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July 1992, Vol 110, No. 7 >
ARTICLE | July 1992

Chondroitin Sulfate-Induced Generation of Epiretinal Membranes FREE

Stephen R. Russell, MD; Gregory S. Hageman, PhD
[+] Author Affiliations

Accepted for publication December 16, 1991.

Portions of this study were presented at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Fla, May 4, 1989.

Reprint requests to Bethesda Eye Institute, 3655 Vista Ave, St Louis, MO 63110 (Dr Russell).


Arch Ophthalmol. 1992;110(7):1000-1006. doi:10.1001/archopht.1992.01080190106037
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Article
References
Comments

• Previous investigations have examined the role of serum and retinal pigment epithelium-derived factors in the elaboration of epiretinal membranes. Alternatively, the contribution of the insoluble interphotoreceptor matrix, known to contain chondroitin-sulfate—containing proteoglycans, in the generation of epiretinal membranes, has not been evaluated, to our knowledge. To investigate the potential role of chondroitin sulfates in eliciting epiretinal membranes, chondroitin sulfate glycosaminoglycans were injected into the vitreous cavity of rabbits. Examination demonstrated epiretinal membranes in 86% of eyes receiving chondroitin-6-sulfate. Temporal development of chondroitin sulfate glycosaminoglycan—induced epiretinal membranes was categorized into three distinct stages: a preretinal cell stage 1 to 3 weeks following injection, a glial "tuft" stage at 3 to 6 weeks, and a "mature" complex membrane stage at 6 weeks or later. Our results suggest that intravitreal administration of chondroitin sulfate glycosaminoglycan, components of insoluble interphotoreceptor matrix proteoglycans, may elicit the generation of epiretinal membranes, even in the absence of retinal disruption.

