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1From the Departments of Ophthalmology and 2Pathology, Wakayama Medical University, Wakayama, Japan; the 3Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida; and the 4Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio.
PURPOSE. The purpose of the present study was to examine the roles of signaling pathways potentially activated by TGFß (i.e., Smad and p38 mitogen-activated kinase [MAPK]) in regulation of cell migration and proliferation of healing mouse corneal epithelium.
METHODS. Activation of Smads or p38MAPK was evaluated by immunohistochemistry in healing mouse corneal epithelium after debridement. The role of endogenous TGFß or p38MAPK in epithelial healing was determined in organ-cultured mouse corneas with an epithelial defect, in the presence or absence of a TGFß-neutralizing antibody or p38MAPK inhibitors, respectively. Cell proliferation was evaluated by incorporation of bromodeoxyuridine.
RESULTS. Migrating mouse corneal epithelium had minimal cell proliferation. Smad3 and -4 were found in nuclei of normal corneal epithelium, whereas they were absent in nuclei of migrating cells in association with Smad7 upregulation on epithelial debridement. Administration of TGFß-neutralizing antibody reduced the protein expression of Smad7 in vivo after a corneal injury. In contrast, phosphorylation and nuclear translocation of p38MAPK were markedly evident in migrating epithelium during healing, but not in uninjured epithelium. In organ culture, addition of p38MAPK inhibitors blocked cell migration more markedly than neutralizing TGFß-antibody and enhanced cell proliferation in the injured corneal epithelium, in association with phosphorylation of Erk.
CONCLUSIONS. Endogenous TGFß enhances migration of corneal epithelium during wound healing in mice. The p38MAPK, but not the Smad, cascade plays a major role in promoting cell migration and in suppressing cell proliferation in migrating epithelium.
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