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. 1995 Sep;147(3):642–653.

Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid.

D S McLeod 1, D J Lefer 1, C Merges 1, G A Lutty 1
PMCID: PMC1870979  PMID: 7545873

Abstract

Elevated expression of intercellular adhesion molecule-1 (ICAM-1) as well as E- and P-selectin occurs on the vascular endothelium in a number of disease states and is thought to play an early critical role in the adhesion of circulating leukocytes to the endothelium. The goal of the present study was to investigate the immunolocalization of these molecules in the retina and choroid of postmortem human tissue sections from nondiabetic and diabetic subjects. Whereas ICAM-1 was localized primarily within the choriocapillaris of nondiabetic subjects, immunoreactivity in diabetics was significantly elevated throughout the choroidal vasculature and within retinal blood vessels (P < 0.05). In the choroid, P-selectin was most prominent in veins of the nondiabetic, whereas in diabetics, P-selectin was significantly elevated in arteries (P < 0.001) and veins (P < 0.05) and, in some cases, was also observed in choriocapillaris. P-selectin immunoreactivity was not observed in the retina of any subject. E-selectin immunoreactivity was not observed in choroid or retina in any subjects. Neutrophil numbers per square millimeter of tissue were significantly elevated in diabetic choroid (P < 0.05) and retina (P < 0.001). Our results demonstrate that ICAM-1 and P-selectin are constitutively expressed in the normal choroid and are upregulated in the choroidal vasculature in diabetes, but only ICAM-1 was upregulated in the retina of diabetic subjects. Increased cell adhesion molecule expression may contribute to the retinal and choroidal microangiopathy observed in diabetics by enhancing leukocyte adhesion and consequently the incidence of capillary obstruction and endothelial cell injury.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aloisi F., Borsellino G., Samoggia P., Testa U., Chelucci C., Russo G., Peschle C., Levi G. Astrocyte cultures from human embryonic brain: characterization and modulation of surface molecules by inflammatory cytokines. J Neurosci Res. 1992 Aug;32(4):494–506. doi: 10.1002/jnr.490320405. [DOI] [PubMed] [Google Scholar]
  2. Arnould T., Michiels C., Remacle J. Increased PMN adherence on endothelial cells after hypoxia: involvement of PAF, CD18/CD11b, and ICAM-1. Am J Physiol. 1993 May;264(5 Pt 1):C1102–C1110. doi: 10.1152/ajpcell.1993.264.5.C1102. [DOI] [PubMed] [Google Scholar]
  3. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  4. Bill A. Blood circulation and fluid dynamics in the eye. Physiol Rev. 1975 Jul;55(3):383–417. doi: 10.1152/physrev.1975.55.3.383. [DOI] [PubMed] [Google Scholar]
  5. Bottazzo G. F., Dean B. M., McNally J. M., MacKay E. H., Swift P. G., Gamble D. R. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med. 1985 Aug 8;313(6):353–360. doi: 10.1056/NEJM198508083130604. [DOI] [PubMed] [Google Scholar]
  6. Carmassi F., Morale M., Puccetti R., De Negri F., Monzani F., Navalesi R., Mariani G. Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992 Sep 15;67(6):643–654. doi: 10.1016/0049-3848(92)90068-l. [DOI] [PubMed] [Google Scholar]
  7. Cavallo M. G., Pozzilli P., Bird C., Wadhwa M., Meager A., Visalli N., Gearing A. J., Andreani D., Thorpe R. Cytokines in sera from insulin-dependent diabetic patients at diagnosis. Clin Exp Immunol. 1991 Nov;86(2):256–259. doi: 10.1111/j.1365-2249.1991.tb05806.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. FRIEDMAN E., KOPALD H. H., SMITH T. R. RETINAL AND CHOROIDAL BLOOD FLOW DETERMINED WITH KRYPTON-85 ANESTHETIZED ANIMALS. Invest Ophthalmol. 1964 Oct;3:539–547. [PubMed] [Google Scholar]
  9. Feke G. T., Buzney S. M., Ogasawara H., Fujio N., Goger D. G., Spack N. P., Gabbay K. H. Retinal circulatory abnormalities in type 1 diabetes. Invest Ophthalmol Vis Sci. 1994 Jun;35(7):2968–2975. [PubMed] [Google Scholar]
  10. Freedman S. F., Hatchell D. L. Enhanced superoxide radical production by stimulated polymorphonuclear leukocytes in a cat model of diabetes. Exp Eye Res. 1992 Nov;55(5):767–773. doi: 10.1016/0014-4835(92)90181-q. [DOI] [PubMed] [Google Scholar]
  11. Harlan J. M. Leukocyte-endothelial interactions. Blood. 1985 Mar;65(3):513–525. [PubMed] [Google Scholar]
