title: Reduction of steroid-induced intraocular pressure elevation in sheep by tissue plasminogen activator.
abstract: OBJECTIVE
  To investigate whether tissue plasminogen activator (tPA) can prevent and/or reverse steroid-induced IOP elevation in an ovine model.
  
  
  METHODS
  Three animal groups were subjected to bilateral steroid-induced IOP elevation using thrice daily topical ocular prednisolone administration. In the first group (N = 8), one eye each of two sheep was injected intravitreally with 100 μg, 200 μg, 500 μg, or 1 mg human recombinant tPA, while contralateral eyes received vehicle. In the second group (N = 2), one eye was injected intravitreally with tPA (100 μg), while contralateral eyes received vehicle containing L-arginine. In the third group (N = 4), each animal received intravitreal tPA in one eye concurrently with initiation of bilateral steroid administration. IOP was monitored for the duration of the experiment. Tissues from eyes of the third group were used to determine relative gene expression.
  
  
  RESULTS
  In the first and second groups, IOP decreased by 9.7 (±2.8) and 9.7 (±1.6) mm Hg, respectively, 24 hours after tPA administration. In the third group, tPA-treated eyes did not develop IOP elevation with ΔIOP of 11.8 (±1.3) mm Hg 8 days later. In all tPA-treated eyes, IOP remained low until the end of the study. mRNA levels in the trabecular meshwork were decreased for plasminogen activator tissue (PLAT), increased for matrix-metalloproteinase 1 (MMP-1), and stable for plasminogen activator inhibitor 1 (PAI-1), MMP-2, MMP-9, and MMP-13 in tPA-treated eyes compared with contralateral controls. PAI-1 mRNA levels in ciliary processes also remained similar.
  
  
  CONCLUSIONS
  Recombinant human tPA is effective in both preventing and reversing steroid-induced IOP elevation in sheep. Tissue plasminogen activator may be useful as a therapeutic agent in steroid-induced glaucoma.
authors.affiliation: Departamento de Oftalmología, UNNE, Corrientes, Argentina.
authors.forename: Rosana
authors.initials: R
authors.lastname: Gerometta
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Shaily
authors.initials: S
authors.lastname: Shah
authors.forename: Larry
authors.initials: L
authors.lastname: Alvarez
authors.forename: Oscar
authors.initials: O
authors.lastname: Candia
authors.forename: John
authors.initials: J
authors.lastname: Danias
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D005786:Gene Expression Regulation; D007429:Intraocular Pressure / Q000187:drug effects*; D058449:Intravitreal Injections; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D009798:Ocular Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011239:Prednisolone / Q000633:toxicity; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012756:Sheep; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D014129:Trabecular Meshwork / Q000201:enzymology
chemical_list: D005343:Fibrinolytic Agents; D012313:RNA; D011239:Prednisolone; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases
keywords: extracellular matrix; intraocular pressure; matrix metalloproteinase; tissue plasminogen activator; trabecular meshwork