Effects of Cigarette Smoke on Leukocyte Adhesion

Direct Effects on Leukocytes

The effects of cigarette smoke directly on adhesive behavior of leukocytes (as opposed to effects via endothelial cells or platelets) are not so clear. In the case of monocytes, in vitro exposure to condensate derived from cigarette smoke caused upregulation of b2-integrin expression and activation of integrin function over tens of minutes, so that adhesion to endothelial cells was enhanced [8]. Ex vivo studies of monocytes from smokers have also indicated that there is an upregulation of b2-integrin expression and adhesiveness associated with cigarette smoking [9]. However, early studies of neutrophils indicated that adhesion of these cells to various surfaces, supported by b2-integrin receptors, was inhibited if the cells had been treated with CS [10]. Neutrophil spreading was also impaired. In vitro exposure, or ex vivo studies after cigarette smoking, did not show changes in level of b2-integrin expression by neutrophils. All of these studies were in static systems where selectin-mediated capture was not tested. In our own unpublished observation, we found that in a flow system, neu-trophils that had been exposed to water-soluble components of CS could adhere effectively to P-selectin. Interestingly, soluble components of CS could cause transformation of rolling to stationary adhesion (suggesting integrin activation), but this stabilization of adhesion lasted only a few minutes.

In summary, exposure to components of CS may be able to activate integrins of either monocytes or neutrophils and upregulate surface expression of integrins in the former. Time courses may differ, in that changes in neutrophils appear to reverse rapidly so that there is no stable enhancement of adhesion, whereas monocytes exposed to CS appear to retain increased integrin expression and adhesiveness. Morphological changes may also hinder stable attachment of neutrophils. Uncertainty arises when comparing the in vitro data for the different types of leukocytes, because monocytes have typically been exposed to condensate from CS, whereas neutrophils have been exposed to nonpar-ticulate components that exchange into an aqueous phase. The responsiveness of neutrophils and monocytes to cigarette smoke is also manifest in changes in other forms of functional response, which may be linked to adhesion or circulation. For instance, monocytes and neutrophils exposed to elements of CS or derived from cigarette smokers show increased secretion of cytokines and granule enzymes that might promote inflammation, although ability of neutrophils to release oxidants may be impaired rather than enhanced by exposure to CS.

Effects on Endothelial Cells or Platelets

Adhesion of leukocytes may also be promoted if endothelial cells become activated to present adhesion receptors of the selectin family, and this attachment will be stabilized if chemokines or modified lipids such as PAF are presented. Condensate of CS has been shown to increase endothelial expression of ICAM-1, VCAM-1, and E-selectin over a period of approximately hours [10]. This, along with the direct effects noted earlier, increased adhesion of monocytes. Plasma levels of soluble ICAM-1 are also elevated in smokers, presumably as a result of shedding from "activated" endothelial cells. We recently investigated effects of water-soluble components of CS partitioned into flowing culture medium, perfused over endothelial cells downstream in an in vitro vascular model [11]. We found that over a period of about 60 to 150 minutes EC responded by upregulating expression of P- and E-selectin and becoming able to efficiently capture flowing neu-trophils. Some of these neutrophils became stationarily attached, implying that the EC also generated activators, as neutrophils were not themselves exposed to CS. Thus direct-contact models using CS condensate, and perfusion models of effects of soluble mediators, indicate that endothelial cells will take on a "proinflammatory" or proadhesive phenotype as a result of cigarette smoking. The different models may be relevant to effects that might occur in the lungs themselves and in tissue remote from lungs, respectively. The response of the endothelial cells develops over hours and might become chronic in a regular cigarette smoker. This contrasts with the rapid responses of leukocytes, which might exacerbate the underlying "mild" inflammation sporadically.

In addition to endothelial cells, it is increasingly recognized that in pathological conditions at least, platelets may act as promoters of leukocyte attachment to the vessel wall. The platelets themselves may bind to intact endothelium in ischemic or atherosclerotic vessels, or to exposed collagen in damaged vessels, and capture flowing leukocytes through presentation of P-selectin. As noted earlier, circumstantial evidence indicates that platelets may promote leukocyte adhesion in arteries of animals inhaling CS, but we are not aware of any studies clarifying the steps by which this might occur. It is known, however, that cigarette smoking can modify the adhesive properties of platelets and their release of vasoactive compounds. The ability of cigarette smoke to cause platelets to bind in the microcirculation and then cause thrombotic or inflammatory responses appears worthy of further investigation.

Table I Changes in the Properties of the Cells of the Vascular System Induced by Exposure to Cigarette Smoke, with Consequences for Circulation of Leukocytes.

Type of leukocyte

Form of exposure

Modification induced

Neutrophil Neutrophils Monocyte Monocytes

Leukocytes (type undefined) Endothelial cells Endothelial cells

Platelets

Human—smoking

Isolated cells exposed to water-soluble components of CS

Human smokers—ex vivo

Isolated cells exposed to CS condensate

Hamster breathing CS

Isolated cells exposed to CS condensate

Isolated cells exposed to water-soluble component(s) of CS

Human smokers—ex vivo

Delay in transit through lungs

Shape change, increased rigidity, and impaired migration Increased integrin expression and adhesiveness Increased integrin expression and adhesiveness Adhesion to wall of large and small blood vessels Upregulation of adhesion receptors for leukocytes Upregulation of adhesion receptors and activating agents for leukocytes Activation, increased adhesion and secretion

The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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