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Anatomy and Pathophysiology of Retinal Pigment Epithelial Detachment

  • Olaf StraußEmail author
Chapter

Abstract

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells localized between the photoreceptors and the blood vessels of the choroid. Being the most important interaction partner with the photoreceptors in visual function, any change in RPE function leads to photoreceptor degeneration. The structural integrity and function of the tissue complex “photoreceptor-RPE-choroid” is dependent on close spatial interaction of those cells. This is achieved on one hand by the interphotoreceptor matrix which forms a matrix between RPE and photoreceptors. On the other hand, Bruch’s membrane forms another interface between RPE and choroid. These interfaces enable free exchange of nutrients, oxygen, and bioactive molecules such as growth factors or cytokines between the cells and layers of the photoreceptor-RPE-choroid complex. The adhesion between the layers is ensured by the elimination of extracellular fluid by the RPE towards the choroid as well as by the maintenance of the protein composition of the extracellular matrix. Pathogenesis of retinal pigment epithelial detachment (PED), however, is not yet fully clarified; different concepts try to explain the development of PED under different circumstances. The most widely accepted concept is that RPE detachment can be caused by a reduced fluid flow through an ageing Bruch’s membrane or by a passive inflow of water caused by changes in osmolarity of the extracellular matrix, e.g., in age-related macular degeneration or degenerative PED. Idiopathic PED (e.g., in central serous chorioretinopathy) is thought to result from choroidal dysfunction and increased permeability of choroidal vessels, possibly due to overactivation of mineralocorticoid receptors in the choroidal endothelial cells. Local inflammation or ischemia can also lead to hyperpermeability of choroidal vessels and thereby to inflammatory/ischemic PED.

References

  1. 1.
    Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease. Curr Mol Med. 2010;10:802–23.CrossRefPubMedGoogle Scholar
  2. 2.
    Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85:845–81. doi: 10.1152/physrev.00021.2004.CrossRefPubMedGoogle Scholar
  3. 3.
    Carter-Dawson L, Burroughs M. Interphotoreceptor retinoid-binding protein (IRBP) and opsin in the rds mutant mouse: EM immunocytochemical analysis. Prog Clin Biol Res. 1989;314:291–300.PubMedGoogle Scholar
  4. 4.
    Hageman GS, Johnson LV. Structure, composition and function of the retinal interphotoreceptor matrix. Prog Retin Eye Res. 1991;10:207–49.CrossRefGoogle Scholar
  5. 5.
    Hodson S, Armstrong I, Wigham C. Regulation of the retinal interphotoreceptor matrix Na by the retinal pigment epithelium during the light response. Experientia. 1994;50:438–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Hollyfield JG. Hyaluronan and the functional organization of the interphotoreceptor matrix. Invest Ophthalmol Vis Sci. 1999;40:2767–9.PubMedGoogle Scholar
  7. 7.
    Uehara F, Matthes MT, Yasumura D, LaVail MM. Light-evoked changes in the interphotoreceptor matrix. Science. 1990;248:1633–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Bird AC. Bruch’s membrane change with age. Br J Ophthalmol. 1992;76:166–8.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen AA. The dynamic nature of Bruch’s membrane. Prog Retin Eye Res. 2010;29:1–18. doi: 10.1016/j.preteyeres.2009.08.003.CrossRefPubMedGoogle Scholar
  10. 10.
    Cao W, Tombran-Tink J, Chen W, Mrazek D, Elias R, McGinnis JF. Pigment epithelium-derived factor protects cultured retinal neurons against hydrogen peroxide-induced cell death. J Neurosci Res. 1999;57:789–800.CrossRefPubMedGoogle Scholar
  11. 11.
    Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285:245–8.CrossRefPubMedGoogle Scholar
  12. 12.
    King GL, Suzuma K. Pigment-epithelium-derived factor—a key coordinator of retinal neuronal and vascular functions. N Engl J Med. 2000;342:349–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Mitchell CH. Release of ATP by a human retinal pigment epithelial cell line: potential for autocrine stimulation through subretinal space. J Physiol. 2001;534:193–202.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wolfensberger TJ, Tufail A. Systemic disorders associated with detachment of the neurosensory retina and retinal pigment epithelium. Curr Opin Ophthalmol. 2000;11:455–61.CrossRefPubMedGoogle Scholar
  15. 15.
