Inhibition of mast cell-dependent conversion of cultured macrophages into foam cells with antiallergic drugs.
Degranulation of isolated, rat peritoneal mast cells in the presence of low density lipoprotein (LDL) induces cholesteryl ester accumulation in cocultured macrophages with ensuing foam cell formation. This event occurs when the macrophages phagocytose LDL particles that have been bound to the heparin proteoglycans of exocytosed granules. In an attempt to inhibit such foam cell formation pharmacologically, rat peritoneal mast cells that had been passively sensitized with anti-ovalbumin-IgE were treated with 2 mast cell-stabilizing antianaphylactic drugs, MY-1250 or disodium cromoglycate (DSCG). Both drugs were found to inhibit antigen (ovalbumin)-triggered release of histamine from the mast cells, revealing mast cell stabilization. In cocultures of rat peritoneal macrophages and passively sensitized mast cells, addition of MY-1250 before addition of the antigen resulted in parallel reductions in histamine release from mast cells, uptake of [(14)C]sucrose-LDL, and accumulation of LDL-derived cholesteryl esters in the cocultured macrophages. Similarly, when passively sensitized mast cells were stimulated with antigen in the presence of DSCG and the preconditioned media containing all substances released from the drug-treated mast cells were collected and added to macrophages cultured in LDL-containing medium, uptake and esterification of LDL cholesterol by the macrophages were inhibited. The inhibitory effects of both drugs were mast cell-specific because neither drug inhibited the ability of macrophages to take up and esterify LDL cholesterol. Analysis of heparin proteoglycan contents of the incubation media revealed that both drugs had inhibited mast cells from expelling their granule remnants. Thus, both MY-1250 and DSCG prevent mast cells from releasing the heparin proteoglycan-containing vehicles that bind LDL and carry it into macrophages. This study suggests that antiallergic pharmacological agents could be used in animal models to prevent mast cell-dependent formation of foam cells in vivo.
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Wihuri Research Institute, Helsinki, Finland.
Kovanen
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PT
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D002788:Cholesterol Esters / Q000096:biosynthesis; D008078:Cholesterol, LDL / Q000378:metabolism; D018920:Coculture Techniques; D004205:Cromolyn Sodium / Q000494:pharmacology; D005487:Foam Cells / Q000502:physiology*; D006046:Gold; D006493:Heparin / Q000031:analogs & derivatives / Q000032:analysis; D006632:Histamine / Q000032:analysis; D007106:Immune Sera; D007073:Immunoglobulin E / Q000276:immunology; D008077:Lipoproteins, LDL / Q000032:analysis; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D008854:Microscopy, Electron; D010047:Ovalbumin / Q000276:immunology; D011509:Proteoglycans / Q000032:analysis; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D018926:Anti-Allergic Agents; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D007106:Immune Sera; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D015363:Quinolones; C036090:heparin proteoglycan; D007073:Immunoglobulin E; C049488:MY 1250; D006046:Gold; D006632:Histamine; D006493:Heparin; D010047:Ovalbumin; D004205:Cromolyn Sodium