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Inhibitory effect of blocking TGF-beta/Smad signal on injury-induced fibrosis of corneal endothelium Sumioka T; Ikeda K; Okada Y; Yamanaka O; Kitano A; Saika SMol Vis 2008[]; 14 (ä): 2272-81PURPOSE: To understand the role of TGF-beta related signals in the repair of a corneal endothelium defect and also to evaluate the therapeutic effect of Smad7 gene transfer on injury induced fibrosis of the corneal endothelium in rats. METHODS: (1) Japanese albino rabbits (n=108) were used. Blocks of central cornea (4 x 4 mm) were prepared. After partially scraping the endothelium to produce a defect, the blocks were organ cultured for 24 h in the presence of either exogenous growth factors, transforming growth factor beta (TGF-beta)-neutralizing antibody, or inhibitors of each TGF-beta related signal. Endothelium repair was assayed under light microscopy. (2) Adult Wistar rats (n=62) were then used. Smad7 expressing adenoviral vector (Smad7-Ad) or non-functioning control vector (Cre-Ad) was administered to the anterior chamber of an eye. The cornea was burned with topical 1 N NaOH (10 microl) three days later. After specific intervals, the eye was histologically observed. RESULTS: (1) The endothelial layer that elongated toward the defect lacked proliferation after 24 h in organ culture. Endogenous TGF-beta was required for endothelium defect repair. Inhibition of p38 and Erk but not c-Jun NH(2)-terminal kinase (JNK) and ALK5 signal (Smad) retarded such cell spreading. (2) Adenoviral Smad7 overexpression suppressed fibrogenic reaction of the endothelium of an alkali-burned cornea as evaluated by immunohistochemistry for phospho-Smad2, collagen I, and alpha-smooth muscle actin, a marker for endothelial-mesenchymal transition (EnMT), and by electron microscopy. CONCLUSIONS: Inhibition of Smad and JNK signals do not affect corneal endothelium defect repair. Inhibition of Smad suppresses fibrogenic reaction via EnMT of corneal endothelium in vivo.|Adenoviridae/genetics[MESH]|Animals[MESH]|Antibodies/pharmacology[MESH]|Burns/pathology[MESH]|Cell Movement/drug effects[MESH]|Cytokines/metabolism[MESH]|Disease Models, Animal[MESH]|Endothelium, Corneal/*drug effects/*pathology/ultrastructure[MESH]|Fibrosis[MESH]|Genetic Vectors/genetics[MESH]|Integrases/metabolism[MESH]|Mice[MESH]|Neutralization Tests[MESH]|Organ Culture Techniques[MESH]|Rabbits[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Signal Transduction/*drug effects[MESH]|Smad Proteins/*antagonists & inhibitors/metabolism[MESH]|Transduction, Genetic[MESH]|Transforming Growth Factor beta1/*antagonists & inhibitors/metabolism/pharmacology[MESH]|Transforming Growth Factor beta2/pharmacology[MESH]|Wound Healing/drug effects[MESH] |
