Abstract
The processes involved in ocular fibrosis after disease or ocular tissue injury, including surgery play an important part in the development or failure of treatment of most blinding diseases. Ocular fibrosis is one of the biggest areas of unmet need in ophthalmology. Effective anti-scarring therapies could potentially revolutionise the management of many diseases like glaucoma worldwide. The response of a quiescent or activated conjunctiva to glaucoma surgery and aqueous flow with different stimulatory components and the response to different interventions and future therapeutics is a paradigm for scarring prevention in other parts of the eye and orbit. Evolution in our understanding of molecular and cellular mechanisms in ocular fibrosis is leading to the introduction of new and re-purposed therapeutic agents, targeting a wide range of key processes. This review provides current and futures perspectives on different approaches to conjunctival fibrosis following glaucoma surgery and highlights the challenges faced in implementing these therapies with maximal effect and minimal side effects.
摘要
疾病或眼组织损伤后包括手术在内的眼纤维化过程在大多数致盲性疾病的进展或治疗失败中起着重要作用。眼纤维化是眼科领域中未满足 (医生与患者) 需求的最大领域之一。有效地抗瘢痕形成治疗可以彻底改变世界范围内诸如青光眼等许多疾病的治疗方法。静止或活化的结膜对青光眼手术和不同刺激成分对房水流动的反应, 以及对不同干预措施和未来治疗的反应, 是预防眼或眼眶其他部位瘢痕形成的范例。我们对眼纤维化分子和细胞机制理解的不断发展, 导致了针对广泛关键过程的新型治疗药物的重新引用。本文提供了关于青光眼手术后结膜纤维化的不同治疗方法的当前及未来的展望, 并着重介绍了在以最大效果和最小副作用实施这些疗法时所面临的挑战。
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References
Jayaram H, Jones MF, Eastlake K, Cottrill PB, Becker S, Wiseman J, et al. Transplantation of photoreceptors derived from human Muller glia restore rod function in the P23H rat. Stem Cells Transl Med. 2014;3:323–33.
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol. 2000;130:429–40.
Van Bergen T, Van de Velde S, Vandewalle E, Moons L, Stalmans I. Improving patient outcomes following glaucoma surgery: state of the art and future perspectives. Clin Ophthalmol. 2014;8:857–67.
Teller P, White TK. The Physiology of Wound Healing: Injury Through Maturation. Surg Clin N Am. 2009;89:599.
Luttikhuizen DT, Harmsen MC, Van Luyn MJA. Cellular and molecular dynamics in the foreign body reaction. Tissue Eng. 2006;12:1955–70.
Khaw PT, Chiang M, Shah P, Sii F, Lockwood A, Khalili A. Enhanced Trabeculectomy: The Moorfields Safer Surgery System. Dev Ophthalmol. 2017;59:15–35.
Saeedi OJ, Jefferys JL, Solus JF, Jampel HD, Quigley HA. Risk factors for adverse consequences of low intraocular pressure after trabeculectomy. J Glaucoma. 2014;23:e60–8.
Schlunck G, Meyer-ter-Vehn T, Klink T, Grehn F. Conjunctival fibrosis following filtering glaucoma surgery. Experimental Eye Research. 2016;142:76–82.
Wells AP, Crowston JG, Marks J, Kirwan JF, Smith G, Clarke JC, et al. A pilot study of a system for grading of drainage blebs after glaucoma surgery. J Glaucoma. 2004;13:454–60.
Bouremel Y, Lee RMH, Eames I, Brocchini S, Khaw PT. Novel approaches to model effects of subconjunctival blebs on flow pressure to improve clinical grading systems after glaucoma drainage surgery. PLoS ONE. 2019;14:e0221715.
Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018;68–69:81–93.
WuDunn D. Intracameral urokinase for dissolution of fibrin or blood clots after glaucoma surgery. Am J Ophthalmol. 1997;124:693–5.
Min J, Lukowski ZL, Levine MA, Meyers CA, Beattie AR, Schultz GS, et al. Prevention of ocular scarring post glaucoma filtration surgery using the inflammatory cell and platelet binding modulator saratin in a rabbit model. PLoS ONE. 2012;7:e35627.
