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Modulation of Fibroblasts in Conjunctival Wound Healing

  • Mark Zada
    Correspondence
    Correspondence: Mark Zada, BMedSci (Hons I), MBBS, Glaucoma Cell Biology Group, The Westmead Institute for Medical Research, Department of Ophthalmology, Westmead Hospital, Westmead 2145, Australia.
    Affiliations
    Glaucoma Cell Biology Group, The Westmead Institute for Medical Research, NSW, Australia

    Discipline of Ophthalmology, Sydney Medical School, University of Sydney, NSW, Australia
    Search for articles by this author
  • Ushasree Pattamatta
    Affiliations
    Glaucoma Cell Biology Group, The Westmead Institute for Medical Research, NSW, Australia

    Discipline of Ophthalmology, Sydney Medical School, University of Sydney, NSW, Australia
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  • Andrew White
    Affiliations
    Glaucoma Cell Biology Group, The Westmead Institute for Medical Research, NSW, Australia

    Discipline of Ophthalmology, Sydney Medical School, University of Sydney, NSW, Australia

    Save Sight Institute, University of Sydney, NSW, Australia
    Search for articles by this author
Published:October 24, 2017DOI:https://doi.org/10.1016/j.ophtha.2017.08.028
      Modulating conjunctival wound healing has the potential to improve outcomes after glaucoma filtration surgery and for several ocular disorders, including ocular cicatrial pemphigoid, vernal keratoconjunctivitis, and pterygium. Although anti-inflammatories and antimetabolites have been used with success, these nonspecific agents are not without their complications. The search for novel and more targeted means to control conjunctival fibrosis without such limitations has brought much attention to the regulation of fibroblast proliferation, differentiation, extracellular matrix production, and apoptosis. This review provides an update on where we stand with current antifibrotic agents and outlines the strategies that novel agents use, as they evolve from the bench to the bedside.

      Abbreviations and Acronyms:

      CTGF (connective tissue growth factor), ECM (extracellular matrix), 5-FU (5 fluorouracil), GFS (glaucoma filtration surgery), MMC (mitomycin C), MMP (matrix metalloproteinase), OCP (ocular cicatrial pemphigoid), PI3K (phosphoinositide 3-kinase), SPARC (secreted protein acidic and rich in cysteine), TGF-β (transforming growth factor β), TIMP (tissue inhibitor of matrix metalloproteinase), VEGF (vascular endothelial growth factor), VKC (vernal keratoconjunctivitis)
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      References

        • Friedlander M.
        Fibrosis and diseases of the eye.
        J Clin Invest. 2007; 117: 576-586
        • Quigley H.A.
        • Broman A.T.
        The number of people with glaucoma worldwide in 2010 and 2020.
        Br J Ophthalmol. 2006; 90: 262-267
        • Roat M.I.
        • Sossi G.
        • Lo C.Y.
        • Thoft R.A.
        Hyperproliferation of conjunctival fibroblasts from patients with cicatricial pemphigoid.
        Arch Ophthalmol. 1989; 107: 1064-1067
        • Razzaque M.S.
        • Foster C.S.
        • Ahmed A.R.
        Role of collagen-binding heat shock protein 47 and transforming growth factor-beta1 in conjunctival scarring in ocular cicatricial pemphigoid.
        Invest Ophthalmol Vis Sci. 2003; 44: 1616-1621
        • Kirzhner M.
        • Jakobiec F.A.
        Ocular cicatricial pemphigoid: a review of clinical features, immunopathology, differential diagnosis, and current management.
        Semin Ophthalmol. 2011; 26: 270-277
        • De Smedt S.
        • Wildner G.
        • Kestelyn P.
        Vernal keratoconjunctivitis: an update.
        Br J Ophthalmol. 2013; 97: 9-14
        • Kim K.W.
        • Park S.H.
        • Kim J.C.
        Fibroblast biology in pterygia.
        Exp Eye Res. 2016; 142: 32-39
        • Saw V.P.
        • Schmidt E.
        • Offiah I.
        • et al.
        Profibrotic phenotype of conjunctival fibroblasts from mucous membrane pemphigoid.
        Am J Pathol. 2011; 178: 187-197
        • Seibold L.K.
        • Sherwood M.B.
        • Kahook M.Y.
        Wound modulation after filtration surgery.
        Surv Ophthalmol. 2012; 57: 530-550
        • Yamanaka O.
        • Kitano-Izutani A.
        • Tomoyose K.
        • Reinach P.S.
        Pathobiology of wound healing after glaucoma filtration surgery.
        BMC Ophthalmol. 2015; 15: 157
        • Razzaque M.S.
        • Ahmed B.S.
        • Foster C.S.
        • Ahmed A.R.
        Effects of IL-4 on conjunctival fibroblasts: possible role in ocular cicatricial pemphigoid.
        Invest Ophthalmol Vis Sci. 2003; 44: 3417-3423
        • Saw V.P.
        • Dart R.J.
        • Galatowicz G.
        • et al.
        Tumor necrosis factor-alpha in ocular mucous membrane pemphigoid and its effect on conjunctival fibroblasts.
        Invest Ophthalmol Vis Sci. 2009; 50: 5310-5317
        • Saw V.P.
        • Offiah I.
        • Dart R.J.
        • et al.
        Conjunctival interleukin-13 expression in mucous membrane pemphigoid and functional effects of interleukin-13 on conjunctival fibroblasts in vitro.
        Am J Pathol. 2009; 175: 2406-2415
        • Leonardi A.
        • Borghesan F.
        • DePaoli M.
        • et al.
        Procollagens and inflammatory cytokine concentrations in tarsal and limbal vernal keratoconjunctivitis.
        Exp Eye Res. 1998; 67: 105-112
        • Leonardi A.
        • Curnow S.J.
        • Zhan H.
        • Calder V.L.
        Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast cultures.
        Clin Exp Allergy. 2006; 36: 777-784
        • Fukagawa K.
        • Okada N.
        • Fujishima H.
        • et al.
        Corneal and conjunctival fibroblasts are major sources of eosinophil-recruiting chemokines.
        Allergol Int. 2009; 58: 499-508
        • Leonardi A.
        • Jose P.J.
        • Zhan H.
        • Calder V.L.
        Tear and mucus eotaxin-1 and eotaxin-2 in allergic keratoconjunctivitis.
        Ophthalmology. 2003; 110: 487-492
        • Fujitsu Y.
        • Fukuda K.
        • Kumagai N.
        • Nishida T.
        IL-4-induced cell proliferation and production of extracellular matrix proteins in human conjunctival fibroblasts.
        Exp Eye Res. 2003; 76: 107-114
        • Leonardi A.
        • Radice M.
        • Fregona I.A.
        • et al.
        Histamine effects on conjunctival fibroblasts from patients with vernal conjunctivitis.
        Exp Eye Res. 1999; 68: 739-746
        • Leonardi A.
        • DeFranchis G.
        • De Paoli M.
        • et al.
        Histamine-induced cytokine production and ICAM-1 expression in human conjunctival fibroblasts.
        Curr Eye Res. 2002; 25: 189-196
        • Knorr M.
        • Volker M.
        • Denk P.O.
        • et al.
