Role of Glucocorticoids and Glucocorticoid Receptors in Glaucoma Pathogenesis.

The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRα and GRß), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e., GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have a lower expression of GRß, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. An increased expression of GRß can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. The endogenous expression of GRß in the TM may relate to differences in the development of GC-OHT in the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease-modifying therapies to better treat these two sight threatening forms of glaucoma. The purpose of this timely review is to highlight the pathological and clinical features of GC-OHT and GIG, mechanisms responsible for GC responsiveness, potential therapeutic options, as well as to compare the similar features of GIG with POAG.

[Steroid glaucoma in patients with hemoblastosis]. / Steroidnaya glaukoma pri gemoblastozakh.

Modern methods of treatment have significantly increased the survival rate of children with oncohematological diseases, and along with it the importance of preserving their quality of life. More than half of patients receiving long-term steroid therapy suffer from glaucoma, which reduces visual acuity. This review analyzes the literature on the patterns of glaucoma development in patients receiving steroid therapy, the results of anatomical, as well as physiological and biochemical changes in the anterior chamber angle leading to the development of glaucoma.

Circumferential (360°) trabeculotomy for steroid-induced glaucoma in adults.

PURPOSE: To evaluate the safety and efficacy of 360° circumferential trabeculotomy (TO) for steroid induced glaucoma (SIG) of short duration. METHODS: Retrospective analysis of surgical results of 46 eyes of 35 patients undergoing microcatheter-assisted TO. All eyes had high intraocular pressure for at most about 3 years due to steroid use. Follow-up was between 2.63 and 47.9 months (mean 23.9, median 25.6). RESULTS: Intraocular pressure (IOP) before surgery was 30.8 ± 8.3 mm Hg, with 3.8 ± 1.0 pressure-lowering medications. After 1 to 2 years, mean IOP was 11.2 ± 2.6 mm Hg (n = 28); mean number of IOP-lowering medications was 0.9 ± 1.3. At their last follow-up, 45 eyes had an IOP < 21 mm Hg, and 39 eyes had an IOP < 18 mm Hg with or without medication. After 2 years, the estimated probability of having an IOP below 18 mm Hg (with or without medication) was 85 ± 6%, and the estimated probability of not using medication was 56 ± 7%. Steroid response was no longer present in all eyes receiving steroids after surgery. Minor complications consisted of hyphema, transient hypotony, or hypertony. One eye proceeded to receiving a glaucoma drainage implant. CONCLUSION: TO is particularly effective in SIG with relative short duration. This concurs with the pathophysiology of the outflow system. This procedure seems particularly suited for eyes for which target pressures in the mid-teens are acceptable, particularly when chronic use of steroids is necessary .

Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis.

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

Stanniocalcin-1 Reduced Intraocular Pressure in Two Models of Ocular Hypertension.

Purpose/Aim: Glaucomatous optic neuropathy (GON) remains the world's leading cause of irreversible blindness. Treatments including topical medications are directed at reducing intraocular pressure (IOP), the most significant risk factor for GON. Current medications, while generally effective, are limited by insufficient response and side-effects in some patients. In search of a more targeted therapy that acts downstream of existing medications that has a potential for a lower side effect profile, our laboratory has identified Stanniocalcin-1 (STC-1), a multifunctional hormone, as an effector molecule in latanoprost-mediated IOP reduction with similar IOP-lowering efficacy as latanoprost in normotensive mice.Materials and methods: To investigate whether STC-1 can also reduce IOP in ocular hypertensive mice, we used a steroid-induced ocular hypertensive mouse model characterized by trabecular meshwork dysfunction as well as the DBA/2J mouse as an inherited model of pigment dispersion and secondary angle closure. Steroid-induced ocular hypertension was induced by weekly injections of dexamethasone into the conjunctival fornix of wild-type C57BL/6J mice (6-8 months old). After confirmation of the steroid response, mice were administered STC-1 or phosphate buffered saline (PBS) topically once daily for six weeks. For DBA/2J mice (14 months old), after baseline IOP measurements, mice were treated topically once daily with STC-1 or PBS for 5 days and IOP was assessed twice daily.Results: In steroid-induced ocular hypertensive mice, STC-1 lowered IOP by 26% (P < .001, week three) and maintained this level of IOP reduction throughout the remainder of the treatment period (P < .001, week six). In DBA/2J mice, STC-1 lowered IOP by 37% (P < .001).Conclusions: Together, these data show that STC-1 reduced IOP in two models of ocular hypertension with different mechanisms of outflow obstruction.

Animal models of glucocorticoid-induced glaucoma.

Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open-angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG.

Ultrastructural changes associated with dexamethasone-induced ocular hypertension in mice.

PURPOSE: To determine whether dexamethasone (DEX)-induced ocular hypertension (OHT) in mice mimics the hallmarks of steroid-induced glaucoma (SIG) in humans, including reduced conventional outflow facility (C), increased extracellular matrix (ECM), and myofibroblasts within the outflow pathway. METHODS: Osmotic mini-pumps were implanted subcutaneously into C57BL/6J mice for systemic delivery of DEX (3-4 mg/kg/d, n = 31 mice) or vehicle (n = 28). IOP was measured weekly by rebound tonometry. After 3 to 4 weeks, mice were euthanized and eyes enucleated for ex vivo perfusion to measure C, for electron microscopy to examine the trabecular meshwork (TM) and Schlemm's canal (SC), or for immunohistochemistry to examine type IV collagen and α-smooth muscle actin. The length of basement membrane material (BMM) was measured along the anterior-posterior extent of SC by electron microscopy. Ultrastructural changes in BMM of DEX-treated mice were compared against archived human SIG specimens. RESULTS: Dexamethasone increased IOP by 2.6 ± 1.6 mm Hg (mean ± SD) over 3 to 4 weeks and decreased C by 52% ± 17% versus controls. Intraocular pressure elevation correlated with decreased C. Dexamethasone treatment led to increased fibrillar material in the TM, plaque-like sheath material surrounding elastic fibers, and myofibroblasts along SC outer wall. The length of BMM underlying SC was significantly increased in mice with DEX and in humans with SIG, and in mice decreased C correlated with increased BMM. CONCLUSIONS: Dexamethasone-induced OHT in mice mimics hallmarks of human SIG within 4 weeks of DEX treatment. The correlation between reduced C and newly formed ECM motivates further study using DEX-treated mice to investigate the pathogenesis of conventional outflow obstruction in glaucoma.

Selective laser trabeculoplasty for elevated intraocular pressure following subtenon injection of triamcinolone acetonide.

PURPOSE: To report on the efficacy of selective laser trabeculoplasty (SLT) for elevated intraocular pressure (IOP) following subtenon injection of triamcinolone acetonide. METHOD: SLT was performed on four of 148 eyes in which IOP was elevated after a subtenon injection of triamcinolone acetonide and could not be maintained within normal limits by conventional medications. Postoperative IOP and relative reduction of IOP were evaluated. RESULTS: IOP was reduced in three eyes to within the normal range without any medications six months after SLT alone, but trabeculotomy was performed on one eye. Percentage reduction in IOP after SLT was 21.6% at one month, 45.0% at three months, and 52.7% at nine months. CONCLUSION: SLT may be effective in reducing elevated IOP following subtenon injection of triamcinolone acetonide and should be considered before glaucoma surgery.