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Review on Hypothetical Implementing TGF-β Family Members in Glaucoma Therapy

Ivan Sosa, Kata Culina, Alan Bosnar

Abstract


For quite some time, glaucoma has been regarded as more than just intraocular pressure [IOP] elevation. Significant contribution to this conceptual improvement has risen from a better understanding of ocular blood flow, vessel wall integrity and certain advanced ideas in neuroophthalmology, for example neuroprotection. Transforming growth factor–β (TGF-β) molecule, its inhibitors and antagonists have been increasingly researched as possible new anti-glaucoma drugs for its many, pleiotropic, effects. Among those effects, enhancing fibrosis is one of the most apparent, but certain members of this cytokine’s superfamily act as anti-fibrotics. Recent scientific efforts strongly support pushing back the frontier of conventional medical treatment. Current medical approaches already use effects on blood flow and neuronal quiescence, with significant systemic side-effects. Endeavours on the ophthalmologic exploitation of selected, favourable effects of pleiotropic TGF-βs could promote TGF-β, its inhibitors or specific antibodies as new, ideal drugs in glaucoma therapy.


References


Infeld DA, O'Shea JG. Glaucoma: diagnosis and management. Postgrad Med J. 1998 Dec;74(878):709-15. PMID: 10320884.

Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. Am J Health Syst Pharm. 2005 Apr 1;62(7):691-9. PMID: 15790795.

Flammer J. The vascular concept of glaucoma. Surv Ophthalmol. 1994 May;38 Suppl:S3-6. PMID: 7940146.

Chung HS, Harris A, Evans DW, Kagemann L, Garzozi HJ, Martin B. Vascular aspects in the pathophysiology of glaucomatous optic neuropathy. Surv Ophthalmol. 1999 Jun;43 Suppl 1:S43-50. PMID: 10416746.

Harris A, Chung HS, Ciulla TA, Kagemann L. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration. Prog Retin Eye Res. 1999 Sep;18(5):669-87. PMID: 10438154.

Resch H, Karl K, Weigert G, Wolzt M, Hommer A, Schmetterer L, Garhöfer G. Effect of dual endothelin receptor blockade on ocular blood flow in patients with glaucoma and healthy subjects. Invest Ophthalmol Vis Sci. 2009 Jan;50(1):358-63. PMID: 18719081.

Flammer J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, Renard JP, Stefánsson E. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002 Jul;21(4):359-93. PMID: 12150988.

Emre M, Orgül S, Gugleta K, Flammer J. Ocular blood flow alteration in glaucoma is related to systemic vascular dysregulation. Br J Ophthalmol. 2004 May;88(5):662-6. PMID: 15090420.

Grieshaber MC, Flammer J. Blood flow in glaucoma. Curr Opin Ophthalmol. 2005 Apr;16(2):79-83. PMID: 15744136.

Yu DY, Su EN, Cringle SJ, Yu PK. Isolated preparations of ocular vasculature and their applications in ophthalmic research. Prog Retin Eye Res. 2003 Mar;22(2):135-69. PMID: 12604056.

Orlova VV, Liu Z, Goumans MJ, ten Dijke P. Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways. Histol Histopathol. 2011 Sep;26(9):1219-30. PMID: 21751154.

Pardali E, Goumans MJ, ten Dijke P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol. 2010 Sep;20(9):556-67. PMID: 20656490.

Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2626-31. PMID: 10716993.

Wrana JL. Crossing Smads. Sci STKE. 2000 Mar 14;2000(23):re1. PMID: 11752591.

Mehra A, Wrana JL. TGF-beta and the Smad signal transduction pathway. Biochem Cell Biol. 2002;80(5):605-22. PMID: 12440701.

Verrecchia F, Mauviel A, Farge D. Transforming growth factor-beta signaling through the Smad proteins: role in systemic sclerosis. Autoimmun Rev. 2006 Oct;5(8):563-9. PMID: 17027893.

Pannu J, Trojanowska M. Recent advances in fibroblast signaling and biology in scleroderma. Curr Opin Rheumatol. 2004 Nov;16(6):739-45. PMID: 15577613.