Yuen D, Buys Y, Jin YP, Alasbali T, Smith M, Trope GE. Corticosteroids Versus NSAIDs on Intraocular Pressure and the Hypertensive Phase After Ahmed Glaucoma Valve Surgery. Journal of Glaucoma. 2011;20:439–44.
Yuki K, Shiba D, Kimura I, Ohtake Y, Tsubota K. Trabeculectomy With or Without Intraoperative Sub-Tenon Injection of Triamcinolone Acetonide in Treating Secondary Glaucoma. American Journal of Ophthalmology. 2009;147:1055–60.
Koval MS, Moster MR, Freidl KB, Waisbourd M, Jain SG, Ichhpujani P, et al. Intracameral Triamcinolone Acetonide in Glaucoma Surgery: A Prospective Randomized Controlled Trial. American Journal of Ophthalmology. 2014;158:395–401.
Vandervoort J, Ludwig A. Ocular drug delivery: nanomedicine applications. Nanomedicine. 2007;2:11–21.
Furino C, Boscia F, Cicinelli MV, Sborgia A, Alessio G. Subconjunctival sustained-release dexamethasone implant as an adjunct to trabeculectomy for primary open angle glaucoma. Indian Journal of Ophthalmology. 2016;64:251.
Hui A. Contact lenses for ophthalmic drug delivery. Clin Exp Optom. 2017;100:494–512.
Fakhraie G, Lopes JF, Spaeth GL, Almodin J, Ichhpujani P, Moster MR. Effects of postoperative cyclosporine ophthalmic emulsion 0.05% (Restasis) following glaucoma surgery. Clin Exp Ophthalmol. 2009;37:842–8.
Khaw PT, Sherwood MB, MacKay SL, Rossi MJ, Schultz G. Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenonʼs capsule fibroblasts. Arch Ophthalmol. 1992;110:1150–4.
Green E, Wilkins M, Bunce C, Wormald R. 5-Fluorouracil for glaucoma surgery. Cochrane Database Syst Rev 2014: CD001132.
Smith MF, Sherwood MB, Doyle JW, Khaw PT. Results of intraoperative 5-fluorouracil supplementation on trabeculectomy for open-angle glaucoma. Am J Ophthalmol. 1992;114:737–41.
Lanigan L, Sturmer J, Baez KA, Hitchings RA, Khaw PT. Single intraoperative applications of 5-fluorouracil during filtration surgery: early results. Br J Ophthalmol. 1994;78:33–37.
Khaw PT, Doyle JW, Sherwood MB, Grierson I, Schultz G, McGorray S. Prolonged localized tissue effects from 5-minute exposures to fluorouracil and mitomycin C. Arch Ophthalmol. 1993;111:263–7.
Khaw PT, Sherwood MB, Doyle JW, Smith MF, Grierson I, McGorray S, et al. Intraoperative and post operative treatment with 5-fluorouracil and mitomycin-c: long term effects in vivo on subconjunctival and scleral fibroblasts. Int Ophthalmol. 1992;16:381–5.
Cabourne E, Clarke JC, Schlottmann PG, Evans JR Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery. Cochrane Database Syst Rev 2015:CD006259.
Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C. Ophthalmology. 2003;110:2192–7.
Constable PH, Crowston JG, Occleston NL, Khaw PT. The effects of single doses of beta radiation on the wound healing behaviour of human Tenonʼs capsule fibroblasts. Br J Ophthalmol. 2004;88:169–73.
Khaw PT, Ward S, Grierson I, Rice NS. Effect of beta radiation on proliferating human Tenonʼs capsule fibroblasts. Br J Ophthalmol. 1991;75:580–3.
Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye (Lond). 2003;17:207–15.
Kirwan JF, Rennie C, Evans JR. Beta radiation for glaucoma surgery. Cochrane Database Syst Rev 2012:CD003433.
Dhalla K, Cousens S, Bowman R, Wood M, Murdoch I. Is Beta Radiation Better than 5 Flurouracil as an Adjunct for Trabeculectomy Surgery When Combined with Cataract Surgery? A Randomised Controlled Trial. PLoS ONE. 2016;11:e0161674.
