Cellular Targets of Cigarette Smoke Induced Microvascular Dysfunction

Endothelial Cells

In the mechanistic insight into cigarette smoke-induced microcirculatory dysfunction, the endothelium appears to play a central role and has thus been called the cornerstone of smoking pathophysiology. Direct toxic effects of cigarette smoking on endothelial cells have been demonstrated in rat aortas by electron microscopy, by the demonstration of anuclear endothelial cell carcasses in the circulating blood of smokers, and by the demonstration of reduced prostacy-clin production by cigarette smoke-exposed endothelial cells. Since the endothelium is involved in the regulation of vasomotor tone, intensive research endeavors have focused on the impact of cigarette smoking on endothelial function. Coronary angiographic studies have shown a significant vasoconstriction after cigarette smoking, and an increase in coronary resistance despite an increase in oxygen demand. In line with these observations, several animal experiments and clinical studies have demonstrated a significant reduction of reactive hyperemia in otherwise healthy smokers. Indeed, the attenuation of endothelium-dependent vasodila-tion was inversely correlated with the number of pack years smoked by the subjects rather than with blood cotinine levels. Similar findings have been demonstrated in veins and large-caliber arteries. A plausible explanation for these findings has been derived from studies on porcine coronary artery rings, where cigarette smoke extracts inactivate endothelium-derived nitric oxide (NO) through reactive

Platelets

For more than 25 years it has been known that cigarette smoking induces platelet aggregation (closely linked to the serum levels of nicotine) and increases urinary excretion of thromboxane. At the same time, smoker's platelets (i) exhibit a significantly increased surface density of receptors for thromboxane and serotonin, (ii) produce increased amounts of eicosanoids, and (iii) show reduced formation of nitric oxide. Of interest, an essential role seems to be played by the lipid profile of the patients, since the most pronounced abnormalities in platelet aggregation have been described in hypercholesterolemic smokers rather than in normocholesterolemic smokers. Platelet aggregation in the bloodstream is an ubiquitous phenomenon that is not confined to either large-caliber conductance vessels or the microcirculation. In intravital microscopic studies from our laboratory, we found that exposure of hamsters to the smoke of one cigarette induced the rapid formation in the bloodstream of platelet/leukocyte aggregates and scanning electron microscopic studies demonstrated the dendritic nature of activated platelets involved in these aggregates. Platelet aggregates were also seen on the endothelial surface of the aorta studied enface in smoke-exposed hamsters [4]. In collaboration with Tom Mclntyre and his coworkers at the University of Utah at Salt Lake City, we were able to demonstrate in the blood of smoke-exposed hamster the formation of platelet-activating factor-like lipids. In a series of ex vivo experiments, we could demonstrate that these PAF-like lipids were responsible for the induction of platelet aggregates in the hamster bloodstream [5]. Pharmacological blockade of the PAF receptor (through injection of WEB2170) or inhibition of the formation of PAF-like lipids (through the administration of the water-soluble antioxidant vitamin C) effectively prevented platelet aggregation after cigarette smoke challenge in the hamsters, emphasizing the relevance of these smoke-induced lipid mediators in the intact organism. Since similar lipids have been described to occur in human smokers, it is likely that similar pathomech-anisms are operative during the induction of platelet activation in human smokers.