        Proliferative response of cultured human tenon's capsule fibroblasts to platelet-derived growth factor isoforms.
        Graefes Arch Clin Exp Ophthalmol. 1997; 235: 667-671
        • Denk P.O.
        • Hoppe J.
        • Hoppe V.
        • Knorr M.
        Effect of growth factors on the activation of human Tenon's capsule fibroblasts.
        Curr Eye Res. 2003; 27: 35-44
        • Leonardi A.
        • Cortivo R.
        • Fregona I.
        • et al.
        Effects of Th2 cytokines on expression of collagen, MMP-1, and TIMP-1 in conjunctival fibroblasts.
        Invest Ophthalmol Vis Sci. 2003; 44: 183-189
        • Viveiros M.M.
        • Kitakawa D.
        • Carvalho C.S.
        • et al.
        [Exposure of recurrent pterygium and normal Tenon's capsule fibroblasts to triamcinolone].
        Arq Bras Oftalmol. 2012; 75: 235-238
        • Frantz A.
        • Becker J.
        [Establishing human, conjunctival fibroblast cultures as a test system for evaluating ophthalmic drugs].
        Klin Monbl Augenheilkd. 1996; 208: 181-187
        • Damji K.F.
        • Rootman J.
        • Palcic B.
        • Thurston G.
        Pharmacological modulation of human subconjunctival fibroblast behavior in vitro.
        Ophthalmic Surg. 1990; 21: 31-43
        • Nguyen K.D.
        • Lee D.A.
        Effect of steroids and nonsteroidal anti-inflammatory agents on human ocular fibroblast.
        Invest Ophthalmol Vis Sci. 1992; 33: 2693-2701
        • Sun R.
        • Gimbel H.V.
        • Liu S.
        • et al.
        Effect of diclofenac sodium and dexamethasone on cultured human Tenon's capsule fibroblasts.
        Ophthalmic Surg Lasers. 1999; 30: 382-388
        • Xu D.D.
        • Li R.M.
        • Lian L.
        • Liu X.P.
        [Modulation of cell proliferation and collagen synthesis of porcine Tenon's fibroblasts by extracts of lens and vitreous with treatment of dexamethasone].
        Zhonghua Yan Ke Za Zhi. 2005; 41: 443-448
        • Hida R.Y.
        • Takano Y.
        • Okada N.
        • et al.
        Suppressive effects of tranilast on eotaxin-1 production from cultured conjunctival fibroblasts.
        Curr Eye Res. 2008; 33: 19-22
        • Giangiacomo J.
        • Dueker D.K.
        • Adelstein E.
        The effect of preoperative subconjunctival triamcinolone administration on glaucoma filtration. I. Trabeculectomy following subconjunctival triamcinolone.
        Arch Ophthalmol. 1986; 104: 838-841
        • Giangiacomo J.
        • Dueker D.K.
        • Adelstein E.H.
        Histopathology of triamcinolone in the subconjunctiva.
        Ophthalmology. 1987; 94: 149-153
        • Yuki K.
        • Shiba D.
        • Kimura I.
        • et al.
        Trabeculectomy with or without intraoperative sub-tenon injection of triamcinolone acetonide in treating secondary glaucoma.
        Am J Ophthalmol. 2009; 147 (1060.e1-1060.e2): 1055-1060
        • Kahook M.Y.
        • Camejo L.
        • Noecker R.J.
        Trabeculectomy with intraoperative retrobulbar triamcinolone acetonide.
        Clin Ophthalmol. 2009; 3: 29-31
        • Araujo S.V.
        • Spaeth G.L.
        • Roth S.M.
        • Starita R.J.
        A ten-year follow-up on a prospective, randomized trial of postoperative corticosteroids after trabeculectomy.
        Ophthalmology. 1995; 102: 1753-1759
        • Starita R.J.
        • Fellman R.L.
        • Spaeth G.L.
        • et al.
        Short- and long-term effects of postoperative corticosteroids on trabeculectomy.
        Ophthalmology. 1985; 92: 938-946
        • Breusegem C.
        • Spielberg L.
        • Van Ginderdeuren R.
        • et al.
        Preoperative nonsteroidal anti-inflammatory drug or steroid and outcomes after trabeculectomy: a randomized controlled trial.
        Ophthalmology. 2010; 117: 1324-1330
        • Loftfield K.
        • Ball S.F.
        Filtering bleb encapsulation increased by steroid injection.
        Ophthalmic Surg. 1990; 21: 282-287
        • SooHoo J.R.
        • Seibold L.K.
        • Laing A.E.
        • Kahook M.Y.
        Bleb morphology and histology in a rabbit model of glaucoma filtration surgery using Ozurdex(R) or mitomycin-C.
        Mol Vis. 2012; 18: 714-719
        • Nguyen K.D.
        • Lee D.A.
        In vitro evaluation of antiproliferative potential of topical cyclooxygenase inhibitors in human Tenon's fibroblasts.
        Exp Eye Res. 1993; 57: 97-105
        • Kent A.R.
        • Dubiner H.B.
        • Whitaker R.
        • et al.
        The efficacy and safety of diclofenac 0.1% versus prednisolone acetate 1% following trabeculectomy with adjunctive mitomycin-C.
        Ophthalmic Surg Lasers. 1998; 29: 562-569
        • Lama P.J.
        • Fechtner R.D.
        Antifibrotics and wound healing in glaucoma surgery.
        Surv Ophthalmol. 2003; 48: 314-346
        • Heuer D.K.
        • Parrish 2nd, R.K.
        • Gressel M.G.
        • et al.
        5-Fluorouracil and glaucoma filtering surgery. III. Intermediate follow-up of a pilot study.
        Ophthalmology. 1986; 93: 1537-1546
        • Kwong E.M.
        • Litin B.S.
        • Jones M.A.
        • Herschler J.
        Effect of antineoplastic drugs on fibroblast proliferation in rabbit aqueous humor.
        Ophthalmic Surg. 1984; 15: 847-851
        • Litin B.S.
        • Kwong E.M.
        • Jones M.A.
        • Herschler J.
        Effect of antineoplastic drugs on cell proliferation–individually and in combination.
        Ophthalmic Surg. 1985; 16: 34-39
        • Mallick K.S.
        • Hajek A.S.
        • Parrish 2nd, R.K.
        Fluorouracil (5-FU) and cytarabine (ara-C) inhibition of corneal epithelial cell and conjunctival fibroblast proliferation.
        Arch Ophthalmol. 1985; 103: 1398-1402
        • Lee D.A.
        • Shapourifar-Tehrani S.
        • Kitada S.
        The effect of 5-fluorouracil and cytarabine on human fibroblasts from Tenon's capsule.
        Invest Ophthalmol Vis Sci. 1990; 31: 1848-1855
        • Wong V.K.
        • Shapourifar-Tehrani S.
        • Kitada S.
        • et al.
        Inhibition of rabbit ocular fibroblast proliferation by 5-fluorouracil and cytosine arabinoside.
        J Ocul Pharmacol. 1991; 7: 27-39
        • Yamamoto T.
        • Varani J.
        • Soong H.K.
        • Lichter P.R.
        Effects of 5-fluorouracil and mitomycin C on cultured rabbit subconjunctival fibroblasts.
