(Circulation. 1997;95:1986-1988.)
© 1997 American Heart Association, Inc.
Articles |
Potential Significance of Circulating E-Selectin
From the Section of Leukocyte Biology, Departments of Pediatrics and Microbiology and Immunology, Baylor College of Medicine, Houston, Tex.
Correspondence to C. Wayne Smith, MD, Leukocyte Biology Section, Clinical Care Center, Suite 1130, 6621 Fannin, MC 3-2372, Houston, TX 77030-2399. E-mail cwsmith{at}bcm.tmc.edu
Key Words: Editorials • leukocytes • restenosis
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Introduction |
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 Top Introduction References |
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In the accompanying article, Belch and colleagues1 propose a model in which baseline levels of serum E-selectin (CD62E) are predictive of restenosis after percutaneous transluminal angioplasty in patients with peripheral arterial occlusive disease. Their data revealed significantly higher baseline serum E-selectin levels in patients who restenosed compared with those who did not. The source of the circulating soluble E-selectin in these patients was not revealed, but other studies have shown E-selectin to be expressed on luminal arterial endothelial cells, neovasculature, and adventitial vasa vasorum associated with atherosclerotic lesions.2 3 4 In these reports, the luminal E-selectin was increased in arterial segments with mononuclear cell infiltration. Extensive immunohistological examinations of a wide variety of tissues and inflammatory lesions have revealed two important features regarding E-selectin expression. It is generally absent in normal tissues,5 6 7 and E-selectin has not been seen on cells other than endothelium. While direct demonstration of endothelium as the source of circulating E-selectin has not been accomplished, in vitro studies have shown that human umbilical vein endothelial cells stimulated with interleukin-1ß, tissue necrosis factor-
, or
endotoxin will release E-selectin into the culture
supernate,8 9 10 and this soluble E-selectin is 5 to 7 kD
smaller than that obtained by detergent extraction of the stimulated
endothelial cells. E-selectin found in human serum also
has a lower apparent molecular weight and appears to lack the
cytoplasmic domain.10 The most likely hypothesis is that
plasma E-selectin results from proteolytic cleavage of
endothelial E-selectin expressed after cytokine
stimulation.11 Elevations of soluble E-selectin have been reported in a variety of systemic inflammatory conditions. Significantly increased plasma levels of E-selectin have been found in diabetes, cancer, systemic lupus erythematosus, scleroderma, giant cell arteritis, polyarteritis nodosa, malaria, sepsis (reviewed in Reference 1111 ), stroke,12 systemic inflammatory response syndrome,13 and Wegener's granulomatosis and related systemic vasculitides.14 Correlation of soluble E-selectin levels with disease activity generally has been difficult, but marked elevations often are seen in sepsis with hypotension10 and systemic inflammatory response syndrome with organ failure13 and are associated with poor prognosis. After endotoxin administration in humans15 and baboons,16 soluble E-selectin levels were seen to rise within 4 to 6 hours and remain elevated for at least 24 hours. Potentially relevant to the Belch et al study,1 significant elevations in soluble E-selectin have been found in patients with atherosclerosis and dyslipidemia.17 18 After lipid-lowering drug treatment, one group of hypercholesterolemic patients had a significant reduction in soluble E-selectin.18 Overall, current evidence indicates that systemic inflammatory conditions generally result in elevations of soluble E-selectin,11 an apparently specific marker of endothelial activation.
Beyond the plausible interpretation that plasma E-selectin reflects release from cytokine- or endotoxin-stimulated endothelial cells, the functional significance of elevated levels is far from clear. Blood levels of soluble E-selectin in many cases may simply indicate the degree of systemic activation of endothelial cells without signifying that E-selectin is directly involved in the pathogenesis of tissue injury. For example, Haring et al19 found that E-selectin appears on endothelium of nonischemic tissue after experimental focal cerebral ischemia in baboons. This probably is caused by the systemic effects of circulating cytokines capable of inducing E-selectin expression. Richardson et al,20 using an en face technique to assess the number of E-selectin–positive endothelial cells in segments of rabbit aorta, found that in control animals there were 4 positive cells per 10 000. This number may account for the basal level of soluble E-selectin and would be very difficult to detect in conventional cross-sectional histopathology. Biologically significant increases in the number of E-selectin–producing cells would still be very difficult to detect histologically if the cells were dispersed, but there may be elevations in soluble E-selectin. Richardson et al found that in diabetic, hyperlipemic rabbits the number of E-selectin–positive endothelial cells was 42 in 10 000, a highly significant increase. The possibility that plasma levels of soluble E-selectin reveal systemic effects of cytokines has not been ruled out in any specific inflammatory disease.