El Mazar HM, Mandour SS, Mostafa MI, Elmorsy OA. Augmented Subscleral Trabeculectomy With Beta Radiation and Mitomycin C in Egyptian Glaucoma Patients. J Glaucoma. 2019;28:637–42.
Cook CPA, Mustak H, Courtright P, Wetter J, du Toit N. Randomised clinical trial of trabeculectomy with mitomycin-C versus trabeculectomy with beta radiation. South African Ophthalmology Journal. 2018;13:11–14.
Perkins TW, Faha B, Ni M, Kiland JA, Poulsen GL, Antelman D, et al. Adenovirus-mediated gene therapy using human p21WAF-1/Cip-1 to prevent wound healing in a rabbit model of glaucoma filtration surgery. Arch Ophthalmol. 2002;120:941–9.
Lockwood A, Brocchini S, Khaw PT. New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery. Curr Opin Pharmacol. 2013;13:65–71.
Hales AM, Chamberlain CG, McAvoy JW. Cataract induction in lenses cultured with transforming growth factor-beta. Invest Ophthalmol Vis Sci. 1995;36:1709–13.
Connor TB Jr, Roberts AB, Sporn MB, Danielpour D, Dart LL, Michels RG, et al. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J Clin Invest. 1989;83:1661–6.
Lutty GA, Merges C, Threlkeld AB, Crone S, McLeod DS. Heterogeneity in localization of isoforms of TGF-beta in human retina, vitreous, and choroid. Invest Ophthalmol Vis Sci. 1993;34:477–87.
Picht G, Welge-Luessen U, Grehn F, Lutjen-Drecoll E. Transforming growth factor beta 2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development. Graefes Arch Clin Exp Ophthalmol. 2001;239:199–207.
Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT. Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci. 2003;44:3394–401.
Group CATTS, Khaw P, Grehn F, Hollo G, Overton B, Wilson R, et al. A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology. 2007;114:1822–30.
Akhurst RJ, Hata A. Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012;11:790–811.
Shu DY, Lovicu FJ. Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. Prog Retin Eye Res. 2017;60:44–65.
Jinek M, Doudna JA. A three-dimensional view of the molecular machinery of RNA interference. Nature. 2009;457:405–12.
Hwang YH, Jung SA, Lyu J, Kim YY, Lee JH. Transforming Growth Factor-beta1-induced Human Subconjunctival Fibrosis is Mediated by MicroRNA 143/145 Expression. Invest Ophthalmol Vis Sci. 2019;60:2064–71.
Li N, Cui J, Duan X, Chen H, Fan F. Suppression of type I collagen expression by miR-29b via PI3K, Akt, and Sp1 pathway in human Tenonʼs fibroblasts. Invest Ophthalmol Vis Sci. 2012;53:1670–8.
Stewart AG, Thomas B, Koff J. TGF-beta: Master regulator of inflammation and fibrosis. Respirology. 2018;23:1096–7.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–38.
Hanna J, Hossain GS, Kocerha J. The Potential for microRNA Therapeutics and Clinical Research. Front Genet. 2019;10:478.
Wang Y, Wang J, Wei LJ, Zhu DM, Zhang JS. Biological function and mechanism of lncRNA-MEG3 in Tenonʼs capsule fibroblasts proliferation: By MEG3-Nrf2 protein interaction. Biomed Pharmacother. 2017;87:548–54.
Zhao Y, Zhang F, Pan Z, Luo H, Liu K, Duan X. LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenonʼs capsule fibroblasts. Cell Death Dis. 2019;10:594.
Liu Y, Liu PP, Liu L, Zheng XS, Zheng H, Yang CC, et al. Triptolide inhibits TGF-beta-induced matrix contraction and fibronectin production mediated by human Tenon fibroblasts. Int J Ophthalmol. 2018;11:1108–13.
Gong W, Li J, Zhu G, Wang Y, Zheng G, Kan Q. Chlorogenic acid relieved oxidative stress injury in retinal ganglion cells through IncRNA-TUG1/Nrf2. Cell Cycle. 2019;18:1549–59.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.
Beddy D, Watson RW, Fitzpatrick JM, OʼConnell PR. Increased vascular endothelial growth factor production in fibroblasts isolated from strictures in patients with Crohnʼs disease. Br J Surg. 2004;91:72–7.