Ihn H. Autocrine TGF-beta signaling in the pathogenesis of systemic sclerosis. J Dermatol Sci. 2008 Feb;49(2):103-13. PMID: 17628443.

Bonniaud P, Margetts PJ, Kolb M, Schroeder JA, Kapoun AM, Damm D, Murphy A, Chakravarty S, Dugar S, Higgins L, Protter AA, Gauldie J. Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med. 2005 Apr 15;171(8):889-98. PMID: 15563636.

Wells RG. Fibrogenesis. V. TGF-beta signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G845-50. PMID: 11052979.

Zode GS, Sethi A, Brun-Zinkernagel AM, Chang IF, Clark AF, Wordinger RJ. Transforming growth factor-ß2 increases extracellular matrix proteins in optic nerve head cells via activation of the Smad signaling pathway. Mol Vis. 2011;17:1745-58.

Jung SA, Lee HK, Yoon JS, Kim SJ, Kim CY, Song H, Hwang KC, Lee JB, Lee JH. Upregulation of TGF-beta-induced tissue transglutaminase expression by PI3K-Akt pathway activation in human subconjunctival fibroblasts. Invest Ophthalmol Vis Sci. 2007 May;48(5):1952-8. PMID: 17460246.

David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007 Mar 1;109(5):1953-61. PMID: 17068149.

Huylebroeck D. Bone morphogenetic proteins go endothelial . Blood. 2007 mar; 109(5):1794-1795.

Gangopahyay A, Oran M, Bauer EM, Wertz JW, Comhair SA, Erzurum SC, Bauer PM. Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation. J Biol Chem. 2011 Sep 23;286(38):33134-40. PMID: 21808054.

Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, Lee SJ, Bidart M, Feige JJ, Bailly S. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood. 2012 Jun 21;119(25):6162-71. PMID: 22566602.

Tian XY, Yung LH, Wong WT, Liu J, Leung FP, Liu L, Chen Y, Kong SK, Kwan KM, Ng SM, Lai PB, Yung LM, Yao X, Huang Y. Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway. J Mol Cell Cardiol. 2012 Jan;52(1):237-44. PMID: 22064324.

David L, Mallet C, Keramidas M, Lamandé N, Gasc JM, Dupuis-Girod S, Plauchu H, Feige JJ, Bailly S. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res. 2008 Apr 25;102(8):914-22. PMID: 18309101.

Orgül S, Prünte C, Flammer J. Endothelium-derived vasoactive substances relevant to normal-tension glaucoma. Curr Opin Ophthalmol. 1998 Apr;9(2):88-94. PMID: 10180520.

Prünte C, Orgül S, Flammer J. Abnormalities of microcirculation in glaucoma: facts and hints. Curr Opin Ophthalmol. 1998 Apr;9(2):50-5. PMID: 10180514.

Nadar S, Blann AD, Lip GY. Endothelial dysfunction: methods of assessment and application to hypertension. Curr Pharm Des. 2004;10(29):3591-605. PMID: 15579056.

Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol. 1999 Jan;31(1):51-60. PMID: 10072715.

Neufeld AH, Sawada A, Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9944-8. PMID: 10449799.

Neufeld AH. Nitric oxide: a potential mediator of retinal ganglion cell damage in glaucoma. Surv Ophthalmol. 1999 Jun;43 Suppl 1:S129-35. PMID: 10416755.

Morgan J, Caprioli J, Koseki Y. Nitric oxide mediates excitotoxic and anoxic damage in rat retinal ganglion cells cocultured with astroglia. Arch Ophthalmol. 1999 Nov;117(11):1524-9. PMID: 10565522.

Tang CH, Wei W, Liu L. Regulation of DNA repair by S-nitrosylation. Biochim Biophys Acta. 2012 Jun;1820(6):730-5. PMID: 21571039.

Taylor EL, Megson IL, Haslett C, Rossi AG. Dissociation of DNA fragmentation from other hallmarks of apoptosis in nitric oxide-treated neutrophils: differences between individual nitric oxide donor drugs. Biochem Biophys Res Commun. 2001 Dec 21;289(5):1229-36. PMID: 11741325.

