Ma H, Kovanen P T
Wihuri Research Institute, Helsinki, Finland.
Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):E134-42. doi: 10.1161/01.atv.20.12.e134.
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.
在低密度脂蛋白（LDL）存在的情况下，分离的大鼠腹膜肥大细胞脱颗粒会诱导共培养的巨噬细胞中胆固醇酯积累，随后形成泡沫细胞。当巨噬细胞吞噬已结合到胞吐颗粒的肝素蛋白聚糖上的LDL颗粒时，就会发生这一事件。为了从药理学上抑制这种泡沫细胞的形成，用抗卵清蛋白-IgE被动致敏的大鼠腹膜肥大细胞用两种肥大细胞稳定抗过敏性药物MY-1250或色甘酸钠（DSCG）进行处理。发现这两种药物均能抑制抗原（卵清蛋白）触发的肥大细胞组胺释放，表明肥大细胞得到了稳定。在大鼠腹膜巨噬细胞和被动致敏肥大细胞的共培养物中，在添加抗原之前添加MY-1250会导致肥大细胞组胺释放、[(14)C]蔗糖-LDL摄取以及共培养巨噬细胞中LDL衍生胆固醇酯积累的平行减少。同样，当在DSCG存在下用抗原刺激被动致敏的肥大细胞，并收集含有药物处理肥大细胞释放的所有物质的预处理培养基并添加到含LDL培养基中培养的巨噬细胞时，巨噬细胞对LDL胆固醇的摄取和酯化受到抑制。两种药物的抑制作用均具有肥大细胞特异性，因为两种药物均未抑制巨噬细胞摄取和酯化LDL胆固醇的能力。对孵育培养基中肝素蛋白聚糖含量的分析表明，两种药物均抑制肥大细胞排出其颗粒残余物。因此，MY-1250和DSCG均可阻止肥大细胞释放结合LDL并将其携带到巨噬细胞中的含肝素蛋白聚糖载体。这项研究表明，抗过敏药理学药物可用于动物模型，以预防体内肥大细胞依赖性泡沫细胞的形成。
