June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Functional and Morphological Alterations Associated with Steroid-Induced Ocular Hypertension in Mice
Author Affiliations & Notes
  • Darryl Overby
    Bioengineering, Imperial College London, London, United Kingdom
  • Jacques Bertrand
    Bioengineering, Imperial College London, London, United Kingdom
  • Ozan Tektas
    Anatomy II, University of Erlangen-Nürnberg, Erlangen, Germany
  • Alexandra Boussommier Calleja
    Bioengineering, Imperial College London, London, United Kingdom
  • W Daniel Stamer
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • C Ethier
    Bioengineering, Imperial College London, London, United Kingdom
    Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA
  • David Woodward
    Biological Sciences, Allergan, Inc., Irvine, CA
  • Elke Luetjen-Drecoll
    Anatomy II, University of Erlangen-Nürnberg, Erlangen, Germany
  • Footnotes
    Commercial Relationships Darryl Overby, Allergan, Inc. (F), Allergan, Inc. (C); Jacques Bertrand, None; Ozan Tektas, None; Alexandra Boussommier Calleja, None; W Daniel Stamer, Allergan (F), Alcon (F), Acucela (C), Aerie (C), Cytokinetics (C); C Ethier, None; David Woodward, Allergan Inc. (E); Elke Luetjen-Drecoll, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 375. doi:
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      Darryl Overby, Jacques Bertrand, Ozan Tektas, Alexandra Boussommier Calleja, W Daniel Stamer, C Ethier, David Woodward, Elke Luetjen-Drecoll; Functional and Morphological Alterations Associated with Steroid-Induced Ocular Hypertension in Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):375.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To determine whether steroid-induced ocular hypertension (OHT) in mice is associated with decreased conventional outflow facility and accumulation of extracellular matrix in the trabecular meshwork (TM) near Schlemm’s canal (SC).

Methods: Osmotic mini-pumps (Alzet model 1004; DURECT, Cupertino CA) were implanted subcutaneously in C57BL/6J male mice for systemic delivery of dexamethasone (DEX, 2.7 to 3.8 mg/kg/d, N = 31) or PBS control (N = 28) over 28 days. IOP was measured weekly by rebound tonometry. After 21-28 days, mice were euthanized and the eyes were enucleated for ex vivo perfusion to measure conventional outflow facility at 35°C with the eye submerged in isotonic saline (21 eyes). Non-perfused eyes were immersion fixed and processed for electron microscopy to visualize the ultrastructure of the TM/SC or immunohistochemistry to stain for alpha-smooth muscle actin (SMA).

Results: In DEX-treated mice, IOP increased from 14.1 ± 1.0 mmHg (mean ± SD) prior to surgery to 16.7 ± 2.2 mmHg after 21-28 days (p = 10-4, N = 20 mice). Eleven DEX mice did not survive to 21 days. In PBS-treated mice, IOP was unaffected (13.6 ± 2.3 vs. 12.7 ± 1.6 mmHg, p = 0.07, N = 28). Conventional outflow facility was 52% lower in DEX-treated mice (0.008 ± 0.003 vs. 0.018 ± 0.005 µL/min/mmHg, N = 10 vs. 11, p = 6 x 10-5), and there was a significant correlation between facility and final IOP (p = 2 x 10-3, R2 = 0.39, N = 21). DEX treatment was associated with increased continuity of the basement membrane underlying the inner wall of SC, which preceded accumulation of plaque-like matrix material within the TM. In DEX-treated mice SMA staining, indicating the presence of myofibroblasts, was observed in the TM and along the outer wall of SC and collector channels but not in the sclera. SMA staining was negligible in the outflow pathway of PBS-treated mice.

Conclusions: Our data show that steroid-induced OHT in mice is associated with a reduction in conventional outflow facility, increased continuity of SC basement membrane, and transformation of outflow pathway cells into myofibroblasts. Because mice have a true SC rather than a discontinuous aqueous plexus as found in most non-human species, the mouse model of steroid-induced OHT may better model steroid-induced glaucoma in humans.

Keywords: 633 outflow: trabecular meshwork • 735 trabecular meshwork • 568 intraocular pressure  
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