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Originally published In Press as doi:10.1167/iovs.08-1675 on December 20, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:1698-1706.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-1675
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SB-431542 Inhibition of Scar Formation after Filtration Surgery and Its Potential Mechanism

Yi-qin Xiao,1 Kun Liu,1 Jian-feng Shen,2 Guo-Tong Xu,*,2,3 and Wen Ye*,1

1From the Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China; the 2Laboratory of Clinical Visual Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China; and the 3Tongji Eye Institute and Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.

PURPOSE. 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 µg/L TGF-β1 and SB-431542 (1–20 µM) was added. The cells were pretreated with SB-431542 or in control medium for 30 minutes before induction with 10 µg/L TGF-β1 or 1 µg/L TGF-β2. 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-β was present in the culture system. SB-431542 abrogated TGF-β-induced upregulation of {alpha}-SM-actin, CTGF, and Col I. It effectively inhibited the phosphorylation of Smad2 stimulated by TGF-β 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-β-induced fibroblast transdifferentiation and then decreasing Col I synthesis.






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