Xiao Yi-qin, Liu Kun, Shen Jian-feng, Xu Guo-tong, Ye Wen
Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China.
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1698-706. doi: 10.1167/iovs.08-1675. Epub 2008 Dec 20.
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).
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.
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.
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.
探讨SB - 431542（一种ALK5抑制剂）对青光眼手术后瘢痕形成的抑制作用，并确定潜在的药理学靶点。
24只新西兰兔右眼接受滤过手术，分为对照组和三个实验组（n = 6）。刮除人Tenon成纤维细胞单层以形成单个间隙，然后添加仅含SB - 431542的对照培养基或含有10μg/L TGF -β1和SB - 431542（1 - 20μM）的培养基。在用10μg/L TGF -β1或1μg/L TGF -β2诱导之前，细胞用SB - 431542或对照培养基预处理30分钟。检测α - SM -肌动蛋白、结缔组织生长因子（CTGF）和I型胶原（Col I）的表达以及Smad、细胞外调节蛋白激酶（ERK）、P38和蛋白激酶B（AKT）信号通路的变化。
与对照兔相比，实验组的眼压在手术后第25天之前一直保持在较低水平（P < 0.05）。组织学分析表明，实验组结膜下间隙仅存在轻度胶原沉积。无论培养系统中是否存在TGF -β，SB - 431542均能有效抑制细胞生长和迁移。SB - 431542消除了TGF -β诱导的α - SM -肌动蛋白、CTGF和Col I的上调。它有效抑制了TGF -β刺激的Smad2磷酸化，但不抑制丝裂原活化蛋白激酶（MAPK）通路成分的磷酸化。
SB - 431542抑制青光眼滤过手术后的瘢痕形成。其机制可能是SB - 431542干扰Smad2的磷酸化，从而消除TGF -β诱导的成纤维细胞转分化，进而减少Col I合成。
