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S. Kenchesowda, Sr., F. R. Jackson, J. A. Johnson, N. G. Bazan, H. E. P. Bazan; EGF Promotes Corneal Epithelial Wound Healing Through Induction of 12/15-Lipoxygenase and Synthesis of Lipoxin A4. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2595.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies show that epidermal growth factor (EGF) stimulates the synthesis of Lipoxin A4 (LxA4), a promoter of epithelial wound healing (ARVO 2008). EGF is a potent inducer of 12-lipoxygenase (12-LOX) in rabbit corneal epithelial cells (RCEC)(Exp.Eye.Res.76:613,2003).This enzyme converts arachidonic acid to 12(S)HETE and is also involved in the synthesis of LxA4. Here we demonstrate that activation of the EGF receptor (EGF-R) is needed for the induction of LxA4 and that 12/15-LOX plays a fundamental role in EGF-induced wound healing.
RCEC were pretreated with the EGF-R inhibitor AG 1478 (10µM) before stimulation with EGF(10ng/ml) for 36 h. Total RCE cell homogenate was incubated with (20µM) LTA4, and the synthesis of 12(S)HETE and LxA4 was analyzed by LC-ESI-MS/MS. To assess corneal epithelial wound healing, 2mm epithelial debridement wounds were made in 12/15-LOX-deficient mice (ALOX-15 knockout mice). Mice corneas were stimulated with EGF or LxA4 for 24 h.
Inhibition of EGF-R decreased during the synthesis of 12(S)HETE and LxA4 by almost 75% and 80% respectively, compared with EGF-stimulated RCE cells. ALOX-15 knockout mice showed a 2-fold decrease in wound healing promoted by EGF, compared to wild type stimulated with EGF. However, stimulation with LxA4 induced similar wound healing in both mice.
Our results demonstrate that activation of the EGF-R induces the synthesis of LxA4 and that the presence of 12/15-LOX is essential to promoting epithelial wound healing activated by EGF.
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