Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali
Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali
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DOI：
10.1016/s0002-9440(10)62358-9
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发表时间：
2005-05-01
影响因子：
6
通讯作者：
Roberts, AB
中科院分区：
文献类型：
--
作者：
Saika, S;Ikeda, K;Roberts, AB
化学烧伤对角膜的损害是一个严重的临床问题，通常会导致永久性视力障碍。由于转化生长因子(TGF)-β参与了角膜损伤的反应，我们在角膜碱烧伤模型中评估了转化生长因子-β信号的改变的影响，使用外用腺病毒(Ad)表达抑制性Smad7的小鼠和靶向缺失TGF-β/激活素信号中介Smad3的小鼠。外源性Smad7在烧伤角膜组织中的表达导致Smad信号和核因子-kappaB信号通过relA/p65的激活减少。Smad7-Ad治疗组在伤后20天角膜基质溃烂、混浊和新生血管形成均受到抑制，结膜上皮细胞表面化和向角膜纤维上皮细胞分化均加快。Smad7基因的导入抑制了单核/巨噬细胞的侵袭，抑制了单核/巨噬细胞趋化蛋白-1、转化生长因子-β1、转化生长因子-β2、血管内皮生长因子、基质金属蛋白酶-9和金属蛋白酶组织抑制因子-2的表达，并取消了肌成纤维细胞的生成。虽然在缺乏Smad3的小鼠身上也观察到了烧伤角膜愈合的加速，但对上皮和间质愈合的影响没有使用Smad7的小鼠那么明显。综上所述，这些数据表明，Smad7的过表达可能具有简单阻断Smad3/转化生长因子-β信号的作用，并可能代表一种有效的治疗眼烧伤的新策略。
Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-beta has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-beta signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-beta/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-kappa B signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-fike epithelium were both accelerated in Smad7-Ad-treated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-beta 1, TGF-beta 2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overexpression of Smad7 may have effects beyond those of simply blocking Smad3/TGF-beta signaling and may represent an effective new strategy for treatment of ocular burns.