SB-431542 inhibition of scar formation after filtration surgery and its potential mechanism.
OBJECTIVE
To explore the inhibitive effect of SB-431542 (an ALK5 inhibitor) on scar formation after glaucoma surgery and to identify the potential pharmacologic target(s).


METHODS
Twenty-four New Zealand rabbits underwent filtration surgery on the right eye and were divided into a control group and three experimental groups (n=6). Human Tenon's fibroblast monolayer was scraped to generate a single gap, and then the control medium with SB-431542 only or containing 10 microg/L TGF-beta1 and SB-431542 (1-20 microM) was added. The cells were pretreated with SB-431542 or in control medium for 30 minutes before induction with 10 microg/L TGF-beta1 or 1 microg/L TGF-beta2. The expression of alpha-SM-actin, CTGF, and Col I, as well as changes in the Smad, ERK, P38, and AKT signaling pathways were detected.


RESULTS
In comparison with the control rabbits, the IOPs in the experimental groups remained at lower levels until day 25 (P<0.05) after the surgery. Histologic profiles showed that there was only a mild deposition of collagen in the subconjunctival space in the experimental groups. The cell growth and migration were inhibited effectively by SB-431542, regardless of whether TGF-beta was present in the culture system. SB-431542 abrogated TGF-beta-induced upregulation of alpha-SM-actin, CTGF, and Col I. It effectively inhibited the phosphorylation of Smad2 stimulated by TGF-beta but not that of the components of the MAPK pathways.


CONCLUSIONS
SB-431542 inhibits scar formation after glaucoma filtration surgery. The mechanism may be that SB-431542 interferes in the phosphorylation of Smad2, thus abrogating TGF-beta-induced fibroblast transdifferentiation and then decreasing Col I synthesis.
Xiao
Yi-qin
YQ
Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China.
Liu
Kun
K
Shen
Jian-feng
JF
Xu
Guo-tong
GT
Ye
Wen
W
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D024042:Collagen Type I / Q000378:metabolism; D003229:Conjunctival Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003239:Connective Tissue Cells / Q000187:drug effects / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018463:Filtering Surgery; D005901:Glaucoma / Q000601:surgery; D006801:Humans; D007267:Injections; D007429:Intraocular Pressure; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000199:Actins; D001549:Benzamides; C526317:CCN2 protein, human; D024042:Collagen Type I; D004149:Dioxoles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human