Chang CJ, Chiang CH, Chow JC, Lu DW. Aqueous humor nitric oxide levels differ in patients with different types of glaucoma. J Ocul Pharmacol Ther. 2000 Oct;16(5):399-406. PMID: 11110031.

Tezel G, Kass MA, Kolker AE, Becker B, Wax MB. Plasma and aqueous humor endothelin levels in primary open-angle glaucoma. J Glaucoma. 1997 Apr;6(2):83-9. PMID: 9098815.

Resch H, Garhofer G, Fuchsjäger-Mayrl G, Hommer A, Schmetterer L. Endothelial dysfunction in glaucoma. Acta Ophthalmol. 2009 Feb;87(1):4-12. PMID: 18507728.

Stefánsson E, Pedersen DB, Jensen PK, la Cour M, Kiilgaard JF, Bang K, Eysteinsson T. Optic nerve oxygenation. Prog Retin Eye Res. 2005 May;24(3):307-32. PMID: 15708831.

Gass A, Flammer J, Linder L, Romerio SC, Gasser P, Haefeli WE. Inverse correlation between endothelin-1-induced peripheral microvascular vasoconstriction and blood pressure in glaucoma patients. Graefes Arch Clin Exp Ophthalmol. 1997 Oct;235(10):634-8. PMID: 9349947.

Wilensky JT. The role of diurnal pressure measurements in the management of open angle glaucoma. Curr Opin Ophthalmol. 2004 Apr;15(2):90-2. PMID: 15021217.

Caprioli J, Coleman AL; Blood Flow in Glaucoma Discussion. Blood pressure, perfusion pressure, and glaucoma. Am J Ophthalmol. 2010 May;149(5):704-12. PMID: 20399924.

Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002 Oct;120(10):1268-79. PMID: 12365904.

Shields MB. Normal-tension glaucoma: is it different from primary open-angle glaucoma? Curr Opin Ophthalmol. 2008 Mar;19(2):85-8. PMID: 18301279.

Doyle KP, Cekanaviciute E, Mamer LE, Buckwalter MS. TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. J Neuroinflammation. 2010 Oct 11;7:62. PMID: 20937129.

Kaushik S, Pandav SS, Ram J. Neuroprotection in glaucoma. J Postgrad Med. 2003 Jan-Mar;49(1):90-5. PMID: 12865582.

García-Campos J, Villena A, Díaz F, Vidal L, Moreno M, Pérez de Vargas I. Morphological and functional changes in experimental ocular hypertension and role of neuroprotective drugs. Histol Histopathol. 2007 Dec;22(12):1399-411. PMID: 17701920.

Grieshaber MC, Flammer J. Is the medication used to achieve the target intraocular pressure in glaucoma therapy of relevance?--an exemplary analysis on the basis of two beta-blockers. Prog Retin Eye Res. 2010 Jan;29(1):79-93. PMID: 19733652.

Tripathi RC, Li J, Chan WF, Tripathi BJ. Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta 2. Exp Eye Res. 1994 Dec;59(6):723-7. PMID: 7698265.

Ito S, Sakamoto T, Tahara Y, Goto Y, Akazawa K, Ishibashi T, Inomata H. The effect of tranilast on experimental proliferative vitreoretinopathy. Graefes Arch Clin Exp Ophthalmol. 1999 Aug;237(8):691-6. PMID: 10459620.

Zimmerman TJ, Leader B, Kaufman HE. Advances in ocular pharmacology. Annu Rev Pharmacol Toxicol. 1980;20:415-28. PMID: 6155823.

Bhargava M, Ikram MK, Wong TY. How does hypertension affect your eyes? J Hum Hypertens. 2012 Feb;26(2):71-83. PMID: 21509040.

Faridi O, Park SC, Liebmann JM, Ritch R. Glaucoma and obstructive sleep apnoea syndrome. Clin Experiment Ophthalmol. 2012 May-Jun;40(4):408-19. PMID: 22339817.