  12. Kantar A., Giorgi P. L., Curatola G., Fiorini R. Alterations in membrane fluidity of diabetic polymorphonuclear leukocytes. Biochem Med Metab Biol. 1991 Dec;46(3):422–426. doi: 10.1016/0885-4505(91)90090-8. [DOI] [PubMed] [Google Scholar]
  13. Kelly L. W., Barden C. A., Tiedeman J. S., Hatchell D. L. Alterations in viscosity and filterability of whole blood and blood cell subpopulations in diabetic cats. Exp Eye Res. 1993 Mar;56(3):341–347. doi: 10.1006/exer.1993.1044. [DOI] [PubMed] [Google Scholar]
  14. Kohner E. M., Porta M. Vascular abnormalities in diabetes and their treatment. Trans Ophthalmol Soc U K. 1980 Sep;100(3):440–444. [PubMed] [Google Scholar]
  15. Kreutzberg G. W., Hussain S. T. Cytochemical heterogeneity of the glial plasma membrane: 5'-nucleotidase in retinal Müller cells. J Neurocytol. 1982 Feb;11(1):53–64. doi: 10.1007/BF01258004. [DOI] [PubMed] [Google Scholar]
  16. Kvale D., Krajci P., Brandtzaeg P. Expression and regulation of adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) in human intestinal epithelial cell lines. Scand J Immunol. 1992 Jun;35(6):669–676. doi: 10.1111/j.1365-3083.1992.tb02973.x. [DOI] [PubMed] [Google Scholar]
  17. Lampeter E. R., Kishimoto T. K., Rothlein R., Mainolfi E. A., Bertrams J., Kolb H., Martin S. Elevated levels of circulating adhesion molecules in IDDM patients and in subjects at risk for IDDM. Diabetes. 1992 Dec;41(12):1668–1671. doi: 10.2337/diab.41.12.1668. [DOI] [PubMed] [Google Scholar]
  18. Langham M. E., Grebe R., Hopkins S., Marcus S., Sebag M. Choroidal blood flow in diabetic retinopathy. Exp Eye Res. 1991 Feb;52(2):167–173. doi: 10.1016/0014-4835(91)90256-e. [DOI] [PubMed] [Google Scholar]
  19. Languino L. R., Plescia J., Duperray A., Brian A. A., Plow E. F., Geltosky J. E., Altieri D. C. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell. 1993 Jul 2;73(7):1423–1434. doi: 10.1016/0092-8674(93)90367-y. [DOI] [PubMed] [Google Scholar]
  20. Larsen E., Celi A., Gilbert G. E., Furie B. C., Erban J. K., Bonfanti R., Wagner D. D., Furie B. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell. 1989 Oct 20;59(2):305–312. doi: 10.1016/0092-8674(89)90292-4. [DOI] [PubMed] [Google Scholar]
  21. Larson R. S., Springer T. A. Structure and function of leukocyte integrins. Immunol Rev. 1990 Apr;114:181–217. doi: 10.1111/j.1600-065x.1990.tb00565.x. [DOI] [PubMed] [Google Scholar]
  22. Lawrence M. B., Springer T. A. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991 May 31;65(5):859–873. doi: 10.1016/0092-8674(91)90393-d. [DOI] [PubMed] [Google Scholar]
  23. Lowe G. D., Lowe J. M., Drummond M. M., Reith S., Belch J. J., Kesson C. M., Wylie A., Foulds W. S., Forbes C. D., MacCuish A. C. Blood viscosity in young male diabetics with and without retinopathy. Diabetologia. 1980 May;18(5):359–363. doi: 10.1007/BF00276814. [DOI] [PubMed] [Google Scholar]
  24. Lutty G. A., McLeod D. S. A new technique for visualization of the human retinal vasculature. Arch Ophthalmol. 1992 Feb;110(2):267–276. doi: 10.1001/archopht.1992.01080140123039. [DOI] [PubMed] [Google Scholar]
  25. Lutty G. A., Merges C., Threlkeld A. B., Crone S., McLeod D. S. Heterogeneity in localization of isoforms of TGF-beta in human retina, vitreous, and choroid. Invest Ophthalmol Vis Sci. 1993 Mar;34(3):477–487. [PubMed] [Google Scholar]
  26. Lutty G., Ikeda K., Chandler C., McLeod D. S. Immunohistochemical localization of transforming growth factor-beta in human photoreceptors. Curr Eye Res. 1991 Jan;10(1):61–74. doi: 10.3109/02713689109007611. [DOI] [PubMed] [Google Scholar]
  27. Mackay C. R., Imhof B. A. Cell adhesion in the immune system. Immunol Today. 1993 Mar;14(3):99–102. doi: 10.1016/0167-5699(93)90205-Y. [DOI] [PubMed] [Google Scholar]
  28. McLeod D. S., Lutty G. A. High-resolution histologic analysis of the human choroidal vasculature. Invest Ophthalmol Vis Sci. 1994 Oct;35(11):3799–3811. [PubMed] [Google Scholar]
  29. McMillan D. E., Utterback N. G., La Puma J. Reduced erythrocyte deformability in diabetes. Diabetes. 1978 Sep;27(9):895–901. doi: 10.2337/diab.27.9.895. [DOI] [PubMed] [Google Scholar]
  30. Murata T., Ishibashi T., Inomata H. Immunohistochemical detection of extravasated fibrinogen (fibrin) in human diabetic retina. Graefes Arch Clin Exp Ophthalmol. 1992;230(5):428–431. doi: 10.1007/BF00175927. [DOI] [PubMed] [Google Scholar]
