Anatomical and physiological background

The trabecular meshwork (TM), a specialized tissue at the chamber angle, is the major site for regulation of the normal bulk flow of the aqueous humor. It functions as a self-cleaning, unidirectional, pressure-sensitive, low-flow (2 µl/min/mmHg) biologic filter for the aqueous humor, and contributes thereby to control of the IOP. The TM tissue is divided into the uveal meshwork, corneoscleral meshwork, and juxtacanalicular connective tissue (JCT) regions ( Figure 22.1 ). In the uveal and corneoscleral meshwork, sheets of trabecular beams that contain lamellae made of connective tissue or extracellular matrix (ECM) materials are lined by TM cells. In the JCT region, the cells reside relatively freely and are embedded in the ECM. In the Schlemm’s canal (SC), there are endothelial cells also referred to as inner wall cells ( Figure 22.2 ). The aqueous humor flows through the TM and the SC into collector channels and aqueous veins, and the outflow resistance is believed to locate largely in the JCT/SC area. In normal outflow homeostasis, a pressure gradient exists between the anterior chamber and the episcleral veins. It is likely that the pressure gradient and the resistance to aqueous outflow are altered in various types of glaucoma ( Box 22.1 ).

Three-dimensional drawing of the aqueous outflow pathway depicting the structural elements of the trabecular meshwork. The uveal meshwork (UM) is a loose lattice of delicate rope-like components in continuity from the base of the iris to Descemet’s membrane (DM). The corneoscleral meshwork (CSM) is more tightly packed and consists of sheets of trabecular lamellae. The juxtacanicular connective tissue (JCT) forms a thin band of connective tissue adjacent to the aqueous collector channel known as Schlemm’s canal (SC).

(Adapted from Weddell JE. The limbus. In: Hogan MJ, Alvarado JA, Weddell JE (eds) Histology of the Human Eye. Philadelphia: WB Saunders, 1971:112–182.)

Three-dimensional drawing of the corneoscleral meshwork, the juxtacanicular connective tissue (JCT), and Schlemm’s canal (SC). Note the trabecular spaces (ts), intervening endothelial processes, the inner wall (iw), the external wall (ew), and the endothelium (e) of the SC. Giant vacuoles (gv), common on the inner wall of the SC, are pressure-sensitive. The aqueous outflow pathway is complex; there are at least three layers of organization. The first layer is formed by a series of perforated trabecular lamellae. Interposed between the last trabecular lamellae and the inner wall of the SC is a thin cellular zone with an abundant extracellular matrix, the JCT, which is a highly fibrillar, cellular, and glycosaminoglycan-enriched area.

(Adapted from Weddell JE. The limbus. In: Hogan MJ, Alvarado JA, Weddell JE (eds) Histology of the Human Eye. Philadelphia: WB Saunders, 1971:112–182.)

Effects of disease

To facilitate comparisons and to offer mechanistic clues, biochemical changes such as up- or downregulation of genes/proteins that have been reported in POAG in the aqueous humor, TM, optic nerve, and blood are organized into three categories: (1) ECM elements and remodeling; (2) cell signaling molecules; and (3) changes related to stress and aging, and listed respectively in Tables 22.1 , 22.2 , and 22.3 .

What follows are discussions of cellular mechanisms in the TM system that may affect the aqueous humor outflow pathway. Although discussed under separate headings, the mechanisms that include the ECM composition, turnover, and modulation, cell adhesion, cytoskeletal structure, and intracellular signaling are all interconnected. The effects or influences of aqueous humor components and stress-inducing conditions are also described.

Trabecular meshwork and Schlemm’s canal cell profiles

TM cells are unique and have the capacity to perform a variety of functions, including phagocytosis, migration, elaboration of metabolic, lysosomal, and matrix-degrading enzymes, and production of ECM elements. TM cells incorporate acetylated low-density lipoprotein (LDL), as do vascular endothelial cells (VEC) in culture. However, they do not stain for factor VIII antigen, a characteristic VEC marker. Neither do TM cells form an endothelium as tight as that of cultured VEC. TM cells on the other hand phagocytose more avidly than VEC.

TM cells are essential for maintenance of the normal aqueous humor outflow system. Disturbances in the vitality and functional status by genetic predisposition, aging, or other insults may result in obstruction of the aqueous outflow, leading to IOP elevation and glaucomatous conditions. In vivo, TM cells have limited proliferative activity. A continuous loss of TM cells occurs during adulthood. In patients with POAG, the cell loss and disruption of the endothelial covering are striking. Areas in which the trabecular beams are denuded of cells are associated with a major loss of outflow channels, which represents a possible mechanism for the decreased outflow facility in POAG.

While TM cells are highly specialized, adaptive, and multifunctional cells, SC cells are pressure-sensitive endothelial cells of vascular origin. SC cells endocytose LDL and acetylated LDL and organize in the presence of Matrigel into multicellular tubelike structures. In situ, cells in the various regions of TM and those in SC appear to be interconnected by cell processes ( Figure 22.3 ). The SC/TM configuration is pressure-sensitive. If the IOP is exceedingly elevated, the SC/TM may be forced on to the outer wall, effectively preventing outflow of the aqueous humor.

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