Article

Pathology of the Outflow System

Better understanding is key to targeted glaucoma treatment.

In the last 5 years, the landscape for glaucoma management has undergone a renaissance that has transformed ophthalmologists’ approach to patient care. This rebirth has occurred due to the advent of minimally invasive glaucoma surgery (MIGS) and has directed ophthalmologists to understand the outflow system as a functioning organ that is dynamic in nature and has pathologic alterations that influence the efficacy of various MIGS procedures. Introductory textbooks, such as the basic and clinical sciences course series texts, have limited discussion on the pathologic variations in the conventional outflow system seen in glaucoma patients. Primary open-angle glaucoma (POAG) is defined herein as glaucoma in an otherwise healthy eye where the resistance to outflow is at the level of the juxtacanalicular trabecular meshwork (JCT). Aqueous humor outflow is generally described as flowing through the trabecular meshwork (TM) and the extracellular matrix (ECM) of the JCT, into Schlemm’s canal, and down through the episceleral system. Although it is important to understand the general physiology of outflow, it is now even more important to understand the pathophysiology of the conventional outflow system, given the rise of MIGS procedures and the newly developed medications that specifically target the diseased state of this pathway.

The Trabecular Meshwork

The TM is not just a static screen door in the angle, and resistance to outflow is not limited to the juxtacanalicular portion of the TM. The TM is a much more complex and intricate pathway, with stretch receptors, intercellular and intracellular communication, tubules, valves, and pulsatile motions. Filtration is not circumferentially homogenous; rather, it is segmental, with areas of high or low flow modulated by variations in genomic expression.1,2 This delicate homeostasis is altered in glaucomatous eyes, showing genetic and microscopic differences compared to nonglaucomatous eyes, which lead to pathologic changes that increase resistance to outflow. Disease is present in all layers of the TM, which can increase the resistance to outflow beyond what is seen in the JCT. Trabecular columns of the uveal and corneal scleral TM are lined by phagocytic trabecular meshwork endothelial (TME) cells, which exhibit an age-related population regression — a dropout accentuated in glaucomatous eyes.3 This regression leads to fusion of adjacent trabecular columns that may reduce the effective filtration area. The pronounced loss of TME in glaucomatous eyes may be due to an underlying genetic mutation,4 oxidative stress,5 or cytotoxic agents, such as benzalkonium chloride (BAK),6 the common preservative seen in many glaucoma medications.

Consequences of Trabecular Meshwork Endothelial Cell Dropout

The adverse consequences of TME dropout on aqueous outflow are not limited to a mechanical reduction of the effective filtration area at the level of the proximal TM. The TME cells are involved in a biochemical pathway that influences resistance to outflow at the level of the JCT3 and permeability of the inner wall of Schlemm’s canal.7 The resistance to outflow is directly proportional to the concentration of ECM proteins in the juxtacanalicular space, and these proteins are regulated by the TME. Variations in the pressure-dependent tensile stress on the TME lead to a genetic upregulation or downregulation of enzymes such as matrix metalloproteinases (MMPs), which leads to ECM remodeling and an increase or decrease in outflow facility.8 Simply said, when the intraocular pressure (IOP) is high, the TME experiences increased tensile stress and upregulates expression of MMPs to reduce the amount of ECM proteins, which in turn decreases outflow resistance, resulting in a lower IOP.

There is a similar relationship between the TME and the endothelial cells lining the inner wall of Schlemm’s canal through cytokine production.7 The inner wall of Schlemm’s canal is a continuous sheet of endothelial cells that are interconnected by tight junctions and is the final cellular barrier to aqueous outflow in the proximal portion of the outflow system. These tight junctions also prohibit blood in the episceleral venous system from regurgitating into the anterior chamber (blood–aqueous barrier), giving the eye its immune privilege. But the tight junctions also prevent aqueous from freely flowing from the TM into the canal.

It is postulated that pressure imposed on the basal surface of Schlemm’s canal endothelium (SCE) causes the cells to bulge into the canal, to form giant vacuoles, and to thin and create paracellular and transcellular micropores that serve as the gateway of flow. Also, pore density increases with increased perfusion pressure.9 Investigators have established that there is a significant reduction in the number of these micropores in the inner wall of Schlemm’s canal in glaucomatous eyes compared to normal eyes. The reduction in micropore population may be multifactorial and is likely affiliated with the abnormally higher tensile stiffness of the SCE, which may be influenced by the abnormal biochemical nature of the ECM of the JCT.9 Work by Alvarado et al has shown in vitro and in vivo that the cytokines produced by the TME lead to an increase in permeability of SCE,7 and although the mechanism of increased permeability has not been elucidated, one possibility is that cytokines lead to a cascade that ultimately results in increased micropore formation.

Once through the proximal outflow system, aqueous still has to flow through the distal portion of the outflow system — Schlemm’s canal, collector channels, and the scleral plexus. Schlemm’s canal has been found to have contractile properties, similar to pulmonary smooth-muscle cells. It is now generally accepted that the enhanced contractility of SCE in glaucomatous eyes leads to increased resistance to outflow, quite possibly due to its reduced pliability and inability to form giant vacuoles and micropores. The increased stiffness may be a direct result of the increased stiffness of the JCT, which itself is regulated by the biochemistry, morphology, and quantity of ECM proteins the TME modulates. The canal in glaucomatous eyes also tends to be shorter, of smaller diameter, and often collapsed.10-12 Many collector channels are obstructed by herniations of the TM/SCE complex.11,13 One study showed that 90% of collector channels are obstructed in POAG eyes, while only 15% of collector channels are obstructed in nonglaucomatous eyes.13 The exact cause for the increase in collector-channel obstruction has yet to be determined, but one hypothesis is that the innermost layers of the TM actually have a reduced tensile stiffness, allowing for the trabeculum to herniate into regions of lower pressure, although there are conflicting reports on the stiffness of the proximal system.

Phagocytic endothelial cell dropout, by age, genetic mutation, or cytotoxic agents, can interfere with outflow dynamics by altering the various layers of the proximal outflow system, which in turn can increase resistance to outflow and lead to an increase in IOP. Although we cannot do much about age or genetic mutations at this time, we can certainly limit exposure to cytotoxic agents (ie, minimize exposure to BAK). Also, recent medications, such as Rho kinase inhibitors and nitric oxide carriers, have been shown to specifically target the abnormal contractility of stiffness of the TM and SCE. There is also research being done that may allow for human TME cell transplantation, which may enhance outflow.14

Conclusion

Primary open-angle glaucoma is certainly not glaucoma in an otherwise normal eye; rather, it is glaucoma in a significantly diseased eye — however, we cannot see the disease clinically. It is important to continue to understand the pathophysiology of the conventional outflow system to better understand how to target therapy. With continued research, we will be able to refine our treatment patterns and will ultimately have enhanced results. GP

References

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