  31. Nagata K., Tsuji T., Todoroki N., Katagiri Y., Tanoue K., Yamazaki H., Hanai N., Irimura T. Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol. 1993 Sep 15;151(6):3267–3273. [PubMed] [Google Scholar]
  32. Nagel T., Resnick N., Atkinson W. J., Dewey C. F., Jr, Gimbrone M. A., Jr Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994 Aug;94(2):885–891. doi: 10.1172/JCI117410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nork T. M., Wallow I. H., Sramek S. J., Anderson G. Müller's cell involvement in proliferative diabetic retinopathy. Arch Ophthalmol. 1987 Oct;105(10):1424–1429. doi: 10.1001/archopht.1987.01060100126042. [DOI] [PubMed] [Google Scholar]
  34. Osborne N. N., Block F., Sontag K. H. Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Müller cells. Vis Neurosci. 1991 Dec;7(6):637–639. doi: 10.1017/s0952523800010427. [DOI] [PubMed] [Google Scholar]
  35. Page C., Rose M., Yacoub M., Pigott R. Antigenic heterogeneity of vascular endothelium. Am J Pathol. 1992 Sep;141(3):673–683. [PMC free article] [PubMed] [Google Scholar]
  36. Resnick N., Collins T., Atkinson W., Bonthron D. T., Dewey C. F., Jr, Gimbrone M. A., Jr Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4591–4595. doi: 10.1073/pnas.90.10.4591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rimmer T., Fallon T. J., Kohner E. M. Long-term follow-up of retinal blood flow in diabetes using the blue light entoptic phenomenon. Br J Ophthalmol. 1989 Jan;73(1):1–5. doi: 10.1136/bjo.73.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rimmer T., Fleming J., Kohner E. M. Hypoxic viscosity and diabetic retinopathy. Br J Ophthalmol. 1990 Jul;74(7):400–404. doi: 10.1136/bjo.74.7.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rothlein R., Dustin M. L., Marlin S. D., Springer T. A. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol. 1986 Aug 15;137(4):1270–1274. [PubMed] [Google Scholar]
  40. Rothlein R., Mainolfi E. A., Czajkowski M., Marlin S. D. A form of circulating ICAM-1 in human serum. J Immunol. 1991 Dec 1;147(11):3788–3793. [PubMed] [Google Scholar]
  41. Schmid-Schönbein G. W. Granulocyte activation and capillary obstruction. Monogr Atheroscler. 1990;15:150–159. [PubMed] [Google Scholar]
  42. Schmid-Schönbein G. W. The damaging potential of leukocyte activation in the microcirculation. Angiology. 1993 Jan;44(1):45–56. doi: 10.1177/000331979304400108. [DOI] [PubMed] [Google Scholar]
  43. Schmid-Schönbein H., Volger E. Red-cell aggregation and red-cell deformability in diabetes. Diabetes. 1976;25(2 Suppl):897–902. [PubMed] [Google Scholar]
  44. Schröder S., Palinski W., Schmid-Schönbein G. W. Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am J Pathol. 1991 Jul;139(1):81–100. [PMC free article] [PubMed] [Google Scholar]
  45. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  46. Subramaniam M., Koedam J. A., Wagner D. D. Divergent fates of P- and E-selectins after their expression on the plasma membrane. Mol Biol Cell. 1993 Aug;4(8):791–801. doi: 10.1091/mbc.4.8.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tschoepe D., Roesen P., Schwippert B., Gries F. A. Platelets in diabetes: the role in the hemostatic regulation in atherosclerosis. Semin Thromb Hemost. 1993;19(2):122–128. doi: 10.1055/s-2007-994015. [DOI] [PubMed] [Google Scholar]
  48. Vicari A. M., Macagni A. Primary platelet activation in recent-onset type 1 diabetes mellitus. Scand J Clin Lab Invest. 1990 Jun;50(4):429–432. doi: 10.3109/00365519009091602. [DOI] [PubMed] [Google Scholar]
  49. Warner S. J., Libby P. Human vascular smooth muscle cells. Target for and source of tumor necrosis factor. J Immunol. 1989 Jan 1;142(1):100–109. [PubMed] [Google Scholar]
  50. Wierusz-Wysocka B., Wysocki H., Siekierka H., Wykretowicz A., Szczepanik A., Klimas R. Evidence of polymorphonuclear neutrophils (PMN) activation in patients with insulin-dependent diabetes mellitus. J Leukoc Biol. 1987 Nov;42(5):519–523. doi: 10.1002/jlb.42.5.519. [DOI] [PubMed] [Google Scholar]
  51. Yamada K., Takane N., Otabe S., Inada C., Inoue M., Nonaka K. Pancreatic beta-cell-selective production of tumor necrosis factor-alpha induced by interleukin-1. Diabetes. 1993 Jul;42(7):1026–1031. doi: 10.2337/diab.42.7.1026. [DOI] [PubMed] [Google Scholar]

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