Effect of inhibitors of arachidonic acid metabolism on corneal reepithelialization in the rat.
We examined the ability of inhibitors of arachidonic acid metabolism to influence the rate of healing of organ-cultured rat corneas with 3-mm diameter central epithelial abrasions. In control corneas, and in the presence of the cyclooxygenase inhibitors indomethacin (1 microM), or flurbiprofen (1 microM), the defect was completely reepithelialized by 25 hr. In contrast, corneas cultured with the lipoxygenase inhibitors quercetin (100 microM), esculetin (100 microM), or baicalein (10 microM) or the dual cyclooxygenase/lipoxygenase inhibitors BW 775C (100 microM) or BW A540C (100 microM) had significantly delayed epithelial healing rates when compared with the controls; complete healing of the epithelial defects required 32.5-40 hr. Dose-response studies with esculetin and BW 755C demonstrated that the concentrations for 50% inhibition of reepithelialization (65.3 microM for esculetin, 39.6 microM for BW 755 C) were significantly greater than those for inhibition of 12-lipoxygenase activity (16.6 microM for esculetin, 21.1 microM for BW 755C), the major lipoxygenase activity in normal rat cornea. Addition of 12(S)-5,8,10,14- hydroxyeicosatetraenoic acid [12(S)-HETE, 0.01-10 microM], the main 12-lipoxygenase metabolite of arachidonic acid in normal rat cornea, to the organ cultures did not influence the rate of epithelial wound healing in the absence of presence of 100 microM esculetin. Our results suggest that lipoxygenase activity is an important factor in regulating corneal epithelial wound healing in the rat, presumably by influencing epithelial cell migration. The lipoxygenase enzyme and metabolite(s) responsible for regulating reepithelialization, and the mechanism of action, remain to be determined.
Gupta
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AG
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Hirakata
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A
Proia
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D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003315:Cornea / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009924:Organ Culture Techniques; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases