title: A closed eye contact lens model of corneal inflammation. Part 2: Inhibition of cytochrome P450 arachidonic acid metabolism alleviates inflammatory sequelae.
abstract: OBJECTIVE
  The authors have previously shown a marked increase in corneal epithelial arachidonic acid metabolism to 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosatrienoic acid (12-HETrE) in a model of closed eye-contact lens wear. Their formation was predominantly cytochrome P450-dependent and significantly correlated with inflammatory score and corneal thickness. In the current study, the authors used stannous chloride to inhibit the epithelial cytochrome P450-dependent synthesis of 12-HETE and 12-HETrE to assess the role of these eicosanoids as mediators of the inflammatory response to contact lens wear in the closed eye.
  
  
  METHODS
  Hydrogel contact lenses were soaked in stannous chloride (100 micrograms/ml) or vehicle and fitted to the rabbit eye in stacked fashion (two lenses/eye), followed by a silk suture tarsorrhaphy of approximately 90%. Eyes were analyzed over a 7-day period for inflammatory responses through slit lamp biomicroscopy, subjective inflammatory scoring, ultrasonic pachymetry, and corneal epithelial [1-14C]-arachidonic acid metabolism.
  
  
  RESULTS
  Closed eye-hydrogel contact lens wear resulted in a progressive anterior surface inflammatory response. Coinciding with these events was a time-dependent increase in corneal thickness and 12-HETE and 12-HETrE production rates by corneal epithelial homogenates. Treatment of the lenses with stannous chloride (100 micrograms/ml) significantly attenuated by day 7 the inflammatory score (56% decrease), corneal thickness (17% decrease), and 12-HETE and 12-HETrE synthesis (77% and 71% decrease, respectively).
  
  
  CONCLUSIONS
  This study further substantiates the involvement of cytochrome P450, through the synthesis of 12-HETE and 12-HETrE, in the inflammatory response associated with hydrogel contact lens wear in the closed eye. Thus, inhibition of cytochrome P450, with subsequent decreases in 12-HETE and 12-HETrE, may attenuate the pathophysiologic response to contact lens wear in the closed eye.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Conners
authors.forename: R A
authors.initials: RA
authors.lastname: Stoltz
authors.forename: K L
authors.initials: KL
authors.lastname: Davis
authors.forename: M W
authors.initials: MW
authors.lastname: Dunn
authors.forename: N G
authors.initials: NG
authors.lastname: Abraham
authors.forename: R D
authors.initials: RD
authors.lastname: Levere
authors.forename: M
authors.initials: M
authors.lastname: Laniado-Schwartzman
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D003262:Contact Lenses, Extended-Wear / Q000009:adverse effects; D003315:Cornea / Q000378:metabolism* / Q000473:pathology; D015715:Corneal Edema / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005143:Eyelids / Q000601:surgery; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007634:Keratitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011817:Rabbits; D013997:Time Factors; D017971:Tin Compounds / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D017971:Tin Compounds; C023599:stannous chloride; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D003577:Cytochrome P-450 Enzyme System