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From the Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
PURPOSE. Epidermal growth factor (EGF) and related growth factors: transforming
growth factor (TGF)-
, heparin-binding (HB)-EGF, and amphiregulin
(AR), have been shown to stimulate events associated with epithelial
wound repair. These growth factors function by binding to a common EGF
receptor (EGFR), tyrosine kinase. We have used in vivo and organ
culture wound-healing models to examine the kinetics and extent of EGFR
activation during corneal epithelial wound repair and whether the
epithelium itself produces EGFR ligands capable of stimulating the
healing process.
METHODS. In the in vivo model, 3-mm débridement wounds were made in rat
corneas and allowed to heal in situ. Activation of EGFR was analyzed by
1) indirect immunofluorescence microscopy, 2) immunoprecipitation using
anti-EGFR and anti-phosphotyrosine (anti-PT), and 3) binding-site
localization using EGF–fluorescein isothiocyanate (FITC). Relative
levels of mRNA for EGF, TGF-, HB-EGF, and AR were determined using
reverse transcription–polymerase chain reaction. To determine whether
inhibiting EGFR activation slows epithelial migration, wounded corneas
were allowed to heal in organ culture in the presence of tyrphostin
AG1478 (0–50 µM), a specific inhibitor of EGFR kinase activity.
RESULTS. In unwounded corneas, EGFR was localized in basal cells and appeared to
be membranous. Within 1 hour after wounding, EGFR was no longer
immunolocalized in the membranes of cells migrating into the wound
area. EGF-FITC–binding assays indicated that EGFR ligands could
penetrate all the way to the limbus. Immunoprecipitation showed that
EGFR was phosphorylated on tyrosine residues within 30 minutes after
wounding and that phosphorylation levels increased after wounding.
Levels of mRNA for TGF-, HB-EGF, and AR all appeared to increase
after wounding. In organ culture experiments, tyrphostin AG1478
inhibited migration rates in a dose-dependent manner.
CONCLUSIONS. These data indicate that EGFR was activated during corneal epithelial wound healing in vivo. Furthermore, this activation appears to be a necessary component of the process, because inhibition of the EGFR signaling cascade significantly slowed migration rates.
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