    Ishida K, Panjwani N, Cao Z, Streilein JW. Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms. Ocul Immunol Inflamm. 2003;11:91–105.CrossRefPubMedGoogle Scholar
  16. 16.
    Frank RN. Growth factors in age-related macular degeneration: pathogenic and therapeutic implications. Ophthalmic Res. 1997;29:341–53.CrossRefPubMedGoogle Scholar
  17. 17.
    Strauss O, Heimann H, Foerster MH, Agostini H, Hansen LL, Rosenthal R. Activation of L-type Ca2+ channels is necessary for growth factor-dependent stimulation of VEGF secretion by RPE cells. Invest Ophthalmol Vis Sci. 2003;44:e-abstract 3926.Google Scholar
  18. 18.
    Sparrow JR, Ueda K, Zhou J. Complement dysregulation in AMD: RPE-Bruch’s membrane-choroid. Mol Aspects Med. 2012;33:436–45. doi: 10.1016/j.mam.2012.03.007.CrossRefPubMedGoogle Scholar
  19. 19.
    Holtkamp GM, de Vos AF, Kijlstra A, Peek R. Expression of multiple forms of IL-1 receptor antagonist (IL-1ra) by human retinal pigment epithelial cells: identification of a new IL-1ra exon. Eur J Immunol. 1999;29:215–24.CrossRefPubMedGoogle Scholar
  20. 20.
    Liversidge J, McKay D, Mullen G, Forrester JV. Retinal pigment epithelial cells modulate lymphocyte function at the blood-retina barrier by autocrine PGE2 and membrane-bound mechanisms. Cell Immunol. 1993;149:315–30.CrossRefPubMedGoogle Scholar
  21. 21.
    Hughes BA, Gallemore RP, Miller SS. Transport mechanisms in the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ, editors. The retinal pigment epithelium. New York: Oxford University Press; 1998. p. 103–34.Google Scholar
  22. 22.
    Gallemore RP, Hughes BA, Miller SS. Retinal pigment epithelial transport mechansisms and their contribution to the electroretinogram. Prog Retin Eye Res. 1997;16:509–66.CrossRefGoogle Scholar
  23. 23.
    Strauss O. Transport mechanisms of the retinal pigment epithelium to maintain visual function. Heat Mass Transf. 2014;50:303–13.CrossRefGoogle Scholar
  24. 24.
    Hu JG, Gallemore RP, Bok D, Frambach DA. Chloride transport in cultured fetal human retinal pigment epithelium. Exp Eye Res. 1996;62:443–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Quinn RH, Miller SS. Ion transport mechanisms in native human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1992;33:3513–27.PubMedGoogle Scholar
  26. 26.
    Hu JG, Gallemore RP, Bok D, Lee AY, Frambach DA. Localization of NaK ATPase on cultured human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1994;35:3582–8.PubMedGoogle Scholar
  27. 27.
    Frambach DA, Roy CE, Valentine JL, Weiter JJ. Precocious retinal adhesion is affected by furosemide and ouabain. Curr Eye Res. 1989;8:553–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Joseph DP, Miller SS. Apical and basal membrane ion transport mechanisms in bovine retinal pigment epithelium. J Physiol. 1991;435:439–63.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Quinn RH, Quong JN, Miller SS. Adrenergic receptor activated ion transport in human fetal retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2001;42:255–64.PubMedGoogle Scholar
  30. 30.
    Wimmers S, Karl MO, Strauss O. Ion channels in the RPE. Prog Retin Eye Res. 2007;26:263–301. doi: 10.1016/j.preteyeres.2006.12.002.CrossRefPubMedGoogle Scholar
  31. 31.
    Stamer WD, Bok D, Hu J, Jaffe GJ, McKay BS. Aquaporin-1 channels in human retinal pigment epithelium: role in transepithelial water movement. Invest Ophthalmol Vis Sci. 2003;44:2803–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Hamann S. Molecular mechanisms of water transport in the eye. Int Rev Cytol. 2002;215:395–431.CrossRefPubMedGoogle Scholar
  33. 33.