Li Z, Van Bergen T, Van de Veire S, Van de Vel I, Moreau H, Dewerchin M, et al. Inhibition of vascular endothelial growth factor reduces scar formation after glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 2009;50:5217–25.
Cheng JW, Cheng SW, Wei RL, Lu GC. Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery. Cochrane Database Syst Rev 2016:CD009782.
Kahook MY. Bleb morphology and vascularity after trabeculectomy with intravitreal ranibizumab: a pilot study. Am J Ophthalmol. 2010;150:399–403e391.
Kahook MY, Schuman JS, Noecker RJ. Needle bleb revision of encapsulated filtering bleb with bevacizumab. Ophthalmic Surg Lasers Imaging. 2006;37:148–50.
Dong Z, Gong J, Liao R, Xu S. Effectiveness of multiple therapeutic strategies in neovascular glaucoma patients: A PRISMA-compliant network meta-analysis. Medicine (Baltimore). 2018;97:e9897.
Cornish KS, Ramamurthi S, Saidkasimova S, Ramaesh K. Intravitreal bevacizumab and augmented trabeculectomy for neovascular glaucoma in young diabetic patients. Eye (Lond). 2009;23:979–81.
Akiyama H, Kachi S, Silva RL, Umeda N, Hackett SF, McCauley D, et al. Intraocular injection of an aptamer that binds PDGF-B: a potential treatment for proliferative retinopathies. J Cell Physiol. 2006;207:407–12.
Lin X, Wen J, Liu R, Gao W, Qu B, Yu M. Nintedanib inhibits TGF-beta-induced myofibroblast transdifferentiation in human Tenonʼs fibroblasts. Mol Vis. 2018;24:789–800.
Conte E, Gili E, Fagone E, Fruciano M, Iemmolo M, Vancheri C. Effect of pirfenidone on proliferation, TGF-beta-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci. 2014;58:13–9.
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–63.
Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, et al. Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol. 1999;181:153–9.
Esson DW, Neelakantan A, Iyer SA, Blalock TD, Balasubramanian L, Grotendorst GR, et al. Expression of connective tissue growth factor after glaucoma filtration surgery in a rabbit model. Invest Ophthalmol Vis Sci. 2004;45:485–91.
Yamanaka O, Saika S, Ikeda K, Miyazaki K, Kitano A, Ohnishi Y. Connective tissue growth factor modulates extracellular matrix production in human subconjunctival fibroblasts and their proliferation and migration in vitro. Jpn J Ophthalmol. 2008;52:8–15.
Razzaque MS, Foster CS, Ahmed AR. Role of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci. 2003;44:1998–2003.
Gooz M. ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol. 2010;45:146–69.
Wang Y, Tang Z, Xue R, Singh GK, Lv Y, Shi K, et al. TGF-beta1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-kappaB. Connect Tissue Res. 2011;52:218–25.
McCluskey P, Molteno A, Wakefield D, Di Girolamo N. Otago Glaucoma Surgery Outcome Study: the pattern of expression of MMPs and TIMPs in bleb capsules surrounding Molteno implants. Invest Ophthalmol Vis Sci. 2009;50:2161–4.
Wong TT, Mead AL, Khaw PT. Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 2003;44:1097–103.
Mohamed-Ahmed AHA, Lockwood A, Li H, Bailly M, Khaw PT, Brocchini S. An Ilomastat-CD Eye Drop Formulation to Treat Ocular Scarring. Invest Ophthalmol Vis Sci. 2017;58:3425–31.
Sen E, Balikoglu-Yilmaz M, Bozdag-Pehlivan S, Sungu N, Aksakal FN, Altinok A, et al. Effect of doxycycline on postoperative scarring after trabeculectomy in an experimental rabbit model. J Ocul Pharmacol Ther. 2010;26:399–406.
Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, et al. Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta. 2003;1647:220–4.
Park HY, Kim JH, Park CK. Lysyl oxidase-like 2 level and glaucoma surgical outcomes. Invest Ophthalmol Vis Sci. 2014;55:3337–43.
