EGF Stimulates Lipoxin A4 Synthesis and Modulates Repair in Corneal Epithelial Cells through ERK and p38 Activation
Open Access
- 1 April 2011
- journal article
- cornea
- Published by Association for Research in Vision and Ophthalmology (ARVO) in Investigative Ophthalmology & Visual Science
- Vol. 52 (5), 2240-2249
- https://doi.org/10.1167/iovs.10-6199
Abstract
Purpose.: To investigate the effect of epidermal growth factor (EGF) on lipoxin A4 (LXA4) synthesis and how it regulates corneal epithelial wound healing through mitogen-activated kinases, extracellular regulated kinase (ERK) 1/2, and p38. Methods.: Rabbit corneal epithelial (RCE) cells were stimulated with EGF or LXA4 at different times. In some experiments, cells were pretreated with 12/15-lipoxygenase (12/15-LOX) inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), ERK1/2 inhibitor PD98059, or p38 inhibitor SB203580. For wound-healing experiments, corneas from rabbits and 12/15-LOX (ALOX-15)-deficient mice were injured by epithelial removal and maintained in organ culture in the presence of EGF or LXA4 with or without inhibitors. Epithelial cell proliferation was assayed by immunofluorescence with Ki67 and cell counting. Scrape migration assays were performed in 6-well plates. LXA4 synthesis was analyzed by liquid chromatography-tandem mass spectrometry analysis. Results.: EGF activated ERK1/2 and p38 in RCE cells in a sustained manner. EGF activation was partially inhibited by CDC. EGF and LXA4 increased corneal epithelial wound closure. ERK1/2 inhibition with PD98059 or p38 with SB203580 blocked the effect of LXA4 on wound healing. ALOX-15 corneas displayed inhibition of epithelial wound closure promoted by EGF, whereas LXA4 stimulation induced similar wound closure in wild-type and knockout mice. EGF-stimulated LXA4 synthesis in RCE cells was inhibited by CDC or the EGF receptor antagonist AG1478. Conclusions.: These results demonstrate that EGF-stimulated epithelial wound healing is partially mediated through a 12/15-LOX-LXA4 pathway, and activation of ERK1/2 and p38 is required for LXA4 action.This publication has 54 references indexed in Scilit:
- Epidermal growth factor receptor transactivation by the cannabinoid receptor (CB1) and transient receptor potential vanilloid 1 (TRPV1) induces differential responses in corneal epithelial cellsExperimental Eye Research, 2010
- Significance of lipid mediators in corneal injury and repairJournal of Lipid Research, 2010
- Endogenous LXA4 Circuits Are Determinants of Pathological Angiogenesis in Response to Chronic InjuryThe American Journal of Pathology, 2010
- ERK1/2 Mediate Wounding- and G-protein-Coupled Receptor Ligands-Induced EGFR Activation via Regulating ADAM17 and HB-EGF SheddingInvestigative Ophthalmology & Visual Science, 2009
- Wounding Sheets of Epithelial Cells Activates the Epidermal Growth Factor Receptor through Distinct Short- and Long-Range MechanismsMolecular Biology of the Cell, 2008
- Epidermal Growth Factor Synergism with TGF-β1 via PI-3 Kinase Activity in Corneal Keratocyte DifferentiationInvestigative Ophthalmology & Visual Science, 2008
- γδ T Cells Are Necessary for Platelet and Neutrophil Accumulation in Limbal Vessels and Efficient Epithelial Repair after Corneal AbrasionThe American Journal of Pathology, 2007
- Cross Talk between c-Met and Epidermal Growth Factor Receptor during Retinal Pigment Epithelial Wound HealingInvestigative Ophthalmology & Visual Science, 2007
- Lysophosphatidic Acid Promoting Corneal Epithelial Wound Healing by Transactivation of Epidermal Growth Factor ReceptorInvestigative Ophthalmology & Visual Science, 2007
- Epithelial cell motility is triggered by activation of the EGF receptor through phosphatidic acid signalingJournal of Cell Science, 2006