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Research ArticleArticle

Hypoxia Stimulates the Synthesis of Cytochrome P450-Derived Inflammatory Eicosanoids in Rabbit Corneal Epithelium

Christina Vafeas, Paul A. Mieyal, Ferdinando Urbano, John R. Falck, Kamlesh Chauhan, Michael Berman and Michal Laniado Schwartzman
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 903-910;
Christina Vafeas
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Paul A. Mieyal
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Ferdinando Urbano
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John R. Falck
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Kamlesh Chauhan
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Michael Berman
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Michal Laniado Schwartzman
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Abstract

The corneal epithelium metabolizes arachidonic acid by a cytochrome P450-(CYP) mediated pathway to 12(R)hydroxy-5,8,10,14-eicosatrienoic acid [12(R)-HETE] and 12(R)hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE]. Both metabolites possess potent inflammatory properties with 12(R)-HETrE being a powerful angiogenic factor and assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea, in vivo. We developed an in vitro model of corneal organ culture to characterize the biochemical and molecular events involved in the increased synthesis of these metabolites. These cultured corneas exhibit epithelial cytochrome P450 CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis as indicated by chiral analysis and by the ability of CYP enzyme inhibitors to repress their synthesis. Hypoxia greatly and selectively stimulated the synthesis of 12(R)-HETE (7-fold over control normoxic conditions) and 12(R)-HETrE. The bacterial endotoxin, lipopolysaccharide, also increased the synthesis of these eicosanoids, substantiating the notion that this activity may function as an inflammatory pathway. These metabolites were detected in the culture medium by gas chromatography/mass spectroscopy (GC/MS) analysis and their levels significantly increased in hypoxia-treated corneas, further indicating their endogenous formation in response to injury. This in vitro model provides an excellent preparation for studying factors regulating the synthesis of these inflammatory eicosanoids and for isolating, identifying and characterizing the CYP protein responsible for their synthesis.

Footnotes

  • Send reprint requests to: Dr. Michal Laniado Schwartzman, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.

  • ↵1 This work was supported by National Institutes of Health Grants EY06513 (M.L.S.) and DK38226 (J.R.F.).

  • Abbreviations:
    CYP
    cytochrome P450
    12-HETE
    12-hydroxy-5,8,10,14-eicosatrienoic acid
    12-HETrE
    12-hydroxy-5,8,14-eicosatrienoic acid
    17-ODYA
    17-octadecynoic acid
    CDC
    cinnamyl-3,4-dihydroxy-α-cyanocinnamate
    NCI-GC/MS
    negative chemical ionization-gas chromatography/mass spectroscopy
    RP-HPLC
    reverse-phase high performance liquid chromatography
    DMEM
    Dulbecco’s modified Eagle’s medium
    PMSF
    phenylmethanesulfonylfluoride
    PFB
    pentafluorobenzyl ester
    TMS
    trimethylsilyl ether
    LH
    lactalbumin enzymatic hydrolysate
    FBS
    fetal bovine serum
    IL
    interleukin
    GC/MS
    gas chromatography/mass spectroscopy
    LPS
    lipopolysaccharide
    • Received March 23, 1998.
    • Accepted June 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Hypoxia Stimulates the Synthesis of Cytochrome P450-Derived Inflammatory Eicosanoids in Rabbit Corneal Epithelium

Christina Vafeas, Paul A. Mieyal, Ferdinando Urbano, John R. Falck, Kamlesh Chauhan, Michael Berman and Michal Laniado Schwartzman
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 903-910;

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Research ArticleArticle

Hypoxia Stimulates the Synthesis of Cytochrome P450-Derived Inflammatory Eicosanoids in Rabbit Corneal Epithelium

Christina Vafeas, Paul A. Mieyal, Ferdinando Urbano, John R. Falck, Kamlesh Chauhan, Michael Berman and Michal Laniado Schwartzman
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 903-910;
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