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Editors Selection IGR 14-3

Basic research: Regulation of outflow

Comment by Martin Wax on:

11728 Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma, Dan J; Belyea D; Gertner G et al., Archives of Ophthalmology, 2005; 123: 220-224

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Dan et al. (8) sought to determine the levels of plasminogen activator inhibitor-1 (PAI-1) in the aqueous humor of patients with glaucoma in comparison to control patients without glaucoma, but necessarily, with cataracts. They observed that the glaucoma group showed a 3.3 fold increase in the mean level of PAI-1 in comparison to the controls. This significant difference prompts several important considerations. The role of PAI-1, a member of the serpin superfamily of serine protease inhibitors, is mainly to inhibit tissue plasminogen activator (tPA) and urokinase plasminogen activator, both of which convert inactive plasminogen into active plasmin. The latter is a protease that degrades fibrin, and thus is part of the fibrinolytic system that helps maintain patency of the vascular bed. However, PAI-1 synthesis, which has been localized only to the apices of the ciliary epithelium in the eye, may impact plasmin in a manner far more recognizable to those interested in the study of glaucoma pathogenesis. That is, plasmin is also involved in directly degrading extracellular matrix components and activating proenzymes of collagen-degrading metalloproteinases (MMPs). Thus we have here a possible anterior segment locus that may be functioning to regulate aqueous outflow through the trabecular meshwork as well as the uveoscleral pathway. To this reader, the authors' finding underscore an observation that has been largely neglected for years, and that is the lack of meaningful studies which explore the role of

Regulation of aqueous humor outflow in the trabecular meshwork and uveoscleral pathways may in fact be governed locally by proteins or enzymes made in the ciliary epithelium

the ciliary epithelium as a source of proteins that may ultimately effect aqueous outflow through the trabecular meshwork, or alternately, the uveoscleral outflow pathway. After all, the ciliary epithelium is literally the nearest neighboring cells to those in the trabecular meshwork. However, because the ciliary epithelium happens to live 'across a lake' of aqueous humor from the trabecular meshwork, it is often ignored or discounted as a neighboring cell that may have direct or meaningful regulatory function on it's neighbor, the trabecular meshwork. This is particularly perplexing when one considers that in most medical diseases which are characterized by aberrant accumulation of substrate, the problem has invariably been a defect or inadequacy in the enzyme that breaks down the stored material (i.e., hexosaminidase A for Tay-Sachs, glucocerebrosidase for Gaucher's) as opposed to the abnormal secretion or deposition of the substance in question. Therefore, it would seem that an obvious target of extracellular debris accumulation in the trabecular meshwork, commonly thought to be a significant factor in glaucoma pathogenesis, might be the study of enzymes such as the MMPs, or other proteins that are made in the ciliary epithelium such as PAI-1, which may directly impact the degradation of the extracellular matrix in the outflow pathways of the anterior segment. Two small caveats that remain to be addressed by the present study are of course whether the findings of increased PAI-1 in aqueous have a causative role in glaucoma, or whether their presence is a secondary compensatory phenomenon that occurs as a result of glaucoma itself. Secondly, although the investigators discuss the possibility of whether the PAI-1 they observed might be sourced from plasma ultrafiltrate, it would have been extremely valuable to measure PAI-1 in serum and report the aqueous/plasma ratios in order to more fully address this concern. Nevertheless, what the authors have demonstrated here that is particularly valuable, is that the regulation of aqueous humor outflow in the trabecular meshwork and uveoscleral pathways may in fact be governed locally by proteins or enzymes made in the ciliary epithelium. As such, this appears to be an area ripe for immediate and future studies.

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