REFERENCES

1 +
Roth AM, Foos RY.  Surface wrinkling retinopathy in eyes enucleated at autopsy . Trans Am Acad Ophthalmol Otolaryngol . 1971;;75:1047-1058.
2 +
Foos RY.  Vitreoretinal juncture: epiretinal membranes and vitreous . Invest Ophthalmol Vis Sci . 1977;;16:416-422.
3 +
Clarkson JG, Green WR, Massof D.  A histopathologic review of 168 cases of preretinal membrane . Am J Ophthalmol . 1977;;84:1-17.
4 +
Jaffe NS.  Macular fibrosis and massive preretinal retraction . Arch Ophthalmol . 1967;;78:585-591.
5 +
Foos RY.  Nonvascular proliferative extraretinal retinopathies . Am J Ophthalmol . 1978;;86:723-725.
6 +
Hiscott PS, Unger WG, Grierson I, McLeod D.  The role of inflammation in the development of epiretinal membranes . Curr Eye Res . 1988;;7:877-892.
7 +
Hiscott PS, Grierson I, Trombetta CJ, Rahi AHS, Marshall J, McLeod D.  Retinal and epiretinal glia: an immunocytochemical study . Br J Ophthalmol . 1984;;68:698-707.
8 +
Hiscott PS, Grierson I, McLeod D.  Retinal pigment epithelial cells in epiretinal membranes: an immunohistochemical study . Br J Ophthalmol . 1984;;68:708-715.
9 +
Hiscott PS, Grierson I, McLeod D.  Natural history of fibrocellular epiretinal membranes: a quantitative, autoradiographic, and immunohistochemical study . Br J Ophthalmol . 1985;;69:810-823.
10 +
Scheiffarth OF, Kampik A, Gunther H, von der Mark K.  Proteins of the extracellular matrix in vitreoretinal membranes . Graefes Arch Clin Exp Ophthalmol . 1988;;226:357-361.
11 +
Hui YN, Goodnight R, Zhang X-J, Sorgente N, Ryan SJ.  Glial epiretinal membranes and contraction: immunohistochemical and morphological studies . Arch Ophthalmol . 1988;;106:1280-1285.
12 +
Sramek SJ, Wallow IH, Stevens TS, Nork TM.  Immunostaining of preretinal membranes for actin, fibronectin, and glial fibrillary acidic protein . Ophthalmology . 1989;;96:835-841.
13 +
Raymond LA, Katakami C, Lipman M, Alexander D, Choromokos E, Kao W.  Further studies on vitreous fibrosis . Invest Ophthalmol Vis Sci . 1984;;25( (suppl) ):273. Abstract.
14 +
Hui YN, Goodnight R, Sorgente N, Ryan SJ.  Fibrovascular proliferation and retinal detachment after intravitreal injection of activated macrophages in the rabbit eye . Am J Ophthalmol . 1984;;108:176-184.
15 +
Monsour AM, Chess J, Henkind P.  Fibrinogen-induced vitreous membranes . Ophthalmic Res . 1987;;19:164-169.
16 +
Constable IG, Oguri M, Chesney CM, Swann PA, Colman RW.  Platelet-induced vitreous membrane formation . Invest Ophthalmol . 1973;;2:680-685.
17 +
Freilich DB, Lee PF, Freeman HM.  Experimental retinal detachment . Arch Ophthalmol . 1966;;76:432-436.
18 +
Regnault FR.  Vitreous hemorrhage: an experimental study . Arch Ophthalmol . 1970;;83:458-474.
19 +
Lam KW, Ashrafzadeh MT, Lee CB.  Vitreous membrane induction in rabbits of intravitreous leukocyte injections . Arch Ophthalmol . 1972;;88:655-658.
20 +
Megusar MA, Lam K-W, Tolentino FI, Liu H-S.  Lymphocyte-induced vitreous membranes: a comparative study with leukocyte and plateletinduced vitreous membranes . Invest Ophthalmol . 1975;;14:240-243.
21 +
Mandelcorn MS, Machemer R, Fineberg E, Hersch SB.  Proliferation and metaplasia of intravitreal retinal pigment epithelium cell autotransplants . Am J Ophthalmol . 1975;;80:227-237.
22 +
Fastenberg DM, Diddie KR, Sorgente N, Ryan SJ.  A comparison of different cellular inocula in an experimental model of massive periretinal proliferation . Am J Ophthalmol . 1982;;93:559-564.
23 +
Forrester JV, Docherty R, Kerr C, Lackie JM.  Cellular proliferation in the vitreous: the use of vitreous explants as a model system . Invest Ophthalmol Vis Sci . 1986;;27:1085-1094.
24 +
Peters MA, Burke JM, Clowry M, Abrams GW, Williams GA.  Development of tractional retinal detachments following intravitreal injections of retinal Müller and pigment epithelial cells . Graefes Arch Clin Exp Ophthalmol . 1986;;224:554-563.
25 +
Sugita G, Tano Y, Machemer R, Abrams G, Claflin A, Fiorentino G.  Intravitreal autotransplantation of fibroblasts . Am J Ophthalmol . 1980;;86:121-130.
26 +
Ophir A, Blumenkranz MS, Claflin AJ.  Experimental intraocular proliferation and neovascularization . Am J Ophthalmol . 1982;;94:450-457.
27 +
Alguere P, Koch E.  Experimental epiretinal membranes induced by intravitreal carbon particles . Am J Ophthalmol . 1983;;96:345-353.
28 +
Alguere P, Wallow IH, Martini B.  The development of vitreous membranes and retinal detachment induced by intravitreal carbon microparticles . Graefes Arch Clin Exp Ophthalmol . 1988;;226:471-478.
29 +
Hsu HT, Ryan SJ.  Natural history of penetrating ocular injury with retinal laceration in the monkey . Graefes Arch Clin Exp Ophthalmol . 1986;;224:1-6.
30 +
Miller B, Miller H, Patterson R, Ryan SJ.  Retinal wound healing: cellular activity at the vitreoretinal interface . Arch Ophthalmol . 1986;;104:281-285.
31 +
Smith RD, Nozik RA.  Retinal detachment and uveitis . In: Uveitis: A Clinical Approach to Diagnosis and Management . Baltimore, Md: Williams & Wilkins; 1983;:99.
32 +
Wilson DJ, Green WR.  Histopathologic study of the effect of retinal detachment surgery on 49 eyes obtained post mortem . Am J Ophthalmol . 1983;;103:167-179.
33 +
Campochiaro PA, Glaser BM.  Plateletderived growth factor is chemotactic for human retinal pigment epithelial cells . Arch Ophthalmol . 1985;;103:576-579.
34 +
Campochiaro PA, Jerdan JA, Glaser BM, Cardin A, Michels MD.  Vitreous aspirates from patients with proliferative vitreoretinopathy stimulate retinal pigment epithelial cell migration . Arch Ophthalmol . 1985;;103:1403-1405.
35 +
Hageman GS, Johnson LV.  Structure, composition, and function of the retinal interphotoreceptor matrix . Prog Retinal Res . 1991;;10:207-249.
36 +
Katakami C, Appel A, Raymond LA, Lipman MJ, Kao W-Y.  Synthesis of chondroitin sulfate by fibrotic vitreous induced by monocytes and lymphocytes . Exp Eye Res . 1985;;41:509-518.
37 +
National Institutes of Health. NIH Guide for the Care and Use of Laboratory Animals . Bethesda, Md: Revised 1985;. NIH publication 86-25.
38 +
 ARVO resolution on the use of animals in research . Invest Ophthalmol Vis Sci . 1989;;30:2418.
39 +
Karnovsky MJ.  A formaldehyde-glutaraldehyde fixative of high osmolarity for use in electron microscopy . J Cell Biol . 1965;;27:137A. Abstract.
40 +
Reynolds ES.  The use of lead citrate at high pH as an electron opaque stain in electron microscopy . J Cell Biol . 1963;;17:208-212.
41 +
Hageman GS, Johnson LV.  Biochemical characterization of the major peanut-agglutininbinding glycoproteins in vertebrate retinae . J Comp Neurol . 1986;;249:499-510.
42 +
Russell SR, Hageman GS.  Insoluble interphotoreceptor matrix is present in human vitreous following rhegmatogenous retinal detachment . Invest Ophthalmol Vis Sci . 1991;;32:878. Abstract.
43 +
Barr CC.  The histopathology of successful retinal reattachment . Retina . 1990;;10:189-194.
44 +
Campochiaro PA, Bryon JA, Conway BP, Iaccoma MD.  Intravitreal chemotactic and mitogenic activity: implications of blood-retinal barrier breakdown . Arch Ophthalmol . 1986;;104:1685-1687.
45 +
Sourek J, Trnka T, Digeon M, Raynaud M.  Some immunochemical and chemical aspects of S and R Shigella dysenteriae 1 endotoxins . J Hyg Epidemiol Microbiol Immunol . 1975;;19:356-374.
46 +
Sourek J, Trnka T, Levin J, Roubal J, Michalec C.  Characteristics of lipid A-protein complex from endotoxin of Shigella dysenteriae type 1 (S and R strains) . Infect Immunol . 1979;;23:465-471.
47 +
Landholm WM, Watzke RC.  Experimental retinal detachment with a sulfated polysaccharide . Invest Ophthalmol . 1965;;4:42-50.
48 +
Doughman DJ, Watzke RC.  Experimental retinal detachment following intravitreal injection of sulfated polymers . Am J Ophthalmol . 1967;;64:893-902.
49 +
Aquino DA, Margolis RU, Margolis RK.  Immunocytochemical localization of a chondroitin sulfate proteoglycan in nervous tissue, I: adult brain, retina, and peripheral nerve . J Cell Biol . 1984;;99:1117-1129.
50 +
McLeod D, Hiscott, PS, Grierson I.  Agerelated cellular proliferation at the vitreoretinal juncture . Eye . 1987;;1:263-281.
51 +
Eisner G.  Clinical anatomy of the vitreous . In: Tasman W, ed. Biochemical Foundations of Ophthalmology . Philadelphia, Pa: JB Lippincott; 1989;;1:1-34.
52 +
Wolburg H, Reichelt W, Stolzenburg JU, Richter W, Reichenbach A.  Rabbit retinal Müller cells in cell culture show gap and tight junctions which they do not express in situ . Neurosci Lett . 1990;;111:58-63.
53 +
Michels RG.  A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery . Trans Am Ophthalmol Soc . 1982;;80:580-656.

