Lipidomic Analysis Reveals Drug-Induced Lipoxins in Glaucoma Treatment

Abstract

Synthetic prostaglandin analogues, such as latanoprost, are first-line treatments to reduce intraocular pressure (IOP) in the management of glaucoma, treating millions of patients daily. Glaucoma is a leading cause of blindness, characterized by progressive optic neuropathy, with elevated IOP being the sole modifiable risk factor. Despite this importance, the underlying latanoprost mechanism is still not well defined, being associated with both acute and long term activities, and ocular side effects. Prostaglandins are eicosanoid lipid mediators. Yet, there has not been a comprehensive assessment of small lipid mediators in glaucomatous eyes. Here we performed a lipidomic screen of aqueous humour sampled from glaucoma patients or healthy control eyes. The resulting signature was surprisingly focused on significantly elevated levels of arachidonic acid (AA) and the potent proresolving mediator, lipoxin A4 (LXA4) in glaucoma eyes. Subsequent experiments revealed that this response is due to latanoprost actions, rather than a consequence of elevated IOP. We demonstrated that increased LXA4 inhibits pro-inflammatory cues and promotes TGF-{beta}3 mediated tissue remodeling in the anterior chamber. In concert, an autocrine prostaglandin circuit mediates rapid IOP-lowering. This work reveals parallel mechanisms underlying acute and long-term latanoprost activities during the treatment of glaucoma.