Another difficulty in these considerations centers on the function of
E-selectin in vivo. Numerous studies in vitro indicate that purified
E-selectin is capable of effecting primary adhesion of leukocytes under
conditions of flow.21 22 In striking contrast,
gene-targeted mice deficient in E-selectin exhibit normal inflammatory
responses.23 It appears that with regard to primary
adhesion of leukocytes to endothelial cells under flow,
there are redundant mechanisms. Another member of the selectin family,
P-selectin (CD62P), is sufficient to support primary adhesion of
granulocytes and mononuclear cells to endothelium in
vitro24 25 as well as in vivo.26 L-selectin
(CD62L) clearly supports primary adhesion of monocytes to
activated endothelial cells in
vitro27 and in vivo.28 Vascular cell adhesion
molecule-1 (VCAM-1, CD106) may function in primary
adhesion,29 especially for mononuclear cells expressing
the ß1 integrin VLA4 (4ß1,
CD49d/CD29), a point particularly relevant to
atherosclerosis.30 Both of these adhesion
molecules are frequently coexpressed with E-selectin.31
The occurrence of E-selectin on endothelial cells at
sites of inflammation does not demonstrate that it actually plays a
significant role in the localization of leukocytes. Monoclonal antibody
blocking of E-selectin on activated endothelial
monolayers produces only 
35% inhibition of primary adhesion of
neutrophils under flow.21 In an example from in vivo
studies, Mulligan et al32 found that in a rat model of
nephrotoxic nephritis, E-selectin was expressed at the site of
glomerular inflammation, but administration of blocking
anti–E-selectin monoclonal antibody failed to reduce inflammation.
While some evidence indicates that E-selectin contributes to
inflammation in vivo,33 34 much more work is required to
determine the actual contribution of E-selectin to inflammatory
diseases, especially atherosclerosis.
Considering a possible biological function of soluble E-selectin, Newman et al10 demonstrated that soluble E-selectin isolated from sera of normal and bacteremic patients was functional in adhesion to the granulocytic cell line HL60. Assuming that circulating E-selectin can bind to leukocytes, the effect this would have on inflammation remains unknown. There are at least two considerations. The first is a possible reduction in the ability of endothelial-bound E-selectin to catch flowing leukocytes if soluble E-selectin would occupy binding sites on circulated leukocytes. Such an anti-inflammatory function seems reasonable but is entirely unproven in vivo. The second may be somewhat more complicated. Lo et al35 published results showing that soluble recombinant E-selectin would activate neutrophils, increasing the motility of the cells and their expression of the ß2 integrin (Mac-1, CD11b/CD18). If blood E-selectin can bind to leukocytes and activate them, their fate is uncertain. The systemic administration of a chemotactic factor that activates neutrophils, for example, causes sequestration of neutrophils in capillary beds (eg, alveolar capillaries36 ). The primary mechanism is physical trapping as a result of increased neutrophil rigidity.37 The ultimate fate of these cells is unknown, but the localization of activated leukocytes in capillary beds may promote inflammation at those sites. Others have shown that activated leukocytes have reduced ability to attach to venular endothelium under conditions of flow,38 in which physical trapping is improbable, possibly the result of shedding of surface receptors needed for primary adhesion under flow. Much work is obviously needed to determine the effects of the putative binding of soluble E-selectin to leukocytes, especially distinguishing what might be strikingly different outcomes for neutrophils from those for mononuclear cells.
The model proposed by Belch and colleagues,1 if confirmed by others, may provide prognostic significance to serum levels of soluble E-selectin. The ready availability of kits for determination of soluble E-selectin greatly facilitates research in this area. Consideration of other variables in which correlations with serum levels of E-selectin have been found (eg, ABO blood groups,39 triglyceride levels,17 and sex17 39 ) may prove useful in understanding the significance of elevated soluble E-selectin in peripheral arterial occlusive disease. While it is tempting to speculate that E-selectin contributes to the localization of leukocytes in arterial lesions, thereby promoting restenosis, there is currently no experimental evidence to support such a conclusion. The levels of soluble E-selectin may correlate with the levels of systemic disease, but causal relationships remain obscure.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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