The Mucin Secretagogue 15(S)-HETE Protects the Cornea and Improves Tear Film Integrity in a Rabbit Model of Lacrimal Gland Inflammation Induced Dry Eye

Abstract

Abstract: : Purpose:To determine the ability of the mucin secretagogue, 15(S)-HETE, to protect the cornea and preserve tear film integrity in a rabbit model of lacrimal gland inflammation induced dry eye. Methods:Rabbit lacrimal glands were injected with the T-cell mitogen Concanavalin A (ConA) and inflammation, tear function and corneal epithelial cell integrity were subsequently assessed. The inflammatory response was characterized by quantifying biochemical markers of inflammation ex vivo and by confirming inflammatory cell influx by histology. Matrix metalloproteinase-9 (MMP-9) and the pro-inflammatory cytokines IL-1ß, IL-8 and TNFα were quantified in lacrimal gland and corneal extracts. Tear function was monitored daily by measuring tear breakup time (TBUT) and corneal epithelial cell integrity was determined by quantifying uptake of methylene blue dye following exposure of rabbits to a low humidity environment. In the pharmacological characterization of 15(S)-HETE, the mucin secretagogue was administered topically. Results:Histopathologic evaluation of ConA injected lacrimal glands revealed a pronounced inflammatory process characterized by moderately severe lymphocytic infiltration, multifocal necrosis and fibroplasia. Lacrimal glands had elevated levels of IL-1ß, IL-8, TNFα and MMP-9 within twenty-four hours of injection with ConA. Biochemical markers of inflammation were also increased in corneal extracts over this time frame. Inflammation of the rabbit lacrimal gland following injection of ConA significantly reduced TBUT and increased susceptibility to desiccation-induced corneal damage. The mucin secretagogue 15(S)-HETE was prophyllactically and therapeutically effective in this inflammation model of dry eye. 15(S)-HETE restored TBUT and inhibited corneal staining at concentrations (0.3µM-3µM) known to stimulate ocular mucin secretion in vitro and in vivo. Conclusions:The mucin secretagogue 15(S)-HETE protected corneal epithelial cells from injury and restored tear film integrity in a rabbit model of lacrimal gland inflammation induced dry eye. These results suggest the potential therapeutic utility of selective mucin secretagogues in dry eye.

Keywords: cornea: tears/tear film/dry eye • inflammation • pharmacology