    Hamann S, la Cour M, Lui GM, Bundgaard M, Zeuthen T. Transport of protons and lactate in cultured human fetal retinal pigment epithelial cells. Pflugers Arch. 2000;440:84–92.CrossRefPubMedGoogle Scholar
  34. 34.
    Lin H, Miller SS. pHi-dependent Cl-HCO3 exchange at the basolateral membrane of frog retinal pigment epithelium. Am J Physiol. 1994;266:C935–45.PubMedGoogle Scholar
  35. 35.
    Marmor MF. Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol. 1999;97:239–49.CrossRefPubMedGoogle Scholar
  36. 36.
    Marmor MF. Control of subretinal fluid: experimental and clinical studies. Eye (Lond). 1990;4(Pt 2):340–4. doi: 10.1038/eye.1990.46.CrossRefGoogle Scholar
  37. 37.
    Guymer R, Luthert P, Bird A. Changes in Bruch’s membrane and related structures with age. Prog Retin Eye Res. 1999;18:59–90.CrossRefPubMedGoogle Scholar
  38. 38.
    Starita C, Hussain AA, Marshall J. Decreasing hydraulic conductivity of Bruch’s membrane: relevance to photoreceptor survival and lipofuscinoses. Am J Med Genet. 1995;57:235–7. doi: 10.1002/ajmg.1320570224.CrossRefPubMedGoogle Scholar
  39. 39.
    Hussain AA, Lee Y, Zhang JJ, Marshall J. Disturbed matrix metalloproteinase activity of Bruch’s membrane in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52:4459–66. doi: 10.1167/iovs.10-6678.CrossRefPubMedGoogle Scholar
  40. 40.
    Itoh Y, Kimoto K, Imaizumi M, Nakatsuka K. Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-beta2 in human retinal pigment epithelial cells. Exp Eye Res. 2007;84:464–72. doi: 10.1016/j.exer.2006.10.017.CrossRefPubMedGoogle Scholar
  41. 41.
    Ahir A, Guo L, Hussain AA, Marshall J. Expression of metalloproteinases from human retinal pigment epithelial cells and their effects on the hydraulic conductivity of Bruch’s membrane. Invest Ophthalmol Vis Sci. 2002;43:458–65.PubMedGoogle Scholar
  42. 42.
    Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med. 2003;9:407–15.CrossRefPubMedGoogle Scholar
  43. 43.
    Bird AC, Marshall J. Retinal pigment epithelial detachments in the elderly. Trans Ophthalmol Soc U K. 1986;105(Pt 6):674–82.PubMedGoogle Scholar
  44. 44.
    Kumar A, El-Osta A, Hussain AA, Marshall J. Increased sequestration of matrix metalloproteinases in ageing human Bruch’s membrane: implications for ECM turnover. Invest Ophthalmol Vis Sci. 2010;51:2664–70. doi: 10.1167/iovs.09-4195.CrossRefPubMedGoogle Scholar
  45. 45.
    Curcio CA, Johnson M, Rudolf M, Huang JD. The oil spill in ageing Bruch membrane. Br J Ophthalmol. 2011;95:1638–45. doi: 10.1136/bjophthalmol-2011-300344.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kirchhof B, Sorgente N. Pathogenesis of proliferative vitreoretinopathy. Modulation of retinal pigment epithelial cell functions by vitreous and macrophages. Dev Ophthalmol. 1989;16:1–53.CrossRefPubMedGoogle Scholar
  47. 47.
    Green K1, Paterson CA, Cheeks L, Slagle T, Jay WM, Aziz MZ. Ocular blood flow and vascular permeability in endotoxin-induced inflammation. Ophthalmic Res 1990;22:287–94.Google Scholar
  48. 48.
    Starita C1, Hussain AA, Patmore A, Marshall J. Localization of the site of major resistance to fluid transport in Bruch’s membrane. Invest Ophthalmol Vis Sci 1997;38:762–7.Google Scholar
  49. 49.
    Zhao M1, Célérier I, Bousquet E, Jeanny JC, Jonet L, Savoldelli M, Offret O, Curan A, Farman N, Jaisser F, Behar-Cohen F. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. J Clin Invest 2012;122:2672–9.Google Scholar
  50. 50.
    Bousquet E1, Beydoun T, Zhao M, Hassan L, Offret O, Behar-Cohen F. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy. A pilot study. Retina 2013;33:2096–102.Google Scholar
  51. 51.
    Stefansson E, Geirsdottir A, Sigurdsson H. Metabolic physiology in age related macular degeneration. Prog Retin Eye Res. 2011;30:72–80. doi: 10.1016/j.preteyeres.2010.09.003.CrossRefPubMedGoogle Scholar
  52. 52.
    Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT. Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol. 1997;81:154–62.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem. 1999;74:135–43.CrossRefPubMedGoogle Scholar
  54. 54.
    Reddy VM, Zamora RL, Kaplan HJ. Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1995;120:291–301.CrossRefPubMedGoogle Scholar
  55. 55.
    Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33:295–317. doi: 10.1016/j.mam.2012.04.005.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Jasielska M, Semkova I, Shi X, Schmidt K, Karagiannis D, Kokkinou D, Mackiewicz J, Kociok N, Joussen AM. Differential role of tumor necrosis factor (TNF)-alpha receptors in the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2010;51:3874–83. doi: 10.1167/iovs.09-5003.CrossRefPubMedGoogle Scholar
  57. 57.
    Oh H, Takagi H, Takagi C, Suzuma K, Otani A, Ishida K, Matsumura M, Ogura Y, Honda Y. The potential angiogenic role of macrophages in the formation of choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1999;40:1891–8.PubMedGoogle Scholar
  58. 58.
    Schlunck G, Martin G, Agostini HT, Camatta G, Hansen LL. Cultivation of retinal pigment epithelial cells from human choroidal neovascular membranes in age related macular degeneration. Exp Eye Res. 2002;74:571–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Rosenthal R, Heimann H, Agostini H, Martin G, Hansen LL, Strauss O. Ca2+ channels in retinal pigment epithelial cells regulate vascular endothelial growth factor secretion rates in health and disease. Mol Vis. 2007;13:443–56.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Baldwin AK, Cain SA, Lennon R, Godwin A, Merry CL, Kielty CM. Epithelial-mesenchymal status influences how cells deposit fibrillin microfibrils. J Cell Sci. 2014;127:158–71. doi: 10.1242/jcs.134270.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chen X, Xiao W, Wang W, Luo L, Ye S, Liu Y. The complex interplay between ERK1/2, TGFbeta/Smad, and Jagged/Notch signaling pathways in the regulation of epithelial-mesenchymal transition in retinal pigment epithelium cells. PLoS One. 2014;9:e96365. doi: 10.1371/journal.pone.0096365.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Saika S, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, Sumioka T, Shirai K, Kitano A, Miyazaki K, Tanaka S, Ikeda K. Epithelial-mesenchymal transition as a therapeutic target for prevention of ocular tissue fibrosis. Endocr Metab Immune Disord Drug Targets. 2008;8:69–76.CrossRefPubMedGoogle Scholar
  63. 63.
    Hoerster R, Muether PS, Vierkotten S, Hermann MM, Kirchhof B, Fauser S. Upregulation of TGF-ss1 in experimental proliferative vitreoretinopathy is accompanied by epithelial to mesenchymal transition. Graefes Arch Clin Exp Ophthalmol. 2014;252:11–6. doi: 10.1007/s00417-013-2377-5.CrossRefPubMedGoogle Scholar
  64. 64.
    Lee J, Moon HJ, Lee JM, Joo CK. Smad3 regulates Rho signaling via NET1 in the transforming growth factor-beta-induced epithelial-mesenchymal transition of human retinal pigment epithelial cells. J Biol Chem. 2010;285:26618–27. doi: 10.1074/jbc.M109.073155.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Saika S, Yamanaka O, Okada Y, Tanaka S, Miyamoto T, Sumioka T, Kitano A, Shirai K, Ikeda K. TGF beta in fibroproliferative diseases in the eye. Front Biosci (Schol Ed). 2009;1:376–90.CrossRefGoogle Scholar
  66. 66.
    Matsumoto M, Yoshimura N, Honda Y. Increased production of transforming growth factor-beta 2 from cultured human retinal pigment epithelial cells by photocoagulation. Invest Ophthalmol Vis Sci. 1994;35:4245–52.PubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Experimental Ophthalmology, Department of OphthalmologyCharite University Medicine BerlinBerlinGermany

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