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Circulation. 1997;95:1986-1988

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(Circulation. 1997;95:1986-1988.)
© 1997 American Heart Association, Inc.

Articles

Potential Significance of Circulating E-Selectin

C. Wayne Smith, MD

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


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
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-{alpha}, 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 ({alpha}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 {approx}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.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Belch JJF, Shaw JW, Kirk G, McLaren M, Robb R, Maple C, Morse P. The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty. Circulation.. 1997;95:2027-2031. [Abstract/Free Full Text]
  2. van der Wal AC, Das PK, Tigges AJ, Becker AE. Adhesion molecules on the endothelium and mononuclear cells in human atherosclerotic lesions. Am J Pathol. 1992;141:1427-1433. [Abstract]
  3. Davies MJ, Gordon JL, Gearing AJH, Pigott R, Woolf N, Katz D, Kyriakopoulos A. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol. 1993;171:223-229. [Medline] [Order article via Infotrieve]
  4. O'Brien KD, McDonald TO, Chait A, Allen MD, Alpers CE. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 1996;93:672-682. [Abstract/Free Full Text]
  5. Cotran RS, Gimbrone MA Jr, Bevilacqua MP, Mendrick DL, Pober JS. Induction and detection of a human endothelial activation antigen in vivo. J Exp Med. 1986;164:661-666. [Abstract/Free Full Text]
  6. Groves RW, Allen MH, Barker JNWN, Haskard DO, MacDonald DM. Endothelial leucocyte adhesion molecule-1 (ELAM-1) expression in cutaneous inflammation. Br J Dermatol. 1991;124:117-123. [Medline] [Order article via Infotrieve]
  7. Norris P, Poston RN, Thomas DS, Thornhill M, Hawk J, Haskard DO. The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a comparison of ultraviolet B erythema and delayed hypersensitivity. J Invest Dermatol. 1991;96:763-770. [Medline] [Order article via Infotrieve]
  8. Kneidinger R, Bahrami S, Redl H, Schlag G, Robinson M, Weichselbraun I, Cremer J. Evaluation of a soluble E-selectin enzyme-linked immunosorbent assay under posttraumatic conditions. J Lab Clin Med. 1996;128:520-523. [Medline] [Order article via Infotrieve]
  9. Pigott R, Dillon LP, Hemingway IH, Gearing AJH. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun. 1992;187:584-589. [Medline] [Order article via Infotrieve]
  10. Newman W, Beall LD, Carson CW, Hunder GG, Graben N, Randhawa ZI, Gopal TV, Wiener-Kronish J, Matthay MA. Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock. J Immunol. 1993;150:644-654. [Abstract]
  11. Gearing AJH, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993;14:506-512. [Medline] [Order article via Infotrieve]
  12. Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M. Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke. 1995;26:1361-1364. [Abstract/Free Full Text]
  13. Cowley HC, Heney D, Gearing AJH, Hemingway I, Wester NR. Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort study. Crit Care Med. 1994;22:651-657. [Medline] [Order article via Infotrieve]
  14. Boehme MWJ, Schmitt WH, Youinou P, Stremmel WR, Gross WL. Clinical relevance of elevated serum thrombomodulin and soluble E-selectin in patients with Wegener's granulomatosis and other systemic vasculitides. Am J Med. 1996;101:387-394. [Medline] [Order article via Infotrieve]
  15. Kuhns DB, Alvord WG, Gallin JI. Increased circulating cytokines, cytokine antagonists, and E-selectin after intravenous administration of endotoxin in humans. J Infect Dis. 1995;171:145-152. [Medline] [Order article via Infotrieve]
  16. Kneidinger R, Bahrami S, Redl H, Schlag G, Robinson M. Comparison of endothelial activation during endotoxic and posttraumatic conditions by serum analysis of soluble E-selectin in nonhuman primates. J Lab Clin Med. 1996;128:515-519. [Medline] [Order article via Infotrieve]
  17. Blann AD, Amiral J, McCollum CN. Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease. Br J Haematol. 1996;95:263-265. [Medline] [Order article via Infotrieve]
  18. Hackman A, Abe Y, Insull W, Pownall H, Smith L, Dunn K, Gotto A Jr, Ballantyne CM. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation. 1996;93:1334-1338. [Abstract/Free Full Text]