Leukocytes

The organism undergoes an inflammatory-type response with every cigarette smoked. This is caused either by combustion products, reactive oxygen species, and other compounds that are inhaled with the cigarette smoke, or by reactive oxygen species and inflammatory mediators released from the organism in response to cigarette smoking (particularly from phagocytic cells that are sequestered in the pulmonary microcirculation in response to cigarette smoke). This is most obviously reflected in an activation of white blood cells. Although leukocyte adhesion and emigration are involved in host defense and phagocytosis and thus serve a beneficial role during a well-contained inflammatory response, leukocytes may also turn against the host and contribute to tissue damage, characterized by the breakdown of capillary perfusion, the loss of endothelial integrity, and the extravasation of fluid and macromolecules into the interstitial space [6]. A feature common to the pathomechanisms of most cigarette smoke-associated diseases (such as atherosclerosis, chronic bronchitis, pulmonary emphysema, and periodontitis) is the activation and adhesion of circulating leukocytes to micro- and macrovascular endothelium, followed by acute or chronic leukocyte-mediated tissue damage. Peripheral blood monocytes isolated from habitual smokers demonstrate significantly increased adherence to cultured endothelial cells, positively correlated with the duration of the smoking habit. Likewise, exposure of peripheral blood mononuclear cells to cigarette smoke condensate in vitro increased cell surface expression of adhesion molecules CD11b and subsequent adhesion to cultured bovine and human endothelial cells through a protein kinase C-dependent mechanism. Direct chemotactic effects of cigarette smoke for leukocytes have been described, as well as enhanced generation of leukocyte chemotaxins or cochemo-taxins including leukotrienes, complement, and Gc globulin. Also, cigarette smoke stimulates the generation of oxida-tively modified low-density lipoproteins that exert powerful chemotactic and adhesion-promoting effects on. With the demonstration of all these proinflammatory changes in leukocytes, it is not surprising that leukocytes have been found sequestered in different organs, particularly in the pulmonary and tracheal microcirculation, but also in pancreatic microvessels of cigarette smoke-exposed experimental animals. Likewise, leukocyte recruitment was found in the pulmonary microcirculation of cigarette smoke-exposed experimental animals and habitual smokers. An alternative explanation for the enhanced sequestration of neutrophils in the pulmonary microcirculation has been proposed by Drost and coworkers, who demonstrated significantly reduced deformability of peripheral blood neu-trophils from habitual smokers and of neutrophils exposed to cigarette smoke in vitro [7]. Cigarette smoke condensate induces functional changes in endothelial cells, leading to the increased expression of adhesion molecules for leuko-cyte-endothelial cell interaction. Increased levels of soluble intercellular adhesion molecule-1 (ICAM-1) have recently been found in the serum of habitual smokers. Through the inhibition of nitric oxide generation and/or its inactivation through radical-dependent mechanisms, cigarette smoking might also contribute to the stimulation of leukocyte and platelet interaction with endothelial cells. Along the same lines, the well-recognized inhibition of prostacyclin generation by cigarette smoking could predispose to increased leukocyte and platelet adhesion. In a recent study, Sikora and her colleagues have demonstrated in an elegant experimental approach using intravital microscopy on transplanted lung tissue in the dorsal skinfold chamber model in nude mice that nicotine-induced inflammation of the airways involves selectin- and MAP kinase-dependent rolling and adhesion of leukocytes [8].

In an effort to further characterize the mechanism of cigarette smoke-induced leukocyte adhesion to the microvas-cular endothelium, we have exposed hamsters to the smoke generated by one cigarette and could demonstrate rolling and subsequent adhesion of fluorescently labeled leukocytes to the endothelium of microvascular and macrovascular endothelium [4]. Cigarette smoke-induced leukocyte adhesion was significantly blunted in animals in which leukotriene generation was blocked pharmacologically by an inhibitor of 5-lipoxygenase, suggesting a mediator role of leukotrienes in this event. Likewise, administration of superoxide dismutase almost entirely prevented cigarette smoke-induced leukocyte adhesion. Of particular interest was the observation not only that leukocyte adhesion was confined to the venular segment of the microcirculation, but that leukocytes were found to adhere to the endothelium in arterioles, as well as on the aortic endothelium. In both microvascular segments, as well as the aortic endothelium, leukocytes tended not to interact with the endothelium as single cells, but mostly in the form of aggregates of two or more cells, loosely held together by activated platelets. Indeed, any intervention that prevented the formation of these aggregates also prevented the interaction of leukocytes in the arteriolar branch of the microcirculation. In analogy to the experiments described earlier in the section on platelets, we found that PAF-like lipids elicited the interaction of leukocytes with endothelial cells in vitro in the intact hamster organism: Pharmacological blockade of the PAF receptor (through injection of WEB2170) or inhibition of the formation of PAF-like lipids (through the administration of the water-soluble antioxidant vitamin C) effectively prevented leukocyte adhesion to venular or arteriolar endothelium in cigarette smoke-exposed hamsters [5].

Beside the stimulation of leukocyte adhesion to endothelial cells, several authors have demonstrated a breakdown of endothelial barrier function in response to cigarette smoke and/or nicotine. Ultrastructural studies have demonstrated modifications in intercellular cleft morphology, the opening of interendothelial junctions, and the formation of subendothelial edema in response to cigarette smoke. Likewise, a compromised endothelial barrier function of microvessels in the oral mucosa has been found in response to smokeless tobacco exposure. Similar observations have been made by intravital microscopy in the hamster cheek pouch and in the gastric microcirculation in rats. The latter findings are of particular importance because they provide an adequate pathophysiological explanation for the clinical observation of delayed gastric ulcer healing and increased frequency of ulcer recurrence in smokers. Indeed, laser Doppler flowmet-ric studies in heavy smokers have demonstrated significantly reduced mucosal blood flow in the gastric antral region, and the reduced mucosal perfusion was associated with reduced basal bicarbonate secretion.

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