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1 +
Roth AM, Foos RY.  Surface wrinkling retinopathy in eyes enucleated at autopsy . Trans Am Acad Ophthalmol Otolaryngol . 1971;;75:1047-1058.
2 +
Foos RY.  Vitreoretinal juncture: epiretinal membranes and vitreous . Invest Ophthalmol Vis Sci . 1977;;16:416-422.
3 +
Clarkson JG, Green WR, Massof D.  A histopathologic review of 168 cases of preretinal membrane . Am J Ophthalmol . 1977;;84:1-17.
4 +
Jaffe NS.  Macular fibrosis and massive preretinal retraction . Arch Ophthalmol . 1967;;78:585-591.
5 +
Foos RY.  Nonvascular proliferative extraretinal retinopathies . Am J Ophthalmol . 1978;;86:723-725.
6 +
Hiscott PS, Unger WG, Grierson I, McLeod D.  The role of inflammation in the development of epiretinal membranes . Curr Eye Res . 1988;;7:877-892.
7 +
Hiscott PS, Grierson I, Trombetta CJ, Rahi AHS, Marshall J, McLeod D.  Retinal and epiretinal glia: an immunocytochemical study . Br J Ophthalmol . 1984;;68:698-707.
8 +
Hiscott PS, Grierson I, McLeod D.  Retinal pigment epithelial cells in epiretinal membranes: an immunohistochemical study . Br J Ophthalmol . 1984;;68:708-715.
9 +
Hiscott PS, Grierson I, McLeod D.  Natural history of fibrocellular epiretinal membranes: a quantitative, autoradiographic, and immunohistochemical study . Br J Ophthalmol . 1985;;69:810-823.
10 +
Scheiffarth OF, Kampik A, Gunther H, von der Mark K.  Proteins of the extracellular matrix in vitreoretinal membranes . Graefes Arch Clin Exp Ophthalmol . 1988;;226:357-361.
11 +
Hui YN, Goodnight R, Zhang X-J, Sorgente N, Ryan SJ.  Glial epiretinal membranes and contraction: immunohistochemical and morphological studies . Arch Ophthalmol . 1988;;106:1280-1285.
12 +
Sramek SJ, Wallow IH, Stevens TS, Nork TM.  Immunostaining of preretinal membranes for actin, fibronectin, and glial fibrillary acidic protein . Ophthalmology . 1989;;96:835-841.
13 +
Raymond LA, Katakami C, Lipman M, Alexander D, Choromokos E, Kao W.  Further studies on vitreous fibrosis . Invest Ophthalmol Vis Sci . 1984;;25( (suppl) ):273. Abstract.
14 +
Hui YN, Goodnight R, Sorgente N, Ryan SJ.  Fibrovascular proliferation and retinal detachment after intravitreal injection of activated macrophages in the rabbit eye . Am J Ophthalmol . 1984;;108:176-184.
15 +
Monsour AM, Chess J, Henkind P.  Fibrinogen-induced vitreous membranes . Ophthalmic Res . 1987;;19:164-169.
16 +
Constable IG, Oguri M, Chesney CM, Swann PA, Colman RW.  Platelet-induced vitreous membrane formation . Invest Ophthalmol . 1973;;2:680-685.
17 +
Freilich DB, Lee PF, Freeman HM.  Experimental retinal detachment . Arch Ophthalmol . 1966;;76:432-436.
18 +
Regnault FR.  Vitreous hemorrhage: an experimental study . Arch Ophthalmol . 1970;;83:458-474.
19 +
Lam KW, Ashrafzadeh MT, Lee CB.  Vitreous membrane induction in rabbits of intravitreous leukocyte injections . Arch Ophthalmol . 1972;;88:655-658.
20 +
Megusar MA, Lam K-W, Tolentino FI, Liu H-S.  Lymphocyte-induced vitreous membranes: a comparative study with leukocyte and plateletinduced vitreous membranes . Invest Ophthalmol . 1975;;14:240-243.
21 +
Mandelcorn MS, Machemer R, Fineberg E, Hersch SB.  Proliferation and metaplasia of intravitreal retinal pigment epithelium cell autotransplants . Am J Ophthalmol . 1975;;80:227-237.
22 +
Fastenberg DM, Diddie KR, Sorgente N, Ryan SJ.  A comparison of different cellular inocula in an experimental model of massive periretinal proliferation . Am J Ophthalmol . 1982;;93:559-564.
23 +
Forrester JV, Docherty R, Kerr C, Lackie JM.  Cellular proliferation in the vitreous: the use of vitreous explants as a model system . Invest Ophthalmol Vis Sci . 1986;;27:1085-1094.
24 +
Peters MA, Burke JM, Clowry M, Abrams GW, Williams GA.  Development of tractional retinal detachments following intravitreal injections of retinal Müller and pigment epithelial cells . Graefes Arch Clin Exp Ophthalmol . 1986;;224:554-563.
25 +
Sugita G, Tano Y, Machemer R, Abrams G, Claflin A, Fiorentino G.  Intravitreal autotransplantation of fibroblasts . Am J Ophthalmol . 1980;;86:121-130.
26 +
Ophir A, Blumenkranz MS, Claflin AJ.  Experimental intraocular proliferation and neovascularization . Am J Ophthalmol . 1982;;94:450-457.
27 +
Alguere P, Koch E.  Experimental epiretinal membranes induced by intravitreal carbon particles . Am J Ophthalmol . 1983;;96:345-353.