        Ophthalmology. 1990; 97: 1204-1210
        • Na J.H.
        • Sung K.R.
        • Shin J.A.
        • Moon J.I.
        Antifibrotic effects of pirfenidone on Tenon's fibroblasts in glaucomatous eyes: comparison with mitomycin C and 5-fluorouracil.
        Graefes Arch Clin Exp Ophthalmol. 2015; 253: 1537-1545
        • Gross R.L.
        Collagen type I and III synthesis by Tenon's capsule fibroblasts in culture: individual patient characteristics and response to mitomycin C, 5-fluorouracil, and ascorbic acid.
        Trans Am Ophthalmol Soc. 1999; 97: 513-543
        • Crowston J.G.
        • Akbar A.N.
        • Constable P.H.
        • et al.
        Antimetabolite-induced apoptosis in Tenon's capsule fibroblasts.
        Invest Ophthalmol Vis Sci. 1998; 39: 449-454
      1. Three-year follow-up of the Fluorouracil Filtering Surgery Study.
        Am J Ophthalmol. 1993; 115: 82-92
        • Ariturk N.
        • Oge I.
        • Baris S.
        • et al.
        The effects of antiglaucomatous agents on conjunctiva used for various durations.
        Int Ophthalmol. 1996; 20: 57-62
        • Goldenfeld M.
        • Krupin T.
        • Ruderman J.M.
        • et al.
        5-Fluorouracil in initial trabeculectomy. A prospective, randomized, multicenter study.
        Ophthalmology. 1994; 101: 1024-1029
        • Dietze P.J.
        • Feldman R.M.
        • Gross R.L.
        Intraoperative application of 5-fluorouracil during trabeculectomy.
        Ophthalmic Surg. 1992; 23: 662-665
        • Smith M.F.
        • Sherwood M.B.
        • Doyle J.W.
        • Khaw P.T.
        Results of intraoperative 5-fluorouracil supplementation on trabeculectomy for open-angle glaucoma.
        Am J Ophthalmol. 1992; 114: 737-741
        • Wong T.T.
        • Khaw P.T.
        • Aung T.
        • et al.
        The Singapore 5-Fluorouracil trabeculectomy study: effects on intraocular pressure control and disease progression at 3 years.
        Ophthalmology. 2009; 116: 175-184
        • Egbert P.R.
        • Williams A.S.
        • Singh K.
        • et al.
        A prospective trial of intraoperative fluorouracil during trabeculectomy in a black population.
        Am J Ophthalmol. 1993; 116: 612-616
        • Mielke C.
        • Dawda V.K.
        • Anand N.
        Intraoperative 5-fluorouracil application during primary trabeculectomy in Nigeria: a comparative study.
        Eye (Lond). 2003; 17: 829-834
        • Green E.
        • Wilkins M.
        • Bunce C.
        • Wormald R.
        5-Fluorouracil for glaucoma surgery.
        Cochrane Database Syst Rev. 2014; : CD001132
        • Lee D.A.
        • Lee T.C.
        • Cortes A.E.
        • Kitada S.
        Effects of mithramycin, mitomycin, daunorubicin, and bleomycin on human subconjunctival fibroblast attachment and proliferation.
        Invest Ophthalmol Vis Sci. 1990; 31: 2136-2144
        • Saika S.
        • Ooshima A.
        • Yamanaka O.
        • et al.
        In vitro effects of doxorubicin and mitomycin C on human Tenon's capsule fibroblasts.
        Ophthalmic Res. 1997; 29: 91-102
        • Kim J.W.
        • Kim S.K.
        • Song I.H.
        • Kim I.T.
        Mitomycin C-induced apoptosis in cultured human Tenon's capsule fibroblasts.
        Korean J Ophthalmol. 1999; 13: 7-15
        • Seong G.J.
        • Park C.
        • Kim C.Y.
        • et al.
        Mitomycin-C induces the apoptosis of human Tenon's capsule fibroblast by activation of c-Jun N-terminal kinase 1 and caspase-3 protease.
        Invest Ophthalmol Vis Sci. 2005; 46: 3545-3552
        • Tappeiner C.
        • Meyenberg A.
        • Goldblum D.
        • et al.
        Antifibrotic effects of tocotrienols on human Tenon's fibroblasts.
        Graefes Arch Clin Exp Ophthalmol. 2010; 248: 65-71
        • Jampel H.D.
        Effect of brief exposure to mitomycin C on viability and proliferation of cultured human Tenon's capsule fibroblasts.
        Ophthalmology. 1992; 99: 1471-1476
        • Chen C.W.
        • Huang H.T.
        • Bair J.S.
        • Lee C.C.
        Trabeculectomy with simultaneous topical application of mitomycin-C in refractory glaucoma.
        J Ocul Pharmacol. 1990; 6: 175-182
        • Cohen J.S.
        • Greff L.J.
        • Novack G.D.
        • Wind B.E.
        A placebo-controlled, double-masked evaluation of mitomycin C in combined glaucoma and cataract procedures.
        Ophthalmology. 1996; 103: 1934-1942
        • Carlson D.W.
        • Alward W.L.
        • Barad J.P.
        • et al.
        A randomized study of mitomycin augmentation in combined phacoemulsification and trabeculectomy.
        Ophthalmology. 1997; 104: 719-724
        • Shin D.H.
        • Ren J.
        • Juzych M.S.
        • et al.
        Primary glaucoma triple procedure in patients with primary open-angle glaucoma: the effect of mitomycin C in patients with and without prognostic factors for filtration failure.
        Am J Ophthalmol. 1998; 125: 346-352
        • Rao A.
        • Chatterjee S.
        Epiconjunctival mitomycin-C application for early failing filtering blebs.
        Semin Ophthalmol. 2014; 29: 48-51
        • Xie Q.
        • Mo X.J.
        • Jiang Y.Q.
        [Study of intraoperative mitomycin C in preventing recurrence after pterygium surgery].
        Hunan Yi Ke Da Xue Xue Bao. 2001; 26: 347-349
        • Sharma A.
        • Gupta A.
        • Ram J.
        • Gupta A.
        Low-dose intraoperative mitomycin-C versus conjunctival autograft in primary pterygium surgery: long term follow-up.
        Ophthalmic Surg Lasers. 2000; 31: 301-307
        • Donnenfeld E.D.
        • Perry H.D.
        • Fromer S.
        • et al.
        Subconjunctival mitomycin C as adjunctive therapy before pterygium excision.
        Ophthalmology. 2003; 110: 1012-1016
        • Chang Y.S.
        • Chen W.C.
        • Tseng S.H.
        • et al.
        Subconjunctival mitomycin C before pterygium excision: an ultrastructural study.
        Cornea. 2008; 27: 471-475
        • Katz G.J.
        • Higginbotham E.J.
        • Lichter P.R.
        • et al.
        Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Extended follow-up.
        Ophthalmology. 1995; 102: 1263-1269
        • Lamping K.A.
        • Belkin J.K.
        5-Fluorouracil and mitomycin C in pseudophakic patients.
        Ophthalmology. 1995; 102: 70-75
        • Palanca-Capistrano A.M.
        • Hall J.
        • Cantor L.B.
        • et al.
        Long-term outcomes of intraoperative 5-fluorouracil versus intraoperative mitomycin C in primary trabeculectomy surgery.