Schor KS, De Moraes CG, Teng CC, Tello C, Liebmann JM, Ritch R. Rates of visual field progression in distinct optic disc phenotypes. Clin Experiment Ophthalmol. 2012 Sep-Oct;40(7):706-12. PMID: 22429789.

Krudysz J. Effect of transfusions of stored blood and blood-substitutes on the intraocular tension. Pol Med J. 1966;5(5):1124-31. PMID: 5958800.

Gasser P, Stümpfig D, Schötzau A, Ackermann-Liebrich U, Flammer J. Body mass index in glaucoma. J Glaucoma. 1999 Feb;8(1):8-11. PMID: 10084268.

Coleman AL, Kodjebacheva G. Risk factors for glaucoma needing more attention. Open Ophthalmol J. 2009 Sep 17;3:38-42. PMID: 19816585.

Renard JP, Rouland JF, Bron A, Sellem E, Nordmann JP, Baudouin C, Denis P, Villain M, Chaine G, Colin J, de Pouvourville G, Pinchinat S, Moore N, Estephan M, Delcourt C. Nutritional, lifestyle and environmental factors in ocular hypertension and primary open-angle glaucoma: an exploratory case-control study. Acta Ophthalmol. 2012 Mar 6. [Epub ahead of print] PMID: 22394398.

Orgül S, Flammer J. Optic-disc hemorrhages: Cause or result of ischemia?. Neuro-ophthalmology. 1994;14(2):97–101.

Singh K, Dion C, Costantino S, Wajszilber M, Lesk MR, Ozaki T. Development of a novel instrument to measure the pulsatile movement of ocular tissues. Exp Eye Res. 2010 Jul;91(1):63-8. PMID: 20398654.

Lee AJ, Goldberg I. Emerging drugs for ocular hypertension. Expert Opin Emerg Drugs. 2011 Mar;16(1):137-61. PMID: 21352074.

Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1-21. PMID: 15663346.

Hopkins SJ. The pathophysiological role of cytokines. Leg Med (Tokyo). 2003 Mar;5 Suppl 1:S45-57. PMID: 12935551.

Haurigot V, Villacampa P, Ribera A, Llombart C, Bosch A, Nacher V, Ramos D, Ayuso E, Segovia JC, Bueren JA, Ruberte J, Bosch F. Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown. J Biol Chem. 2009 Aug 21;284(34):22961-9. PMID: 19473988.

Zalta AH, Sweeney CP, Zalta AK, Kaufman AH. Intracameral tissue plasminogen activator use in a large series of eyes with valved glaucoma drainage implants. Arch Ophthalmol. 2002 Nov;120(11):1487-93. PMID: 12427061.

Azuara-Blanco A, Wilson RP. Intraocular and extraocular bleeding after intracameral injection of tissue plasminogen activator. Br J Ophthalmol. 1998 Nov;82(11):1345-6. PMID: 9924355.

Khaw PT, Occleston NL, Schultz G, Grierson I, Sherwood MB, Larkin G. Activation and suppression of fibroblast function. Eye (Lond). 1994;8 ( Pt 2):188-95. PMID: 7958020.

Cybulska-Heinrich AK, Mozaffarieh M, Flammer J. Ginkgo biloba: an adjuvant therapy for progressive normal and high tension glaucoma. Mol Vis. 2012;18:390-402. PMID: 22355250.

Parikh RS, Parikh SR. Alternative therapy in glaucoma management: is there any role? Indian J Ophthalmol. 2011 Jan;59 Suppl:S158-60. PMID: 21150028.

Park JW, Kwon HJ, Chung WS, Kim CY, Seong GJ. Short-term effects of Ginkgo biloba extract on peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol. 2011 Oct;25(5):323-8. PMID: 21976939.

Lugasi A, Horvahovich P, Dworschák E. Additional information to the in vitro antioxidant activity of Ginkgo biloba L. Phytother Res. 1999 Mar;13(2):160-2. PMID: 10190193.

Arthur S, Cantor LB. Update on the role of alpha-agonists in glaucoma management. Exp Eye Res. 2011 Sep;93(3):271-83. PMID: 21524649.


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