28 +
Alguere P, Wallow IH, Martini B.  The development of vitreous membranes and retinal detachment induced by intravitreal carbon microparticles . Graefes Arch Clin Exp Ophthalmol . 1988;;226:471-478.
29 +
Hsu HT, Ryan SJ.  Natural history of penetrating ocular injury with retinal laceration in the monkey . Graefes Arch Clin Exp Ophthalmol . 1986;;224:1-6.
30 +
Miller B, Miller H, Patterson R, Ryan SJ.  Retinal wound healing: cellular activity at the vitreoretinal interface . Arch Ophthalmol . 1986;;104:281-285.
31 +
Smith RD, Nozik RA.  Retinal detachment and uveitis . In: Uveitis: A Clinical Approach to Diagnosis and Management . Baltimore, Md: Williams & Wilkins; 1983;:99.
32 +
Wilson DJ, Green WR.  Histopathologic study of the effect of retinal detachment surgery on 49 eyes obtained post mortem . Am J Ophthalmol . 1983;;103:167-179.
33 +
Campochiaro PA, Glaser BM.  Plateletderived growth factor is chemotactic for human retinal pigment epithelial cells . Arch Ophthalmol . 1985;;103:576-579.
34 +
Campochiaro PA, Jerdan JA, Glaser BM, Cardin A, Michels MD.  Vitreous aspirates from patients with proliferative vitreoretinopathy stimulate retinal pigment epithelial cell migration . Arch Ophthalmol . 1985;;103:1403-1405.
35 +
Hageman GS, Johnson LV.  Structure, composition, and function of the retinal interphotoreceptor matrix . Prog Retinal Res . 1991;;10:207-249.
36 +
Katakami C, Appel A, Raymond LA, Lipman MJ, Kao W-Y.  Synthesis of chondroitin sulfate by fibrotic vitreous induced by monocytes and lymphocytes . Exp Eye Res . 1985;;41:509-518.
37 +
National Institutes of Health. NIH Guide for the Care and Use of Laboratory Animals . Bethesda, Md: Revised 1985;. NIH publication 86-25.
38 +
 ARVO resolution on the use of animals in research . Invest Ophthalmol Vis Sci . 1989;;30:2418.
39 +
Karnovsky MJ.  A formaldehyde-glutaraldehyde fixative of high osmolarity for use in electron microscopy . J Cell Biol . 1965;;27:137A. Abstract.
40 +
Reynolds ES.  The use of lead citrate at high pH as an electron opaque stain in electron microscopy . J Cell Biol . 1963;;17:208-212.
41 +
Hageman GS, Johnson LV.  Biochemical characterization of the major peanut-agglutininbinding glycoproteins in vertebrate retinae . J Comp Neurol . 1986;;249:499-510.
42 +
Russell SR, Hageman GS.  Insoluble interphotoreceptor matrix is present in human vitreous following rhegmatogenous retinal detachment . Invest Ophthalmol Vis Sci . 1991;;32:878. Abstract.
43 +
Barr CC.  The histopathology of successful retinal reattachment . Retina . 1990;;10:189-194.
44 +
Campochiaro PA, Bryon JA, Conway BP, Iaccoma MD.  Intravitreal chemotactic and mitogenic activity: implications of blood-retinal barrier breakdown . Arch Ophthalmol . 1986;;104:1685-1687.
45 +
Sourek J, Trnka T, Digeon M, Raynaud M.  Some immunochemical and chemical aspects of S and R Shigella dysenteriae 1 endotoxins . J Hyg Epidemiol Microbiol Immunol . 1975;;19:356-374.
46 +
Sourek J, Trnka T, Levin J, Roubal J, Michalec C.  Characteristics of lipid A-protein complex from endotoxin of Shigella dysenteriae type 1 (S and R strains) . Infect Immunol . 1979;;23:465-471.
47 +
Landholm WM, Watzke RC.  Experimental retinal detachment with a sulfated polysaccharide . Invest Ophthalmol . 1965;;4:42-50.
48 +
Doughman DJ, Watzke RC.  Experimental retinal detachment following intravitreal injection of sulfated polymers . Am J Ophthalmol . 1967;;64:893-902.
49 +
Aquino DA, Margolis RU, Margolis RK.  Immunocytochemical localization of a chondroitin sulfate proteoglycan in nervous tissue, I: adult brain, retina, and peripheral nerve . J Cell Biol . 1984;;99:1117-1129.
50 +
McLeod D, Hiscott, PS, Grierson I.  Agerelated cellular proliferation at the vitreoretinal juncture . Eye . 1987;;1:263-281.
51 +
Eisner G.  Clinical anatomy of the vitreous . In: Tasman W, ed. Biochemical Foundations of Ophthalmology . Philadelphia, Pa: JB Lippincott; 1989;;1:1-34.
52 +
Wolburg H, Reichelt W, Stolzenburg JU, Richter W, Reichenbach A.  Rabbit retinal Müller cells in cell culture show gap and tight junctions which they do not express in situ . Neurosci Lett . 1990;;111:58-63.
53 +
Michels RG.  A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery . Trans Am Ophthalmol Soc . 1982;;80:580-656.

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