Current understanding of conventional outflow dysfunction in glaucoma

Abstract

Purpose of review: Regulation of intraocular pressure by the conventional (trabecular) outflow pathway is complicated, involving a myriad of mechanical and chemical signals. In most, intraocular pressure is maintained within a tight range over a lifetime. Unfortunately in some, dysfunction results in ocular hypertension and open-angle glaucoma. In the context of established knowledge, this review summarizes recent investigations of conventional outflow function, with the goal of identifying areas for future inquiry and therapeutic targeting.

Recent findings: Mechanical stimulation of conventional outflow cells due to intraocular pressure fluctuations impacts contractility, gene expression, pore formation, enzyme activity, and signaling. Numerous local signaling mediators in the conventional pathway such as bioactive lipids, cytokines, nitric oxide, and nucleotides participate in the regulation of outflow. Interestingly outflow through the conventional pathway is not uniform, but segmental, with passageways constantly changing due to focal protease activity of trabecular cells clearing extracellular matrix materials. The relationship between extracellular matrix expression and trabecular meshwork contractility appears to coordinately impact outflow resistance and is the target of a new class of drugs, the Rho kinase inhibitors.

Summary: The conventional outflow pathway is a dynamic, pressure-sensitive tissue that is vulnerable to pathology on many fronts, each representing a therapeutic opportunity.

Figure 1. Dose-related intraocular pressure-lowering effects of a rho kinase inhibitor, AR-12286, in ocular hypertensive patients enrolled in phase 2A trial

Shown are mean change in diurnal intraocular pressure measurements from baseline for each treatment group. bid: twice daily, q.d.: daily Source: reproduced with permission from Robert D. Williams, Gary D. Novack, Thomas van Haarlem, Casey Kopczynski and AR-12286 Phase 2A Study Group; Ocular Hypotensive Effect of the Rho Kinase Inhibitor AR-12286 in Patients With Glaucoma and Ocular Hypertension; Am J Ophthalmol 2011: 152: 838

Figure 2. Segmental flow patterns through the human trabecular meshwork

Enucleated human donor eyes were perfused with a bolus of green fluorescent tracer microspheres (200 nm) and perfusion fixed. The trabecular meshwork was imaged en face after removing the iris and ciliary body. The non-uniform pattern of fluorescent tracer decoration suggests segmental flow within the trabecular meshwork. Arrows indicate areas of high flow and arrowheads show areas of low/no flow through the trabecular meshwork. Sc: sclera; C: cornea Source: image provided by Darryl Overby, Ph.D.

Figure 3. Effects of mechanical stretch on podosome/invadosome-like structures (PILS) component distribution

TM cells were exposed to ~10% radial stretch for 24 hours (stretch) or were not stretched (control). Component localization was imaged by confocal microscopy examining microtubules (green), MMP-14 (red) and actin microfilaments (blue). Yellow (arrowheads) indicate colocalization of microtubule clusters and MMP-14 at sites of PILS Source: image provided by Ted Acott, Ph.D