Connexin43 Modulation Inhibits Scarring in a Rabbit Eye Glaucoma Trabeculectomy Model
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Connexin43 Modulation Inhibits Scarring in a Rabbit Eye Glaucoma Trabeculectomy Model Narmadai C. Deva,1 Jie Zhang,1 Colin R. Green,1 and Helen V. Danesh-Meyer1,2
Abstract—We investigated whether one subconjunctival injection of connexin43 antisense oligodeoxynucleotides (Cx43 AsODN) modulates postoperative scarring in a rabbit model of glaucoma trabeculectomy surgery. In a randomised, controlled, masked-observer study, 39 rabbits underwent trabeculectomy surgery with insertion of a 22-gauge cannula in the right eyes and were randomly divided into three treatment groups. Each rabbit received an injection of Cx43 AsODN in Pluronic gel, balanced salt solution or Pluronic gel alone into the formed bled. The animals were euthanized at 8 and 24 h and at 5 and 21 days. Histology and immunohistochemistry results demonstrated that Cx43 AsODN decreased Cx43 upregulation at 8 and 24 h which led to less myofibroblast upregulation at days 5 and 21 and reduced scarring at day 21 compared to controls. We conclude that postoperative use of Cx43 AsODN inhibited subconjunctival scarring and fibrosis. Cx43 AsODN injection may be a safe and effective anti-scarring agent in glaucoma trabeculectomy surgery. KEY WORDS: scar reduction; gap junction; connexin43; glaucoma; trabeculectomy.
INTRODUCTION Glaucoma is a progressive optic neuropathy and the second leading cause of irreversible blindness in the world [1]. When topical medical therapy and/or laser treatment are inadequate, surgical intervention is used to improve aqueous fluid egress. Trabeculectomy is the most widely used incisional surgery to enhance aqueous drainage, involving the removal of partial thickness limbal tissue containing, trabecular meshwork, sclera and cornea under a lamellar scleral flap [2, 3]. The surgery results in an internal sclerostomy that is partially covered with a flap of tissue from the sclera and the conjunctiva. As the fluid flows through the new drainage opening, the tissue over the
1
Department of Ophthalmology, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand 2 To whom correspondence should be addressed at Department of Ophthalmology, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand. E-mail: [email protected] ABBREVIATIONS: 5-FU, 5-Fluorouracil; α-SMA, Alpha smooth muscle actin; BSS, Balanced salt solution; Cx43, Connexin 43; Cx43 AsODN, Connexin43 antisense oligodeoxynucleotides; IOP, Intraocular pressure; MMC, Mitomycin-C
opening rises to form a blister in the subconjunctival space, called a bleb. The primary mechanism by which a trabeculectomy lowers intraocular pressure (IOP) is via subconjunctival filtration with subepithelial microcysts forming channels for the passage of aqueous [4]. The aqueous exits across the conjunctival epithelium into the tear film or by direct absorption into blood vessels in the subepithelial connective tissue [5]. There is consensus that when there is an elevation of IOP following trabeculectomy, it is due to an exaggerated p
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