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Involvement of 5-lipoxygenase products in cigarette smoke-induced leukocyte/endothelium interaction in hamsters
H A Lehr1, E Kress, M D Menger
1Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Germany.
Insights
Cigarette smoke increases leukocyte adhesion to blood vessels, a key step in cardiovascular disease. Inhibiting leukotriene production significantly reduces this adhesion, suggesting a new therapeutic target.
Area of Science:
- Cardiovascular Science
- Microcirculation Research
- Pharmacology
Background:
- Cigarette smoke (CS) is a risk factor for cardiovascular diseases like atherosclerosis and sudden cardiac death.
- Leukocyte adhesion to vascular endothelium is a common mechanism in atherogenesis and myocardial infarction.
- The precise mechanism by which CS impacts the cardiovascular system requires further elucidation.
Purpose of the Study:
- To investigate the effect of CS exposure on leukocyte-endothelium interactions in microvessels.
- To determine the role of leukotrienes as mediators in CS-induced leukocyte adhesion.
- To explore potential therapeutic targets for mitigating CS-related cardiovascular pathology.
Main Methods:
- Utilized a dorsal skinfold chamber model in hamsters for intravital microscopy.
- Observed the interaction of fluorescently stained leukocytes with microvascular endothelium after CS exposure.
- Administered MK-886, a leukotriene biosynthesis inhibitor, to assess its effect on CS-induced leukocyte adhesion.
Main Results:
- CS exposure (5 minutes) induced significant rolling and adhesion of leukocytes to arterioles and venules.
- MK-886 pretreatment markedly reduced CS-induced leukocyte adhesion to both arterioles and venules.
- MK-886 did not affect CS-induced leukocyte rolling, indicating a specific role in adhesion.
Conclusions:
- CS exposure stimulates leukocyte-endothelium interactions, potentially contributing to cardiovascular damage.
- Leukotrienes play a crucial mediator role in CS-induced leukocyte adhesion.
- Targeting leukotriene pathways may offer novel strategies for preventing cigarette smoke-induced cardiovascular disease.
Abstract:
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.