Lehr H A, Kress E, Menger M D
Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Germany.
Int J Microcirc Clin Exp. 1993 Feb;12(1):61-73.
Although cigarette smoke (CS) has been identified as an independent risk factor for atherogenesis and sudden cardiac death, the underlying pathomechanism has not been clarified. A common factor of both atherogenesis and ischemia/reperfusion damage associated with myocardial infarction is the adhesion of circulating leukocytes to the vascular endothelium. Searching for the mechanism by which CS exerts its deleterious effects on the cardiovascular system, we used a dorsal skinfold chamber model in hamsters for intravital microscopy to examine the effect of CS on the interaction of fluorescently stained leukocytes with the microvascular endothelium in striated muscle. Exposure of awake animals (n = 7) for 5 minutes to the mainstream smoke of one cigarette (2R1 research cigarette) elicited rolling and subsequent adhesion of circulating leukocytes to the endothelium of both arterioles and postcapillary venules with a maximum 30 minutes after CS-exposure. In order to test a putative mediator role of the chemotactic and adhesion-promoting leukotrienes in this event, we pretreated another group of 7 animals with MK-886, a potent and specific inhibitor of leukotriene biosynthesis (20 mumol/kg body weight, iv, 30 minutes prior to CS exposure). While no inhibitory effect was seen on CS-induced leukocyte rolling along the microvascular endothelium. MK-886 pretreatment significantly attenuated leukocyte adhesion to arterioles (5.2 +/- 13.7 cells/mm2 vs. 54.1 +/- 54.8 in control animals. P < 0.01) and venules (37.0 +/- 33.6 cells/mm2 vs. 161.6 +/- 91.1 in control animals, P < 0.01), 30 minutes after CS exposure, suggesting a key mediator role of leukotrienes in this event. We propose that the stimulation of leukocyte/endothelium interaction by CS may provide the pathophysiologic basis for--or at least contribute to--its deleterious effects on cardiovascular mortality and morbidity. The identification of the mediator role of leukotrienes in this event may open the way to novel pharmacologic and dietary approaches for the prophylaxis of CS-induced cardiovascular pathology.
尽管香烟烟雾(CS)已被确定为动脉粥样硬化形成和心源性猝死的独立危险因素,但其潜在的发病机制尚未阐明。动脉粥样硬化形成以及与心肌梗死相关的缺血/再灌注损伤的一个共同因素是循环白细胞与血管内皮的黏附。为了探寻CS对心血管系统产生有害影响的机制,我们使用仓鼠背部皮褶腔室模型进行活体显微镜检查,以研究CS对横纹肌中荧光染色白细胞与微血管内皮相互作用的影响。将清醒动物(n = 7)暴露于一支香烟(2R1研究用香烟)的主流烟雾中5分钟,会引发循环白细胞在小动脉和毛细血管后微静脉的内皮上滚动并随后黏附,在CS暴露后30分钟达到最大值。为了测试趋化和促进黏附的白三烯在这一过程中可能的介导作用,我们用MK - 886对另一组7只动物进行预处理,MK - 886是一种强效且特异性的白三烯生物合成抑制剂(20 μmol/kg体重,静脉注射,在CS暴露前30分钟)。虽然未观察到对CS诱导的白细胞沿微血管内皮滚动有抑制作用,但MK - 886预处理在CS暴露30分钟后显著减弱了白细胞对小动脉(5.2±13.7个细胞/mm²,对照组动物为54.1±54.8个细胞/mm²,P < 0.01)和微静脉(37.0±33.6个细胞/mm²,对照组动物为161.6±91.1个细胞/mm²,P < 0.01)的黏附,这表明白三烯在这一过程中起关键介导作用。我们认为,CS刺激白细胞/内皮相互作用可能为其对心血管死亡率和发病率的有害影响提供病理生理基础,或者至少对此有一定作用。确定白三烯在这一过程中的介导作用可能为预防CS诱导的心血管病变开辟新的药理学和饮食学途径。