Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Abstract

Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells

“…[17][18][19][20][21][22][23][24] LPA also influences the contractile and adhesive properties of TM and SC cells, and is suggested to be involved in the pathogenesis of glaucoma. [25][26][27][28][29][30] LPA is derived, under various conditions both in cells and biological fluids, mainly from lysophosphatidylcholine (LPC) and predominantly through the lysophospholipase D (lysoPLD) activity of ATX. [31][32][33][34][35] ATX is a secreted glycoprotein, widely present in biological fluids, and originally isolated from the supernatants of melanoma cells as an autocrine motility stimulation factor.…”

Sphingolipids and ceramides of mouse aqueous humor: Comparative profiles from normotensive and hypertensive DBA/2J mice

“…Recent studies have shown the effect on AH outflow by selected species of others classes of lipids including sphingolipids and ceramides [6, 38, 39]. However, the identification of all lipid species of these classes in the AH remained unknown, which is why we undertook the current mass spectrometric investigation.…”

“…1, Table 4 and Supplementary Table S3) involved in sphingolipid metabolism [45]. The application of specific sphingolipids such as S1P has been known to modulate AH outflow [6, 46]. …”

“…Lipids have been found to regulate AH outflow [5, 6]. Prostaglandins (PGs), a single sub-class of lipids found endogenously in the iris and termed irin [7, 8], have been found to significantly increase the AH outflow and reduce IOP [9].…”

“…Prostaglandins (PGs), a single sub-class of lipids found endogenously in the iris and termed irin [7, 8], have been found to significantly increase the AH outflow and reduce IOP [9]. A few non-PG lipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) also have been found to decrease aqueous humor outflow as well [6]. The precise source of PGs in the anterior eye chamber is still not clear, however, PGF 2α analogues have been shown to upregulate the expression of extracellular matrix metalloproteinases (MMPs), which in turn, degrade the extracellular matrix (ECM) of the ciliary muscle.…”