        Ophthalmology. 2009; 116: 185-190
        • Cabourne E.
        • Clarke J.C.
        • Schlottmann P.G.
        • Evans J.R.
        Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery.
        Cochrane Database Syst Rev. 2015; : CD006259
        • Ophir A.
        • Ticho U.
        Toxic effects of 5-fluorouracil on fibroblasts following trabeculectomy.
        Ophthalmic Res. 1992; 24: 298-302
        • Khaw P.T.
        • Ward S.
        • Porter A.
        • et al.
        The long-term effects of 5-fluorouracil and sodium butyrate on human Tenon's fibroblasts.
        Invest Ophthalmol Vis Sci. 1992; 33: 2043-2052
        • Gressel M.G.
        • Parrish 2nd, R.K.
        • Folberg R.
        5-fluorouracil and glaucoma filtering surgery: I. An animal model.
        Ophthalmology. 1984; 91: 378-383
        • Heuer D.K.
        • Parrish 2nd, R.K.
        • Gressel M.G.
        • et al.
        5-fluorouracil and glaucoma filtering surgery. II. A pilot study.
        Ophthalmology. 1984; 91: 384-394
        • Araie M.
        • Shoji N.
        • Shirato S.
        • Nakano Y.
        Postoperative subconjunctival 5-fluorouracil injections and success probability of trabeculectomy in Japanese: results of 5-year follow-up.
        Jpn J Ophthalmol. 1992; 36: 158-168
        • Shapiro M.S.
        • Thoft R.A.
        • Friend J.
        • et al.
        5-Fluorouracil toxicity to the ocular surface epithelium.
        Invest Ophthalmol Vis Sci. 1985; 26: 580-583
        • Khaw P.T.
        • Sherwood M.B.
        • MacKay S.L.
        • et al.
        Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon's capsule fibroblasts.
        Arch Ophthalmol. 1992; 110: 1150-1154
        • Anand N.
        • Arora S.
        • Clowes M.
        Mitomycin C augmented glaucoma surgery: evolution of filtering bleb avascularity, transconjunctival oozing, and leaks.
        Br J Ophthalmol. 2006; 90: 175-180
        • Zhivov A.
        • Beck R.
        • Guthoff R.F.
        Corneal and conjunctival findings after mitomycin C application in pterygium surgery: an in-vivo confocal microscopy study.
        Acta Ophthalmol. 2009; 87: 166-172
        • Zacharia P.T.
        • Deppermann S.R.
        • Schuman J.S.
        Ocular hypotony after trabeculectomy with mitomycin C.
        Am J Ophthalmol. 1993; 116: 314-326
        • Van Bergen T.
        • Vandewalle E.
        • Van de Veire S.
        • et al.
        The role of different VEGF isoforms in scar formation after glaucoma filtration surgery.
        Exp Eye Res. 2011; 93: 689-699
        • Cheng G.W.
        • Zhao J.L.
        • Ma J.M.
        [Expressions of vascular endothelial growth factor and its receptors in rat conjunctival fibroblasts].
        Zhonghua Yan Ke Za Zhi. 2012; 48: 513-518
        • Asano-Kato N.
        • Fukagawa K.
        • Okada N.
        • et al.
        TGF-beta1, IL-1beta, and Th2 cytokines stimulate vascular endothelial growth factor production from conjunctival fibroblasts.
        Exp Eye Res. 2005; 80: 555-560
        • Li Z.
        • Van Bergen T.
        • Van de Veire S.
        • et al.
        Inhibition of vascular endothelial growth factor reduces scar formation after glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2009; 50: 5217-5225
        • Park H.Y.
        • Kim J.H.
        • Park C.K.
        VEGF induces TGF-beta1 expression and myofibroblast transformation after glaucoma surgery.
        Am J Pathol. 2013; 182: 2147-2154
        • O'Neill E.C.
        • Qin Q.
        • Van Bergen N.J.
        • et al.
        Antifibrotic activity of bevacizumab on human Tenon's fibroblasts in vitro.
        Invest Ophthalmol Vis Sci. 2010; 51: 6524-6532
        • Liu W.
        • Sha X.
        • Wen Y.
        • et al.
        Effect of Avastin on the migration and invasion of pterygium fibroblasts.
        Eye Sci. 2014; 29: 214-218
        • Memarzadeh F.
        • Varma R.
        • Lin L.T.
        • et al.
        Postoperative use of bevacizumab as an antifibrotic agent in glaucoma filtration surgery in the rabbit.
        Invest Ophthalmol Vis Sci. 2009; 50: 3233-3237
        • Kahook M.Y.
        • Schuman J.S.
        • Noecker R.J.
        Needle bleb revision of encapsulated filtering bleb with bevacizumab.
        Ophthalmic Surg Lasers Imaging. 2006; 37: 148-150
        • Kitnarong N.
        • Chindasub P.
        • Metheetrairut A.
        Surgical outcome of intravitreal bevacizumab and filtration surgery in neovascular glaucoma.
        Adv Ther. 2008; 25: 438-443
        • Cornish K.S.
        • Ramamurthi S.
        • Saidkasimova S.
        • Ramaesh K.
        Intravitreal bevacizumab and augmented trabeculectomy for neovascular glaucoma in young diabetic patients.
        Eye (Lond). 2009; 23: 979-981
        • Grewal D.S.
        • Jain R.
        • Kumar H.
        • Grewal S.P.
        Evaluation of subconjunctival bevacizumab as an adjunct to trabeculectomy a pilot study.
        Ophthalmology. 2008; 115: 2141-2145.e2
        • Sedghipour M.R.
        • Mostafaei A.
        • Taghavi Y.
        Low-dose subconjunctival bevacizumab to augment trabeculectomy for glaucoma.
        Clin Ophthalmol. 2011; 5: 797-800
        • Chua B.E.
        • Nguyen D.Q.
        • Qin Q.
        • et al.
        Bleb vascularity following post-trabeculectomy subconjunctival bevacizumab: a pilot study.
        Clin Exp Ophthalmol. 2012; 40: 773-779
        • Sengupta S.
        • Venkatesh R.
        • Ravindran R.D.
        Safety and efficacy of using off-label bevacizumab versus mitomycin C to prevent bleb failure in a single-site phacotrabeculectomy by a randomized controlled clinical trial.
        J Glaucoma. 2012; 21: 450-459
        • Noh S.M.
        • Abdul Kadir S.H.
        • Bannur Z.M.
        • et al.
        Effects of ranibizumab on the extracellular matrix production by human Tenon's fibroblast.
        Exp Eye Res. 2014; 127: 236-242
        • Kahook M.Y.
        Bleb morphology and vascularity after trabeculectomy with intravitreal ranibizumab: a pilot study.
        Am J Ophthalmol. 2010; 150: 399-403.e1
        • Bochmann F.
        • Kaufmann C.
        • Becht C.N.
        • et al.
        ISRCTN12125882-Influence of topical anti-VEGF (Ranibizumab) on the outcome of filtration surgery for glaucoma - Study Protocol.
        BMC Ophthalmol. 2011; 11: 1
        • Cheng J.W.
        • Cheng S.W.
        • Wei R.L.
        • Lu G.C.
        Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery.
        Cochrane Database Syst Rev. 2016; : CD009782
        • Banifatemi M.
        • Razeghinejad M.R.
        • Hosseini H.
        • Gholampour A.
        Bevacizumab and ocular wound healing after primary pterygium excision.
        J Ocul Pharmacol Ther. 2011; 27: 17-21
        • Li D.Q.
        • Lee S.B.
        • Tseng S.C.
        Differential expression and regulation of TGF-beta1, TGF-beta2, TGF-beta3, TGF-betaRI, TGF-betaRII and TGF-betaRIII in cultured human corneal, limbal, and conjunctival fibroblasts.
        Curr Eye Res. 1999; 19: 154-161
        • Denk P.O.
        • Roth-Eichhorn S.
        • Gressner A.M.
        • Knorr M.
        Effect of cytokines on regulation of the production of transforming growth factor beta-1 in cultured human Tenon's capsule fibroblasts.
        Eur J Ophthalmol. 2000; 10: 110-115
        • Pasquale L.R.
        • Dorman-Pease M.E.
        • Lutty G.A.
        • et al.
        Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye.
        Invest Ophthalmol Vis Sci. 1993; 34: 23-30
        • Bernauer W.
        • Wright P.
        • Dart J.K.
        • et al.
        The conjunctiva in acute and chronic mucous membrane pemphigoid. An immunohistochemical analysis.
        Ophthalmology. 1993; 100: 339-346
        • Mietz H.
        • Chevez-Barrios P.
        • Lieberman M.W.
        A mouse model to study the wound healing response following filtration surgery.
        Graefes Arch Clin Exp Ophthalmol. 1998; 236: 467-475
        • Saika S.
        • Yamanaka O.
        • Baba Y.
        • et al.
        Accumulation of latent transforming growth factor-beta binding protein-1 and TGF beta 1 in extracellular matrix of filtering bleb and of cultured human subconjunctival fibroblasts.
        Graefes Arch Clin Exp Ophthalmol. 2001; 239: 234-241
        • Meyer-Ter-Vehn T.
        • Grehn F.
        • Schlunck G.
        Localization of TGF-beta type II receptor and ED-A fibronectin in normal conjunctiva and failed filtering blebs.
        Mol Vis. 2008; 14: 136-141
        • Cunliffe I.A.
        • Rees R.C.
        • Rennie I.G.
        The effect of TGF-beta 1 and TGF-beta 2 on the proliferation of human Tenon's capsule fibroblasts in tissue culture.
        Acta Ophthalmol Scand. 1996; 74: 31-35
        • Browning A.C.
        • Alibhai A.
        • McIntosh R.S.
        • et al.
        Effect of diabetes mellitus and hyperglycemia on the proliferation of human Tenon's capsule fibroblasts: implications for wound healing after glaucoma drainage surgery.
        Wound Repair Regen. 2005; 13: 295-302
        • Kay E.P.
        • Lee H.K.
        • Park K.S.
        • Lee S.C.
        Indirect mitogenic effect of transforming growth factor-beta on cell proliferation of subconjunctival fibroblasts.
        Invest Ophthalmol Vis Sci. 1998; 39: 481-486
        • Cordeiro M.F.
        • Bhattacharya S.S.
        • Schultz G.S.
        • Khaw P.T.
        TGF-beta1, -beta2, and -beta3 in vitro: biphasic effects on Tenon's fibroblast contraction, proliferation, and migration.
        Invest Ophthalmol Vis Sci. 2000; 41: 756-763
        • Seong G.J.
        • Hong S.
        • Jung S.A.
        • et al.
        TGF-beta-induced interleukin-6 participates in transdifferentiation of human Tenon's fibroblasts to myofibroblasts.
        Mol Vis. 2009; 15: 2123-2128
        • Kottler U.B.
        • Junemann A.G.
        • Aigner T.
        • et al.
        Comparative effects of TGF-beta 1 and TGF-beta 2 on extracellular matrix production, proliferation, migration, and collagen contraction of human Tenon's capsule fibroblasts in pseudoexfoliation and primary open-angle glaucoma.
        Exp Eye Res. 2005; 80: 121-134
        • Cordeiro M.F.
        • Reichel M.B.
        • Gay J.A.
        • et al.
        Transforming growth factor-beta1, -beta2, and -beta3 in vivo: effects on normal and mitomycin C-modulated conjunctival scarring.
        Invest Ophthalmol Vis Sci. 1999; 40: 1975-1982
        • Cordeiro M.F.
        • Gay J.A.
        • Khaw P.T.
        Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent.
        Invest Ophthalmol Vis Sci. 1999; 40: 2225-2234
        • Siriwardena D.
        • Khaw P.T.
        • King A.J.
        • et al.
        Human antitransforming growth factor beta(2) monoclonal antibody–a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study.
        Ophthalmology. 2002; 109: 427-431
        • Khaw P.
        • Grehn F.
        • Hollo G.
        • 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: 1822-1830
        • Zhu X.
        • Li L.
        • Zou L.
        • et al.
        A novel aptamer targeting TGF-beta receptor II inhibits transdifferentiation of human tenon's fibroblasts into myofibroblast.
        Invest Ophthalmol Vis Sci. 2012; 53: 6897-9603
        • Zhu X.
        • Xu D.
        • Zhu X.
        • et al.
        Evaluation of Chitosan/aptamer targeting TGF-beta receptor ii thermo-sensitive gel for scarring in rat glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2015; 56: 5465-5476
        • Mietz H.
        • Chevez-Barrios P.
        • Lieberman M.W.
        • et al.
        Decorin and suramin inhibit ocular fibroblast collagen production.
        Graefes Arch Clin Exp Ophthalmol. 1997; 235: 399-403
        • Grisanti S.
        • Szurman P.
        • Warga M.
        • et al.
        Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study.
        Invest Ophthalmol Vis Sci. 2005; 46: 191-196
        • Akman A.
        • Bilezikci B.
        • Kucukerdonmez C.
        • et al.
        Suramin modulates wound healing of rabbit conjunctiva after trabeculectomy: comparison with mitomycin C.
        Curr Eye Res. 2003; 26: 37-43
        • Mietz H.
        • Krieglstein G.K.
        Suramin to enhance glaucoma filtering procedures: a clinical comparison with mitomycin.
        Ophthalmic Surg Lasers. 2001; 32: 358-369
        • Razzaque M.S.
        • Foster C.S.
        • Ahmed A.R.
        Role of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid.
        Invest Ophthalmol Vis Sci. 2003; 44: 1998-2003
        • Gressner O.A.
        • Gressner A.M.
        Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases.
        Liver Int. 2008; 28: 1065-1079
        • Yuan H.P.
        • Li X.H.
        • Yang B.B.
        • et al.
        [Expression of connective tissue growth factor after trabeculectomy in rabbits].
        Zhonghua Yan Ke Za Zhi. 2009; 45: 168-174
        • Zhang J.Y.
        • Gao P.
        • Ye W.
        • Xiao Y.Q.
        Functional characteristics of connective tissue growth factor on human tenon's capsule fibroblast.
        Curr Eye Res. 2014; 39: 53-61
        • Blalock T.D.
        • Yuan R.
        • Lewin A.S.