Van Bergen T, Marshall D, Van de Veire S, Vandewalle E, Moons L, Herman J, et al. The role of LOX and LOXL2 in scar formation after glaucoma surgery. Invest Ophthalmol Vis Sci. 2013;54:5788–96.
Tovell VE, Chau CY, Khaw PT, Bailly M. Rac1 inhibition prevents tissue contraction and MMP mediated matrix remodeling in the conjunctiva. Invest Ophthalmol Vis Sci. 2012;53:4682–91.
Honjo M, Tanihara H, Kameda T, Kawaji T, Yoshimura N, Araie M. Potential role of Rho-associated protein kinase inhibitor Y-27632 in glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 2007;48:5549–57.
Evelyn CR, Wade SM, Wang Q, Wu M, Iniguez-Lluhi JA, Merajver SD, et al. CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol Cancer Ther. 2007;6:2249–60.
Tagalakis AD, Madaan S, Larsen SD, Neubig RR, Khaw PT, Rodrigues I, et al. In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. J Nanobiotechnology. 2018;16:97.
Yu-Wai-Man C, Spencer-Dene B, Lee RMH, Hutchings K, Lisabeth EM, Treisman R, et al. Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci Rep. 2017;7:518.
Shao T, Li X, Ge J. Target drug delivery system as a new scarring modulation after glaucoma filtration surgery. Diagn Pathol. 2011;6:64.
Barton K, Budenz DL, Khaw PT, Tseng SC. Glaucoma filtration surgery using amniotic membrane transplantation. Invest Ophthalmol Vis Sci. 2001;42:1762–8.
Pakravan M, Rad SS, Yazdani S, Ghahari E, Yaseri M. Effect of early treatment with aqueous suppressants on Ahmed glaucoma valve implantation outcomes. Ophthalmology. 2014;121:1693–8.
Law SK, Kornmann HL, Giaconi JA, Kwong A, Tran E, Caprioli J. Early Aqueous Suppressant Therapy on Hypertensive Phase Following Glaucoma Drainage Device Procedure: A Randomized Prospective Trial. J Glaucoma. 2016;25:248–57.
Liu Y, Ko JA, Yanai R, Kimura K, Chikama T, Sagara T, et al. Induction by latanoprost of collagen gel contraction mediated by human tenon fibroblasts: role of intracellular signaling molecules. Invest Ophthalmol Vis Sci. 2008;49:1429–36.
Jung KI, Woo JE, Park CK. Effects of aqueous suppressants and prostaglandin analogues on early wound healing after glaucoma implant surgery. Sci Rep. 2019;9:5251.
Than JYL, Al-Mugheiry TS, Gale J, Martin KR. Factors predicting the success of trabeculectomy bleb enhancement with needling. Br J Ophthalmol. 2018;102:1667–71.
Siriwardena D, Kotecha A, Minassian D, Dart JK, Khaw PT. Anterior chamber flare after trabeculectomy and after phacoemulsification. Br J Ophthalmol. 2000;84:1056–7.
Husain R, Liang S, Foster PJ, Gazzard G, Bunce C, Chew PT, et al. Cataract surgery after trabeculectomy: the effect on trabeculectomy function. Arch Ophthalmol. 2012;130:165–70.
Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, et al. Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell Stem Cell. 2016;18:797–808.
Acknowledgements
The authors would like to acknowledge the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, Moorfields Eye Charity, the Michael and Ilse Katz Foundation, the Helen Hamlyn Trust, John Nolan and Fight for Sight (UK). PTK received the medal honouring Peter Watson at the XLIX Cambridge Ophthalmological Symposium in 2019.
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PTK is a consultant to Aerie Pharmaceuticals, Glaukos, Novartis, Santen, Thea. PTK and SB are founders and shareholders of Optceutics Ltd. PTK is a founder, director and shareholder of Radiance Therapeutics.YB is a consultant to Optceutics Ltd.
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Khaw, P.T., Bouremel, Y., Brocchini, S. et al. The control of conjunctival fibrosis as a paradigm for the prevention of ocular fibrosis-related blindness. “Fibrosis has many friends”. Eye 34, 2163–2174 (2020). https://doi.org/10.1038/s41433-020-1031-9
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DOI: https://doi.org/10.1038/s41433-020-1031-9
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