The cell and molecular biology of glaucoma: mechanisms in the conventional outflow pathway.

Glaucoma, a blinding disease that affects millions in the United States, is treatable. Multiple clinical trials involving thousands of patients have repeatedly shown that lowering intraocular pressure (IOP) saves vision in those with glaucoma. In fact, if IOP in those with glaucoma is lowered sufficiently, vision loss dramatically slows—nearly stopping. IOP is a function of the balance of fluid (aqueous humor) entering and leaving the eye. Although there are very good medications that lower IOP by decreasing fluid production by the inflow pathway and increasing fluid egress via the secondary outflow pathway, unfortunately there is not a daily medication that enhances outflow through the primary outflow route: the conventional pathway. The conventional outflow pathway is the tissue that becomes diseased and is responsible for ocular hypertension (elevated IOP) in those with glaucoma. 1 Consequently, persons with glaucoma have elevated IOP and higher resistance to outflow than do those of similar age without glaucoma. Although this extra resistance to outflow can be removed surgically to bypass the dysfunctional tissue, a primary focus of glaucoma research is to understand the molecular and cellular mechanisms that control resistance, so that medications can be developed that can lower resistance and return function to the conventional outflow pathway. The conventional (or trabecular) outflow pathway has a fascinating design (Fig. 1). Fluid flow through the tissue and out of the eye is driven by a pressure gradient across the tissue. Thus, the pressure difference inside (IOP) and outside (episcleral venous pressure [EVP]) the eye moves aqueous humor through an area that functions like a filter positioned in front of a region that acts like a resistor. The cell surfaces in the innermost parts of the trabecular meshwork (TM) tissue act like a filter, removing cell debris, pigment, and reactive oxygen species from aqueous humor before it reaches (and has the opportunity to clog) the resistant part of the pathway located near the inner wall of Schlemm’s canal (SC), called the juxtacanalicular (JCT) region. Resistance to outflow is generated in the JCT region of the conventional pathway and most likely involves a funneling mechanism. 2 Hence, resistance due to funneling is a function of two parameters: (1) spacing in the JCT due to the interaction between TM cells and inner wall cells of SC and (2) the number of openings (pores) in the inner wall. The theory is that as fluid moves through the TM and approaches the inner wall, it is funneled toward the pores in the inner wall, creating a bottleneck that generates resistance and thus IOP. MOLECULAR AND CELLULAR TARGETS IN THE CONVENTIONAL OUTFLOW PATHWAY If most of the fluid leaves the eye by way of (and pathology resides in) the conventional outflow pathway, then why is there no daily medication for glaucoma patients that targets conventional outflow? The simple answer is that the conventional outflow system is complicated, with many backup and compensatory mechanisms, keeping IOP within a very narrow range (usually, 2 mm Hg) in most people throughout life. Moreover, it appears that autoregulatory systems in the conventional pathway are geared toward preventing IOP from descending below a critical level, no matter how effective current medications affect inflow and the secondary outflow route in glaucoma patients. Such a design is probably due to a biological tolerance for elevated IOP, but not for reduced IOP, which may destabilize the ocular structures from the visual axis of the eye and disrupt vision.