Glucocorticoids (natural steroid hormones) are pivotal to the regulation of the inflammatory mechanisms of the ocular microenvironment.
We have a specific interest in the expression of a bidirectional isozyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) that inter-converts active cortisol and inactive cortisone. Over the last decade, 11beta-HSD1 has emerged as a critical determinant of glucocorticoid function in tissues such as the liver, adipose and bone. Interest in the isozyme has escalated primarily because of its putative role in diseases such as human obesity, insulin resistance and osteoporosis, and also its role in the regulation of immune-cell function and inflammation.
The eye represents an important corticosteroid target tissue and our descriptive studies have localised 11beta-HSD1 to the human corneal epithelium and ciliary body epithelium. We believe that this enzyme may be a feature of a number of blinding conditions. Our ongoing studies focus on several areas:
Glaucoma - This is a leading cause of blindness in the Western world resulting from high pressure inside the eye causing permanent damage to the main nerve of sight (optic nerve). We have already shown that 11beta-HSD1 is involved in keeping the pressure inside the eye normal, and that the pressure can be reduced if the action of 11beta-HSD1 is prevented by a tablet called carbenoxolone, a non-specific inhibitor of 11beta-HSD1. Through a material transfer agreement with Pfizer Inc we are now examining specific 11beta-HSD1 inhibitors in the laboratory. We hope that our results may pave the way for a new treatment for glaucoma.
The Ocular Surface - Corneal scarring where the clear window of the eye becomes damaged from infection or inflammation is a leading cause of blindness worldwide. The cornea provides both protective and refractive properties essential for sight. The corneal epithelium is the most superficial layer formed from highly specialised cells that are rapidly proliferating from a peripheral (limbal) stem cell population, replenishing the ocular surface. Our data have demonstrated the expression of 11beta-HSD1 to the basal cells of the corneal epithelium. Our current studies are exploring the role of this isozyme in ocular surface renewal, combating inflammation via the generation of local cortisol, and fighting infection through activation of sentinel receptors called toll-like receptors. We believe that 11beta-HSD1 is of paramount importance to the ocular surface.
Thyroid hormone related eye problems (‘bulgy’ eyes) - This is a common condition where 5% of patients can go blind. Thyroid-associated ophthalmopathy is a condition where the tissues behind the eyes become inflamed and swollen often associated with an overactive thyroid gland in the neck. This not only causes the eyes to be pushed forwards (proptosis) becoming red and sore, but the swelling squeezes the optic nerve behind the eye (optic neuropathy) and this can result in complete blindness. The two most common reasons for the eye becoming bulgy are firstly, too much fat is made in the eye socket ad secondly, inflammation causes swelling. As 11beta-HSD1 appears to be involved in increasing the amount of fat in some obese patients, and is a key player in inflammation, we are currently investigating how 11beta-HSD1 influences orbital fat physiology and inflammation within the socket of patients with thyroid-associated ophthalmopathy providing us with a better understanding of the disease.
Intracranial pressure (ICP) - Cerebrospinal fluid (CSF) is a clear fluid that surrounds the brain and spinal cord. It is crucial for normal brain function and provides a very important role in protecting the brain from injury. If too much CSF accumulates in the space around the brain, the intracranial pressure (the pressure of CSF surrounding the brain) increases and causes visual loss by compression of the optic nerve. We believe that the ICP may be regulated 11beta-HSD1 in the same way it regulates aqueous humour within the eye and intraocular pressure. By conducting a range of laboratory and clinical-based studies we hope to define 11beta-HSD1 as a novel determinant of CSF dynamics and ICP balance. If this is the case, 11beta-HSD1 could be targeted for the treatment of patients with raised ICP thereby preventing visual loss.