        • Schultz G.S.
        Hammerhead ribozyme targeting connective tissue growth factor mRNA blocks transforming growth factor-beta mediated cell proliferation.
        Exp Eye Res. 2004; 78: 1127-1136
        • Yamanaka O.
        • Saika S.
        • Ikeda K.
        • et al.
        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
        • Fuchshofer R.
        • Kottler U.B.
        • Ohlmann A.V.
        • et al.
        SPARC is expressed in scars of the Tenon's capsule and mediates scarring properties of human Tenon's fibroblasts in vitro.
        Mol Vis. 2011; 17: 177-185
        • Seet L.F.
        • Su R.
        • Barathi V.A.
        • et al.
        SPARC deficiency results in improved surgical survival in a novel mouse model of glaucoma filtration surgery.
        PLoS One. 2010; 5: e9415
        • Seet L.F.
        • Su R.
        • Toh L.Z.
        • Wong T.T.
        In vitro analyses of the anti-fibrotic effect of SPARC silencing in human Tenon's fibroblasts: comparisons with mitomycin C.
        J Cell Mol Med. 2012; 16: 1245-1259
        • Yamanaka O.
        • Saika S.
        • Ikeda K.
        • et al.
        Interleukin-7 modulates extracellular matrix production and TGF-beta signaling in cultured human subconjunctival fibroblasts.
        Curr Eye Res. 2006; 31: 491-499
        • Leonardi A.
        • Di Stefano A.
        • Motterle L.
        • et al.
        Transforming growth factor-beta/Smad - signalling pathway and conjunctival remodelling in vernal keratoconjunctivitis.
        Clin Exp Allergy. 2011; 41: 52-60
        • Xiao Y.Q.
        • Liu K.
        • Shen J.F.
        • et al.
        SB-431542 inhibition of scar formation after filtration surgery and its potential mechanism.
        Invest Ophthalmol Vis Sci. 2009; 50: 1698-1706
        • Sapitro J.
        • Dunmire J.J.
        • Scott S.E.
        • et al.
        Suppression of transforming growth factor-beta effects in rabbit subconjunctival fibroblasts by activin receptor-like kinase 5 inhibitor.
        Mol Vis. 2010; 16: 1880-1892
        • Chen J.Y.
        • Sun X.H.
        [Changes of Smad2 and type I collagen expressions on cultured human Tenon's capsule fibroblasts transfected with Smad7 vector].
        Fen Zi Xi Bao Sheng Wu Xue Bao. 2006; 39: 265-270
        • Chen J.Y.
        • Sun X.H.
        [Changes of type I collagen and fibronectin expressions on cultured human Tenon's capsule fibroblasts transfected with Smad 7 vector].
        Zhonghua Yan Ke Za Zhi. 2007; 43: 124-128
        • Yamanaka O.
        • Ikeda K.
        • Saika S.
        • et al.
        Gene transfer of Smad7 modulates injury-induced conjunctival wound healing in mice.
        Mol Vis. 2006; 12: 841-851
        • Yamanaka O.
        • Saika S.
        • Ohnishi Y.
        • et al.
        Inhibition of p38MAP kinase suppresses fibrogenic reaction in conjunctiva in mice.
        Mol Vis. 2007; 13: 1730-1739
        • Luo Y.H.
        • Ouyang P.B.
        • Tian J.
        • et al.
        Rosiglitazone inhibits TGF-beta 1 induced activation of human Tenon fibroblasts via p38 signal pathway.
        PLoS One. 2014; 9: e105796
        • Nassar K.
        • Tura A.
        • Luke J.
        • et al.
        A p38 MAPK inhibitor improves outcome after glaucoma filtration surgery.
        J Glaucoma. 2015; 24: 165-178
        • Ran W.
        • Zhu D.
        • Feng Q.
        TGF-beta2 stimulates Tenon's capsule fibroblast proliferation in patients with glaucoma via suppression of miR-29b expression regulated by Nrf2.
        Int J Clin Exp Pathol. 2015; 8: 4799-4806
        • Li N.
        • Cui J.
        • Duan X.
        • et al.
        Suppression of type I collagen expression by miR-29b via PI3K, Akt, and Sp1 pathway in human Tenon's fibroblasts.
        Invest Ophthalmol Vis Sci. 2012; 53: 1670-1678
        • Yu J.
        • Luo H.
        • Li N.
        • Duan X.
        Suppression of type I collagen expression by miR-29b via PI3K, Akt, and Sp1 pathway, part II: an in vivo investigation.
        Invest Ophthalmol Vis Sci. 2015; 56: 6019-6028
        • Chung E.J.
        • Sohn Y.H.
        • Kwon S.H.
        • et al.
        Lithium chloride inhibits TGF-beta1-induced myofibroblast transdifferentiation via PI3K/Akt pathway in cultured fibroblasts from Tenon's capsule of the human eye.
        Biotechnol Lett. 2014; 36: 1217-1224
        • Hong S.
        • Lee J.B.
        • Iizuka Y.
        • et al.
        The role of focal adhesion kinase in the TGF-beta-induced myofibroblast transdifferentiation of human Tenon's fibroblasts.
        Korean J Ophthalmol. 2012; 26: 45-48
        • Hong S.
        • Park K.
        • Kim J.H.
        • et al.
        Role of heat shock protein 47 in transdifferentiation of human tenon's fibroblasts to myofibroblasts.
        BMC Ophthalmol. 2012; 12: 49
        • Tong J.
        • Fu Y.
        • Xu X.
        • et al.
        TGF-beta1 stimulates human Tenon's capsule fibroblast proliferation by miR-200b and its targeting of p27/kip1 and RND3.
        Invest Ophthalmol Vis Sci. 2014; 55: 2747-2756
        • Sun L.
        • Dong Y.
        • Zhao J.
        • et al.
        The CLC-2 chloride channel modulates ECM synthesis, differentiation, and migration of human conjunctival fibroblasts via the PI3K/Akt signaling pathway.
        Int J Mol Sci. 2016; 17
        • Kawashima Y.
        • Saika S.
        • Yamanaka O.
        • et al.
        Immunolocalization of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human subconjunctival tissues.
        Curr Eye Res. 1998; 17: 445-451
        • Liu C.J.
        • Huang Y.L.
        • Chiu A.W.
        • Ju J.P.
        Transcript expression of matrix metalloproteinases in the conjunctiva following glaucoma filtration surgery in rabbits.
        Ophthalmic Res. 2004; 36: 114-119
        • 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: 2161-2164
        • Nakamura-Shibasaki M.
        • Ko J.A.
        • Takenaka J.
        • et al.
        Matrix metalloproteinase and cytokine expression in Tenon fibroblasts during scar formation after glaucoma filtration or implant surgery in rats.
        Cell Biochem Funct. 2013; 31: 482-488
        • Li D.Q.
        • Lee S.B.
        • Gunja-Smith Z.
        • et al.
        Overexpression of collagenase (MMP-1) and stromelysin (MMP-3) by pterygium head fibroblasts.
        Arch Ophthalmol. 2001; 119: 71-80
        • An M.X.
        • Wu K.L.
        • Lin S.C.
        Detection and comparison of matrix metalloproteinase in primary and recurrent pterygium fibroblasts.
