The Biology, Pathology and Therapeutic Use of Prostaglandins in the Eye

Carol B Toris; Vikas Gulati

Disclosures

Clin Lipidology. 2011;6(5):577-591. 

In This Article

Biological Functions of PGs

Prostaglandins have essential homeostatic functions under normal physiologic conditions, one of which is the maintenance of IOP. Additionally, PGs have been implicated in a number of pathological conditions, one of which is, ocular inflammation. This article focuses on these two topics.

Maintenance of IOP

To understand how PGs regulate IOP, one must have a cursory understanding of aqueous humor dynamics. The production, circulation and drainage of ocular aqueous humor against a resistance in tissues of the anterior chamber angle maintain the pressure in the eye within a physiological range (Figure 2). Aqueous humor is produced by the pigmented and nonpigmented epithelia of the ciliary processes of the ciliary body in the ocular anterior segment and is secreted into the posterior chamber. It is generally accepted that PGs have little to no role in the production of the aqueous humor, however a few studies have reported the stimulation of aqueous humor production by topical exogenous PGs.[20] The mechanism by which this occurs is unclear but stimulation of ocular blood flow may provide a partial explanation.

Figure 2.

Aqueous humor dynamics. The production, circulation and drainage of ocular aqueous humor is the source of nourishment for the avascular tissues of the anterior segment and the conduit for removal of waste products. A stable intraocular pressure (IOP) is maintained by the secretion of aqueous humor into the posterior chamber (A), its circulation into the anterior chamber (B) and its drainage from the anterior chamber angle. There are two drainage routes, the pressure-dependent trabecular outflow pathway (C) and the relatively pressure-independent uveoscleral outflow pathway (D). IOP is reduced and glaucoma is treated by altering aqueous humor dynamics. Topical prostaglandin F analogs effectively lower IOP predominantly by improving the drainage rate of aqueous humor through the uveoscleral outflow pathway and secondarily by improving the facility of trabecular outflow.
Adapted with permission from [153].

Aqueous humor flows from the posterior chamber, through the pupil and into the anterior chamber. It drains out of the eye via two routes, the trabecular outflow pathway and the uveoscleral outflow pathway. The trabecular outflow pathway, also called the 'conventional outflow pathway' is pressure dependent, meaning as IOP increases, the flow through this pathway increases. The tissues of this pathway include the trabecular meshwork, Schlemm's canal, collector channels and episcleral veins. The inner wall of Schlemm's canal provides the greatest resistance to outflow. This resistance is crucial in maintaining a healthy IOP while simultaneously enabling drainage of the continuously produced aqueous humor. When the IOP is abnormally elevated, it is usually because of an increase in resistance in the trabecular outflow pathway.

All prostanoid receptors are expressed at different levels in the trabecular meshwork of human eyes.[21] PGs may directly control the resistance to trabecular outflow by initiating the degradation of the extracellular matrix via their effects on matrix metalloproteinases (MMPs) expressed in the trabecular meshwork.[22] The activity of MMPs is regulated by tissue inhibitors of metalloproteinases (TIMPs),[23] four of which are found in mammals (TIMP-1, -2, -3 and -4). Each TIMP targets specific MMPs.[24] PGs in aortic smooth muscle cells disassemble actin stress fibers and inhibit phosphorylation of paxillin and other focal adhesion proteins.[25] Similar events may be occurring in the trabecular meshwork.

Regions of focal detachment and loss of Schlemm's canal endothelial cells and trabecular meshwork extracellular matrix have been observed in tissues treated with the topical PG, latanoprost.[26] The cell loss was thought to be due to changes in focal adhesion and alterations of the cytoskeleton.[26] When latanoprost acid was applied to cultures of human trabecular meshwork cells, increased expression of MMPs-1, -3, -17 and -24 and TIMPs-2, -3 and -4 were found at 24 h after treatment. Outflow facility was increased in human organ-cultured anterior segments infused with latanoprost acid for 24 h but no changes in scleral hydraulic conductivity[26] were found. The results suggested that the IOP-lowering effect of PG analogs was due, in part, to a direct trabecular meshwork effect.

The second aqueous humor outflow route, termed the uveoscleral outflow pathway, includes flow through the ciliary muscle and then into numerous tissues, including the sclera and choroid. This pathway does not have well defined tubes and channels and for that reason it is often called the 'unconventional' outflow pathway. Another distinction from the trabecular outflow pathway, is that resistance to flow through the uveoscleral pathway is approximately ten-times less, thus the term 'pressure independent' is often used to describe this pathway. The IOP is reduced when the uveoscleral outflow is increased. Increased levels of PGs in uveal tissues cause an increase in uveoscleral outflow. Like the trabecular meshwork, the ciliary muscle also has MMPs, TIMPs[27] and PG receptors.[28,29]

Regulate Inflammatory Mediation

Elevated levels of PGs in animal models of induced inflammation have been known for a long time.[30–32] Increased PG activity has also been demonstrated in aqueous humor samples from cases of untreated anterior uveitis. Suppression of PG-like activity of aqueous humor was noted with topical steroid use.[33] Latanoprost has been shown to increase MMP-3 in rabbit conjunctiva.[34] In addition, latanoprost was shown to increase the number of fibroblasts with markers of proliferation in the conjunctiva compared with control treated eyes.[35] Dendritiform keratopathy and cystoid macular edema have been reported in patients on topical PG use; however, the causative role of PGs in these conditions is unclear.[36] The role of PGs in ocular inflammation is the basis for the use of NSAIDs in the management of a variety of ocular inflammatory conditions discussed subsequently.

Effects on Melanogenesis

Topical ocular use of PG analogs in some individuals has been reported to darken the iris color. This change may be consequent to an increase in the size of intracellular melanin granules and possibly to an increase in the thickness of the anterior border layer of the iris.[37–39] An ex vivo evaluation using the Monte Carlo technique[40] has found that this seemingly innocuous increase in melanin granule size is sufficient to explain the more dramatic iris color changes observed clinically. These changes may be secondary to the upregulation of the tyrosinase gene by PGF analogs.[41,42] Clinically, PG-induced iris discoloration is evident at a higher frequency in patients with mixed-colored irides such as hazel compared with those with uniform iris colors of blue or brown.[43]

Eyelid & Periocular Effects

Topical PG use has been found to produce darkening and thickening of eyelashes[44] and darkening of eyelid and periocular skin color in some patients.[45,46] Several recent studies of patients treated with PG analogs have described deepening of the upper lid sulcus and enophthalmos thought to be related to the decrease in the amount of fat located in the lid and orbit.[47–53] The lid changes have been reported to occur as early as 3 months after starting therapy.[47] Partial resolution of these changes upon cessation of therapy or switching to an alternate PG analog have been described.[47–52] However, these reported changes have not been systematically analyzed and their incidence, course and pathophysiology are not well known at this time. The fat atrophy has been confirmed histopathologically by an increase in cell density, which was considered a surrogate for cell hypotrophy.[54]

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