Involvement of 5-lipoxygenase products in cigarette smoke-induced leukocyte/endothelium interaction in hamsters.
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.
Lehr
H A
HA
Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Germany.
Kress
E
E
Menger
M D
MD
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects / Q000648:ultrastructure; D008856:Microscopy, Fluorescence; D009132:Muscles / Q000098:blood supply*; D012907:Smoking / Q000009:adverse effects*; D002722:Chlorobenzenes
D001094:Arachidonate 5-Lipoxygenase; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; C060893:MK-886; D002722:Chlorobenzenes