        Int J Ophthalmol. 2011; 4: 353-356
        • Yang S.F.
        • Lin C.Y.
        • Yang P.Y.
        • et al.
        Increased expression of gelatinase (MMP-2 and MMP-9) in pterygia and pterygium fibroblasts with disease progression and activation of protein kinase C.
        Invest Ophthalmol Vis Sci. 2009; 50: 4588-4596
        • Chen Y.H.
        • Sun X.H.
        [Effects of latanoprost eye drops on the proliferation of human Tenon's fibroblasts in tissue culture].
        Zhonghua Yan Ke Za Zhi. 2005; 41: 620-624
        • Mietz H.
        • Esser J.M.
        • Welsandt G.
        • et al.
        Latanoprost stimulates secretion of matrix metalloproteinases in tenon fibroblasts both in vitro and in vivo.
        Invest Ophthalmol Vis Sci. 2003; 44: 5182-5188
        • Daniels J.T.
        • Cambrey A.D.
        • Occleston N.L.
        • et al.
        Matrix metalloproteinase inhibition modulates fibroblast-mediated matrix contraction and collagen production in vitro.
        Invest Ophthalmol Vis Sci. 2003; 44: 1104-1110
        • Wong T.T.
        • Mead A.L.
        • Khaw P.T.
        Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2003; 44: 1097-1103
        • Wong T.T.
        • Mead A.L.
        • Khaw P.T.
        Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2005; 46: 2018-2022
        • Kondo S.
        • Yamamoto M.
        • Takeuchi A.
        • et al.
        [Anti-allergic drugs inhibit the proliferation of human Tenon's capsule fibroblast and maintain the experimental filtering blebs on rabbit eyes].
        Nippon Ganka Gakkai Zasshi. 2002; 106: 325-331
        • Ji C.N.
        • Hu Y.Z.
        • Ding Z.P.
        • Li G.G.
        [The investigation of tranilast on the proliferation and migration of human Tenon's capsule fibroblasts].
        Zhonghua Yan Ke Za Zhi. 2004; 40: 165-169
        • Asaoka R.
        • Nakagamil T.
        • Zhu H.
        • et al.
        The effect of levocabastine hydrochloride on human Tenon's capsule fibroblasts: inhibition of proliferation, suppression of DNA synthesis and induction of apoptosis.
        Cutan Ocul Toxicol. 2009; 28: 83-89
        • Oshima T.
        • Kurosaka D.
        • Kato K.
        • et al.
        Tranilast inhibits cell proliferation and collagen synthesis by rabbit corneal and Tenon's capsule fibroblasts.
        Curr Eye Res. 2000; 20: 283-286
        • Chihara E.
        • Dong J.
        • Ochiai H.
        • Hamada S.
        Effects of tranilast on filtering blebs: a pilot study.
        J Glaucoma. 2002; 11: 127-133
        • Micera A.
        • Stampachiacchiere B.
        • Di Zazzo A.
        • et al.
        NGF modulates trkANGFR/p75NTR in alphaSMA-expressing conjunctival fibroblasts from human ocular cicatricial pemphigoid (OCP).
        PLoS One. 2015; 10: e0142737
        • Wang H.
        • Wang R.
        • Thrimawithana T.
        • et al.
        The nerve growth factor signaling and its potential as therapeutic target for glaucoma.
        Biomed Res Int. 2014; 2014: 759473
        • Micera A.
        • Puxeddu I.
        • Lambiase A.
        • et al.
        The pro-fibrogenic effect of nerve growth factor on conjunctival fibroblasts is mediated by transforming growth factor-beta.
        Clin Exp Allergy. 2005; 35: 650-656
        • Micera A.
        • Lambiase A.
        • Stampachiacchiere B.
        • et al.
        Nerve growth factor has a modulatory role on human primary fibroblast cultures derived from vernal keratoconjunctivitis-affected conjunctiva.
        Mol Vis. 2007; 13: 981-987
        • Micera A.
        • Puxeddu I.
        • Balzamino B.O.
        • et al.
        Chronic nerve growth factor exposure increases apoptosis in a model of in vitro induced conjunctival myofibroblasts.
        PLoS One. 2012; 7: e47316
        • Siak J.J.
        • Ng S.L.
        • Seet L.F.
        • et al.
        The nuclear-factor kappaB pathway is activated in pterygium.
        Invest Ophthalmol Vis Sci. 2011; 52: 230-236
        • Naruse S.
        • Yamada J.
        • Hamuro J.
        • et al.
        APC0576 decreases production of pro-inflammatory chemokine and extracellular matrix by human Tenon's capsule fibroblasts.
        Exp Eye Res. 2004; 79: 223-230
        • Zhou J.
        • Zhong D.W.
        • Wang Q.W.
        • et al.
        Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-beta/Smad activity.
        World J Gastroenterol. 2010; 16: 3330-3334
        • Zhang L.
        • Xu X.
        • Yang R.
        • et al.
        Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling.
        Drug Des Devel Ther. 2015; 9: 2139-2148
        • Koz O.G.
        • Ozhuy S.
        • Tezel G.G.
        • et al.
        The effect of paclitaxel on conjunctival wound healing: a pilot study.
        J Glaucoma. 2007; 16: 610-615
        • Choritz L.
        • Grub J.
        • Wegner M.
        • et al.
        Paclitaxel inhibits growth, migration and collagen production of human Tenon's fibroblasts–potential use in drug-eluting glaucoma drainage devices.
        Graefes Arch Clin Exp Ophthalmol. 2010; 248: 197-206
        • Occhiutto M.L.
        • Freitas F.R.
        • Lima P.P.
        • et al.
        Paclitaxel associated with lipid nanoparticles as a new antiscarring agent in experimental glaucoma surgery.
        Invest Ophthalmol Vis Sci. 2016; 57: 971-978
        • Tang W.
        • Zhang Y.
        • Zhang Q.
        • et al.
        Hydroxycamptothecin-induced apoptotic gene expression profiling by PCR array in human Tenon's capsule fibroblasts.
        Int J Clin Exp Pathol. 2015; 8: 2649-2659
        • Tang W.
        • Zhang Y.
        • Qian C.
        • et al.
        Induction and mechanism of apoptosis by hydroxycamptothecin in human Tenon's capsule fibroblasts.
        Invest Ophthalmol Vis Sci. 2012; 53: 4874-4880
        • Yin X.
        • Sun H.
        • Yu D.
        • et al.
        Hydroxycamptothecin induces apoptosis of human tenon's capsule fibroblasts by activating the PERK signaling pathway.
        Invest Ophthalmol Vis Sci. 2013; 54: 4749-4758
        • Xu X.
        • Fu Y.
        • Tong J.
        • et al.
        MicroRNA-216b/Beclin 1 axis regulates autophagy and apoptosis in human Tenon's capsule fibroblasts upon hydroxycamptothecin exposure.
        Exp Eye Res. 2014; 123: 43-55
        • Musso G.
        • Cassader M.
        • Paschetta E.
        • Gambino R.
        Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis.
        JAMA Intern Med. 2017; 177: 633-640
        • Huxlin K.R.
        • Hindman H.B.
        • Jeon K.I.
        • et al.
        Topical rosiglitazone is an effective anti-scarring agent in the cornea.
