Yin Z L, Hickey H, Dusting G J
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
J Vasc Res. 1998 May-Jun;35(3):156-64. doi: 10.1159/000025579.
Platelet-activating factor (PAF) may be involved in adhesion of leucocytes and migration of cells during vascular remodelling for it is expressed in leucocytes after cytokine priming and is required for cell adhesion. We studied the effects of WEB 2170, a potent PAF antagonist, on the development of an atheroma-like neo-intima induced by a peri-arterial collar in rabbits. Either WEB 2170 (3 mg/kg/day) or vehicle was given by subcutaneous injection once a day for 4 or 9 days, and on day 3 peri-arterial collars were applied to both carotid arteries in all animals. Two or 7 days after implanting the collars vasodilator responses to the endothelium-dependent vasodilator, acetylcholine and the endothelium-independent vasodilator, sodium nitroprusside were studied in isolated artery rings from both groups of rabbits. Neo-intima formation after 7 days (day 10 of treatment) was measured by light microscopy as the ratio of cross-sectional areas of intima and media, and expression of inducible nitric oxide synthase (iNOS) was studied by immunohistochemistry. PAF-induced platelet aggregation ex vivo was inhibited specifically in WEB 2170-treated rabbits. At day 5, acetylcholine-induced vasorelaxation in collared artery rings was markedly impaired as compared to control sections from both vehicle- and WEB 2170-treated rabbits. At day 10, acetylcholine-induced vasorelaxation in collared artery rings from vehicle rabbits was markedly less than in controls, but in WEB 2170-treated rabbits, the acetylcholine response in collared arteries was similar to control sections. Intimal thickening was much reduced in WEB 2170-treated rabbits, ratios of intima/media areas being vehicle: 0.21 +/- 0.02 (n = 5) and WEB 2170: 0.07 +/- 0.01 (n = 7; p < 0.01). Immunofluorescence showed expression of iNOS only in the neo-intima of vehicle-treated, collared arteries, but not in the residual neo-intima of WEB 2170-treated, collared arteries. These results suggest that WEB 2170 is effective in preserving endothelial function, prevents the development of neo-intima and blocks iNOS expression in the neo-intima in this model.
血小板活化因子（PAF）可能参与白细胞黏附和血管重塑过程中的细胞迁移，因为它在细胞因子启动后在白细胞中表达，并且是细胞黏附所必需的。我们研究了强效PAF拮抗剂WEB 2170对兔动脉周围套环诱导的动脉粥样硬化样新生内膜形成的影响。将WEB 2170（3mg/kg/天）或赋形剂每天皮下注射一次，持续4天或9天，在第3天对所有动物的双侧颈动脉施加动脉周围套环。在植入套环2天或7天后，研究两组兔离体动脉环对内皮依赖性血管舒张剂乙酰胆碱和内皮非依赖性血管舒张剂硝普钠的血管舒张反应。在治疗第10天（7天后），通过光学显微镜测量新生内膜形成，即内膜和中膜横截面积之比，并通过免疫组织化学研究诱导型一氧化氮合酶（iNOS）的表达。在WEB 2170治疗的兔中，PAF诱导的体外血小板聚集受到特异性抑制。在第5天，与赋形剂和WEB 2170治疗兔的对照切片相比，套环动脉环中乙酰胆碱诱导的血管舒张明显受损。在第10天，赋形剂处理兔的套环动脉环中乙酰胆碱诱导的血管舒张明显低于对照组，但在WEB 2170治疗的兔中，套环动脉中的乙酰胆碱反应与对照切片相似。WEB 2170治疗的兔内膜增厚明显减轻，内膜/中膜面积比为：赋形剂组0.21±0.02（n = 5），WEB 2170组0.07±0.01（n = 7；p < 0.01）。免疫荧光显示，iNOS仅在赋形剂处理的套环动脉新生内膜中表达，而在WEB 2170治疗的套环动脉残余新生内膜中不表达。这些结果表明，在该模型中，WEB 2170可有效保留内皮功能，防止新生内膜形成并阻断新生内膜中iNOS的表达。