  19. Haring HP, Berg EL, Tsurushita N, Tagaya M, Del Zoppo GJ. E-selectin appears in nonischemic tissue during experimental focal cerebral ischemia. Stroke. 1996;27:1386-1391. [Abstract/Free Full Text]
  20. Richardson M, Hadcock SJ, DeReske M, Cybulsky MI. Increased expression in vivo of VCAM-1 and E-selectin by the aortic endothelium of normolipemic and hyperlipemic diabetic rabbits. Arterioscler Thromb. 1994;14:760-769. [Abstract/Free Full Text]
  21. Abbassi O, Kishimoto TK, McIntire LV, Anderson DC, Smith CW. E-Selectin supports neutrophil rolling in vitro under conditions of flow. J Clin Invest. 1993;92:2719-2730.
  22. Lawrence MB, Springer TA. Neutrophils roll on E-selectin. J Immunol. 1993;151:6338-6346. [Abstract]
  23. Labow MA, Norton CR, Rumberger JM, Lombard-Gillooly KM, Shuster DJ, Hubbard J, Bertko R, Knaack PA, Terry RW, Harbison ML, Kontgen F, Stewart CL, McIntyre KW, Will PC, Burns DK, Wolitzky BA. Characterization of E-selectin-deficient mice: demonstration of overlapping function of the endothelial selectins. Immunity. 1994;1:709-720. [Medline] [Order article via Infotrieve]
  24. Jones DA, Abbassi O, McIntire LV, McEver RP, Smith CW. P-selectin mediates neutrophil rolling on histamine-stimulated endothelial cells. Biophys J. 1993;65:1560-1569. [Abstract/Free Full Text]
  25. Luscinskas FW, Ding H, Lichtman AH. P-selectin and vascular cell adhesion molecule 1 mediate rolling and arrest, respectively, of CD4+ T lymphocytes on tumor necrosis factor {alpha}-activated vascular endothelium under flow. J Exp Med. 1995;181:1179-1186. [Abstract/Free Full Text]
  26. Ley K. Gene-targeted mice in leukocyte adhesion research. Microcirc Soc. 1995;2:141-150.
  27. Luscinskas FW, Kansas GS, Ding H, Pizcueta P, Schleiffenbaum BE, Tedder TF, Gimbrone MA Jr. Monocyte rolling, arrest and spreading on IL-4-activated vascular endothelium under flow is mediated via sequential action of L-selectin, ß1-integrins, and ß2-integrins. J Cell Biol. 1994;125:1417-1427.[Abstract/Free Full Text]
  28. Pizcueta P, Luscinskas FW. Monoclonal antibody blockade of L-selectin inhibits mononuclear leukocyte recruitment to inflammatory sites in vivo. Am J Pathol. 1994;145:461-469. [Abstract]
  29. Jones DA, McIntire LV, Smith CW, Picker LJ. A two-step adhesion cascade for T cell/endothelial cell interactions under flow conditions. J Clin Invest. 1994;94:2443-2450.
  30. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809. [Medline] [Order article via Infotrieve]
  31. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57:827-872. [Medline] [Order article via Infotrieve]
  32. Mulligan MS, Johnson KJ, Todd RF III, Issekutz TB, Miyasaka M, Tamatani T, Smith CW, Anderson DC, Ward PA. Requirements for leukocyte adhesion molecules in nephrotoxic nephritis. J Clin Invest. 1993;91:577-587.
  33. Gundel RH, Wegner CD, Torcellini CA, Clarke CC, Haynes N, Rothlein R, Smith CW, and Letts LG. Endothelial-leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys. J Clin Invest. 1991;88:1407-1411.
  34. Picker LJ, Kishimoto TK, Smith CW, Warnock RA, Butcher EC. ELAM-1 is an adhesion molecule for skin-homing T-cells. Nature. 1991;349:796-799. [Medline] [Order article via Infotrieve]
  35. Lo SK, Lee S, Ramos RA, Lobb R, Rosa M, Chi-Rosso G, Wright SD. Endothelial-leukocyte adhesion molecule 1 stimulates the adhesive activity of leukocyte integrin CR3(CD11b/CD18, Mac-1, alpha m beta 2) on human neutrophils. J Exp Med. 1991;173:1493-1500. [Abstract/Free Full Text]
  36. Doerschuk CM. The role of CD18-mediated adhesion in neutrophil sequestration induced by infusion of activated plasma in rabbits. Am J Respir Cell Mol Biol. 1992;7:140-148.
  37. Worthen GS, Schwab B III, Elson EL, Downey GP. Mechanics of stimulated neutrophils: cell stiffening induces retention of capillaries. Science. 1989;245:183-186. [Abstract/Free Full Text]
  38. von Andrian UH, Hansell P, Chambers JD, Berger EM, Filho IT, Butcher EC, Arfors KE. L-selectin function is required for beta-2 integrin-mediated neutrophil adhesion at physiologic shear rates in vivo. Am J Physiol. 1992;263:H1034-H1044. [Abstract/Free Full Text]
  39. Blann AD, Daly RJ, Amiral J. The influence of age, gender and ABO blood group on soluble endothelial cell markers and adhesion molecules. Br J Haematol. 1996;92:498-500. [Medline] [Order article via Infotrieve]



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