        PLoS One. 2013; 8: e70785
        • Zheng K.K.
        • Yu M.B.
        • Jiang R.Z.
        • Li Q.N.
        [Effect of Rosiglitazone on the proliferation and the production of transforming growth factor-beta 1 in cultured human Tenon' s capsule fibroblasts].
        Zhonghua Yan Ke Za Zhi. 2008; 44: 413-417
        • Fan F.
        • Li Y.
        • Duan X.
        • et al.
        Rosiglitazone attenuates activation of human Tenon's fibroblasts induced by transforming growth factor-beta1.
        Graefes Arch Clin Exp Ophthalmol. 2012; 250: 1213-1220
        • Shimizu T.
        • Liao J.K.
        Rho kinases and cardiac remodeling.
        Circ J. 2016; 80: 1491-1498
        • Knipe R.S.
        • Tager A.M.
        • Liao J.K.
        The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.
        Pharmacol Rev. 2015; 67: 103-117
        • Tura A.
        • Grisanti S.
        • Petermeier K.
        • Henke-Fahle S.
        The Rho-kinase inhibitor H-1152P suppresses the wound-healing activities of human Tenon's capsule fibroblasts in vitro.
        Invest Ophthalmol Vis Sci. 2007; 48: 2152-2161
        • Van de Velde S.
        • Van Bergen T.
        • Vandewalle E.
        • et al.
        Rho kinase inhibitor AMA0526 improves surgical outcome in a rabbit model of glaucoma filtration surgery.
        Prog Brain Res. 2015; 220: 283-297
        • Honjo M.
        • Tanihara H.
        • Kameda T.
        • et al.
        Potential role of Rho-associated protein kinase inhibitor Y-27632 in glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2007; 48: 5549-5557
        • Futakuchi A.
        • Inoue T.
        • Fujimoto T.
        • et al.
        The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts.
        Exp Eye Res. 2016; 149: 107-115
        • Ubels J.L.
        • Dennis M.H.
        • Mitchell J.H.
        • et al.
        Biological activity of N-(4-hydroxyphenyl) retinamide-O-glucuronide in corneal and conjunctival cells of rabbits and humans.
        Curr Eye Res. 1995; 14: 1115-1124
        • Ubels J.L.
        • Woo E.M.
        • Curley Jr., R.W.
        N-linked glycoside and glucuronide conjugates of the retinoid, acitretin, are biologically active in cornea and conjunctiva.
        J Ocul Pharmacol Ther. 1998; 14: 505-516
        • Liu Y.
        • Kimura K.
        • Orita T.
        • et al.
        Inhibition by all-trans-retinoic acid of transforming growth factor-beta-induced collagen gel contraction mediated by human tenon fibroblasts.
        Invest Ophthalmol Vis Sci. 2014; 55: 4199-4205
        • Liu Y.
        • Kimura K.
        • Orita T.
        • et al.
        All-trans-retinoic acid inhibition of transforming growth factor-beta-induced collagen gel contraction mediated by human Tenon fibroblasts: role of matrix metalloproteinases.
        Br J Ophthalmol. 2015; 99: 561-565
        • Liu Y.
        • Kimura K.
        • Orita T.
        • et al.
        Inhibition by a retinoic acid receptor gamma agonist of extracellular matrix remodeling mediated by human Tenon fibroblasts.
        Mol Vis. 2015; 21: 1368-1377
        • Lin X.
        • Yu M.
        • Wu K.
        • et al.
        Effects of pirfenidone on proliferation, migration, and collagen contraction of human Tenon's fibroblasts in vitro.
        Invest Ophthalmol Vis Sci. 2009; 50: 3763-3770
        • Stahnke T.
        • Kowtharapu B.S.
        • Stachs O.
        • et al.
        Suppression of TGF-beta pathway by pirfenidone decreases extracellular matrix deposition in ocular fibroblasts in vitro.
        PLoS One. 2017; 12: e0172592
        • Zhong H.
        • Sun G.
        • Lin X.
        • et al.
        Evaluation of pirfenidone as a new postoperative antiscarring agent in experimental glaucoma surgery.
        Invest Ophthalmol Vis Sci. 2011; 52: 3136-3142
        • Jung K.I.
        • Park C.K.
        Pirfenidone inhibits fibrosis in foreign body reaction after glaucoma drainage device implantation.
        Drug Des Devel Ther. 2016; 10: 1477-1488
        • Van Bergen T.
        • Marshall D.
        • Van de Veire S.
        • et al.
        The role of LOX and LOXL2 in scar formation after glaucoma surgery.
        Invest Ophthalmol Vis Sci. 2013; 54: 5788-5796
        • Janda J.
        • Nfonsam V.
        • Calienes F.
        • et al.
        Modulation of ROS levels in fibroblasts by altering mitochondria regulates the process of wound healing.
        Arch Dermatol Res. 2016; 308: 239-248
        • Richter K.
        • Kietzmann T.
        Reactive oxygen species and fibrosis: further evidence of a significant liaison.
        Cell Tissue Res. 2016; 365: 591-605
        • Saika S.
        • Yamanaka O.
        • Kawashima Y.
        • et al.
        OPC-15161 suppresses the proliferation of Tenon's capsule fibroblasts and the production of type I collagen and fibronectin stimulated by TGF-beta1 in vitro.
        Curr Eye Res. 1998; 17: 933-940
        • Moreira de Macedo S.
        • Guimaraes T.A.
        • Feltenberger J.D.
        • Sousa Santos S.H.
        The role of renin-angiotensin system modulation on treatment and prevention of liver diseases.
        Peptides. 2014; 62: 189-196
        • van Thiel B.S.
        • van der Pluijm I.
        • te Riet L.
        • et al.
        The renin-angiotensin system and its involvement in vascular disease.
        Eur J Pharmacol. 2015; 763: 3-14
        • Simoes E.S.A.C.
        • Teixeira M.M.
        ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.
        Pharmacol Res. 2016; 107: 154-162
        • Shi H.
        • Zhang Y.
        • Fu S.
        • et al.
        Angiotensin II as a morphogenic cytokine stimulating fibrogenesis of human tenon's capsule fibroblasts.
        Invest Ophthalmol Vis Sci. 2015; 56: 855-864
        • Mizoue S.
        • Iwai M.
        • Ide A.
        • et al.
        Role of angiotensin II receptor subtypes in conjunctival wound healing.
        Curr Eye Res. 2006; 31: 129-136
        • Wang X.
        • Fan Y.Z.
        • Yao L.
        • Wang J.M.
        Anti-proliferative effect of olmesartan on Tenon's capsule fibroblasts.
        Int J Ophthalmol. 2016; 9: 669-676
        • How A.
        • Chua J.L.
        • Charlton A.
        • et al.
        Combined treatment with bevacizumab and 5-fluorouracil attenuates the postoperative scarring response after experimental glaucoma filtration surgery.
        Invest Ophthalmol Vis Sci. 2010; 51: 928-932
        • Martorana G.M.
        • Schaefer J.L.
        • Levine M.A.
        • et al.
        sequential therapy with saratin, bevacizumab and ilomastat to prolong bleb function following glaucoma filtration surgery in a rabbit model.
        PLoS One. 2015; 10: e0138054