title: Corneal protection by the ocular mucin secretagogue 15(S)-HETE in a rabbit model of desiccation-induced corneal defect.
abstract: The mucin secretagogue 15(S)-HETE was found to stimulate glycoprotein secretion in human ocular tissue at submicromolar concentrations in the present studies. Therefore, the ability of topically applied 15(S)-HETE to preserve corneal integrity was investigated in a rabbit model of desiccation-induced corneal defect. Desiccation-induced corneal injury was elicited in anesthetized rabbits by maintaining one eye open with a speculum. Corneal staining and corneal thickness changes were determined immediately following desiccation. 15(S)-HETE dose-dependently reduced corneal damage (ED50 = 120 nM) during a two-hour desiccation. Corneal staining was unchanged relative to control using a 1 microM dose of 15(S)-HETE. Through four hours of desiccation, 15(S)-HETE (500 nM) decreased corneal staining by 71% and completely prevented corneal thinning. 15(S)-HETE (1 microM) was significantly more efficacious than an artificial tear product over the 4-hour desiccation period. There was no evidence of tachyphylaxis following repeated topical ocular dosing of 15(S)-HETE. These studies demonstrate that 15(S)-HETE stimulates ocular mucin secretion in vitro and effectively protects the cornea in a rabbit model of desiccation-induced injury. The results suggest that the ocular mucin secretagogue 15(S)-HETE may have therapeutic utility in dry eye patients, alleviating corneal injury and restoring corneal integrity.
authors.affiliation: Pharmaceutical Products Research, Alcon Research, Ltd, Fort Worth, TX, 76134, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Gamache
authors.forename: Zhong-You
authors.initials: ZY
authors.lastname: Wei
authors.forename: Lori K
authors.initials: LK
authors.lastname: Weimer
authors.forename: Steven T
authors.initials: ST
authors.lastname: Miller
authors.forename: Joan M
authors.initials: JM
authors.lastname: Spellman
authors.forename: John M
authors.initials: JM
authors.lastname: Yanni
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003890:Desiccation; D004305:Dose-Response Relationship, Drug; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D009077:Mucins / Q000378:metabolism*; D011817:Rabbits
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D009077:Mucins; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid