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A Rabbit Model for Evaluating Corticosteroid Metabolism in Ocular and Orbital Tissues

^A Endocrinology, Division of Medical Sciences, ^B Ophthalmology, Division of Immunity and Infection, ¹ The University of Birmingham, Birmingham, United Kingdom
² Regional Endocrine Unit, Southampton General Hospital, Southampton, United Kingdom

Commercial Relationships: E.A. Walker, None; J.W. Tomlinson, None; S.V. Hughes, None; P.J. Wood, None; P.I. Murray, None; P.M. Stewart, None; S. Rauz, None.

Grant Identification: Medical Research Council, UK

Abstract

Purpose:Our recent studies have localised 11beta–hydroxysteroid dehydrogenase type 1 (11ß–HSD1), an oxo–reductase that activates cortisol (F) from cortisone (E), to the non–pigmented layer (NPE) of the human ocular ciliary epithelium. Its role in aqueous humour (AH) production provides a novel target for AH suppression and the treatment of raised intraocular pressure (IOP). We have also defined expression of 11ß–HSD1 in subcutaneous and omental fat, implicating a role in the pathogenesis of obesity. Detailed evaluation of corticosteroid metabolism in the retro–orbital fat (ROF) depot, an important target tissue for orbital inflammatory disease remains unexplored largely due to inaccessibility of human tissue. Animal models are essential for further evaluation of both the NPE and ROF.

Methods:Using our in–house generated primary antibody to 11ß–HSD1, immunohistochemical analyses were performed on 5µm sections from New Zealand White Albino Rabbits (NZWAR). Enzyme assays were conducted on dissected ciliary body tissue. AH and serum F and E levels were determined by radioimmunoassay. Enzyme assays for oxo–reductase (E to F) and dehydrogenase (F to E) activity were assessed on primary cultures established from ROF, omental and subcutaneous fat depots.

Results:Expression of 11ß–HSD1 was confined to the NPE layer of the ciliary body. No staining was seen in the albino pigmented ciliary epithelium. Thin layer radio–chromatograms confirmed predominant conversions of E to F by the ciliary body, which was supported by a high F:E ratio in AH (2.67 (1.25–5.2) median (range)) versus plasma 11.25 (10–12.5). 11ß–HSD1 expression was also defined in the ROF. Primary ROF cultures demonstrated abundant oxo–reductase activity (E to F) compared with paired omental and subcutaneous fat cultures.

Conclusions:These results endorse our human studies suggesting that modulation of AH production by 11ß–HSD1 is important in the regulation of IOP, and the NZWAR model may now be used for further evaluation of this isozyme as a therapeutic target for treatment of raised IOP. Expression of 11ß–HSD1 in ROF may have important implications in differentiation, proliferation and inflammatory infiltration of this fat depot. As T3 regulates 11ß–HSD1 activity, manipulation of this isozyme could play a role in the treatment of orbital disease.

Keywords: corticosteroids • enzymes/enzyme inhibitors • microscopy: light/fluorescence/immunohistochemistry

© 2004, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.