Abstract
Synthetic prostaglandin analogs, 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 of action is still not well defined, being associated with both acute and long-term activities, and a growing list of 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 humor sampled from patients with glaucoma and healthy control eyes. The resulting signature was surprisingly focused on significantly elevated levels of arachidonic acid (AA) and its derivative, the antiinflammatory and cytoprotective mediator, lipoxin A4 (LXA4), in glaucomatous eyes. Subsequent experiments revealed that this response was drug induced, due to latanoprost actions on trabecular meshwork cells, rather than a consequence of elevated IOP. We demonstrate that increased LXA4 inhibited proinflammatory cues and promoted TGF-β production in the anterior chamber. In concert, an autocrine prostaglandin circuit mediated canonical rapid IOP lowering. This work reveals parallel mechanisms underlying acute and long-term latanoprost activities during glaucoma treatment.
Authors
David J. Mathew, Shubham Maurya, Julian Ho, Izhar Livne-Bar, Darren Chan, Jenny Wanyu Zhang, Yvonne M. Buys, Marisa Sit, Graham Trope, Donna M. Peters, John G. Flanagan, Karsten Gronert, Jeremy M. Sivak
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