Effects of Cigarette Smoking on Behavior of Leukocytes in the Microcirculation

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In assessing the effects of cigarette smoke on leukocyte rheology and passage through the microcirculation, one must consider potential modifications in their mechanical and adhesive properties, and also possible effects on the endothelial cells that can promote adhesion. In general, studies of the effects of cigarette smoke or its constituents on leukocyte behavior fall into one of the following categories: (i) studies in which humans or animals are acutely exposed to cigarette smoke and observations are made on changes in circulatory behavior in vivo; (ii) studies in which blood is withdrawn from human cigarette smokers or non-smokers (with or without additional acute smoking), and properties of leukocytes are tested ex vivo; (iii) studies in which blood or isolated leukocytes from humans are exposed to cigarette smoke or components of cigarette smoke in vitro; (iv) occasional studies in which endothelial cells are cultured and exposed to cigarette smoke or components of cigarette smoke in vitro, and ability to bind leukocytes is tested. The direct in vivo observations will be described first, before considering the more reductive analyses related to cell mechanics and adhesion that may explain the phenomena seen in vivo and predict behavior in the microcirculation.

In Vivo Studies of Effects of Cigarette Smoke on Leukocyte Behavior in Humans

It is possible to extract leukocytes (usually neutrophils) from blood, to radiolabel them, and then to reinject them, in order to examine their fate in the circulation. Such an approach can be used to locate sites of inflammation where cells accumulate, but can also be used to study the kinetics of passage of leukocytes through the human lung. It has been shown, for instance, that a large pool of neutrophils is usually moving more slowly through the lung than the bulk of red blood cells, so that about 50 percent of all circulating neutrophils are located there at any time [2]. This is believed to arise from the restricted rate of passage of the neutrophils through the many capillary segments in the pulmonary circulation. Of particular interest here are studies made in 1989, which showed that when humans smoked a cigarette there was an immediate sequestration of neutrophils in the lungs that took longer than usual to wash out of the lungs [3]. Linked studies indicated that in vitro measurements of the resistance to flow of neutrophils through capillary-sized pores correlated, on a person-by-person basis, with the number of cells sequestered in the pulmonary circulation. Such changes have been associated with evidence of systemic oxidative stress [4]. The implication is that upon cigarette smoking, neutrophils are exposed to agents in smoke (such as oxidants) that delay their passage through the lungs, possibly by causing an increase in their rigidity. However, from these studies, it cannot be ruled out that passage through the microcirculation is also impaired through changes in neu-trophil or endothelial adhesive properties. Indeed, acute cigarette smoking has been associated with increased migration of neutrophils into the lung airspaces.

In Vivo Studies of Effects of Cigarette Smoke in Experimental Animals

Direct visual observations of the systemic microcirculation have been made before and after exposure to cigarette smoke in animals, and larger vessels have been removed and examined [5]. In these studies, inhalation of cigarette smoke was associated with an increase in rolling and stationary adhesion of leukocytes in arterioles and venules within minutes. Postmortem examination also revealed deposition of leukocytes in large arteries, typically associated with deposition of platelets. In general, induction of rolling adhesion requires no change in the properties of leukocytes, but a stimulus to endothelial cells is needed to express selectins on their surface. This can occur within minutes after stimulation with agonists, such as thrombin and histamine, within approximately hours of cytokine stimulation, and after an intermediate period upon stimulation by oxidants such as oxidized LDL.

Transformation to stationary adhesion requires either that the endothelial cells generate and present chemotactic agents, or that the leukocytes are directly activated by soluble agents. It is also worth noting that activated platelets attached to the vessel wall can support capture, rolling, and, under some conditions, immobilization of flowing leukocytes. It is instructive that oxidative mechanisms were strongly implicated in the response to CS because treatment with superoxide dismutase or the water-soluble antioxidant vitamin C reduced the adhesive response to smoke inhalation. Thus, dramatic changes in leukocyte-vessel wall interactions occurred in tissues remote from the lungs in animals inhaling cigarette smoke, and it is possible that these arose from responses in leukocytes, endothelial cells, and/or platelets.

Exposure to cigarette smoke also leads to sequestration of neutrophils in the pulmonary microcirculation in animals. This sequestration has been linked to changes in expression of adhesion molecules suggesting local activation, and also to release of immature and less deformable neutrophils from the bone marrow [6].

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