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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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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).
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).
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.
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.
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