen-positive cells in HM psi s (15.8 vs. 8.8%), indicating that these cells were in a state of activation. To investigate the mitotic activity, the proliferative potential of M psi s was determined both in vivo and in vitro using monoclonal anti-bromodeoxyuridine (anti-BrdU) antibody to detect BrdU incorporated into cell DNA. However, both NM psi s and HM psi s showed little proliferation; proliferative indices were less than 2%. This implies that M psi s are barely replicating, and hypercholesterolemia does not stimulate M psi s in this aspect.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pathology, Saga Medical School, Japan.
J
J
Fan
T
T
Shimokama
O
O
Tokunaga
T
T
Watanabe
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008262:Macrophage Activation / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley
D008055:Lipids; D004247:DNA; D002784:Cholesterol; D001973:Bromodeoxyuridine