Saika Shizuya, Ikeda Kazuo, Yamanaka Osamu, Miyamoto Takeshi, Ohnishi Yoshitaka, Sato Misako, Muragaki Yasuteru, Ooshima Akira, Nakajima Yuji, Kao Winston W-Y, Flanders Kathleen C, Roberts Anita B
Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan.
Am J Pathol. 2005 May;166(5):1405-18. doi: 10.1016/S0002-9440(10)62358-9.
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-kappaB signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like 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-beta1, TGF-beta2, 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.
化学烧伤导致的角膜损伤是一个严重的临床问题，常常会导致永久性视力损害。由于转化生长因子（TGF）-β与角膜损伤反应有关，我们在角膜碱烧伤模型中评估了TGF-β信号改变的影响，该模型使用局部用表达抑制性Smad7的腺病毒（Ad）处理的小鼠以及靶向缺失TGF-β/激活素信号传导介质Smad3的小鼠。在烧伤的角膜组织中外源性Smad7的表达导致通过RelA/p65的Smad信号传导和核因子-κB信号传导的激活减少。在损伤后20天，结膜上皮对烧伤角膜的重新覆盖及其向角膜样上皮的分化在经Smad7-Ad处理的角膜中均加速，同时基质溃疡、混浊和新生血管形成受到抑制。Smad7基因的导入抑制了单核细胞/巨噬细胞的浸润以及单核细胞/巨噬细胞趋化蛋白-1、TGF-β1、TGF-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剂-2的表达，并消除了肌成纤维细胞的产生。虽然在缺乏Smad3的小鼠中也观察到烧伤角膜愈合加速，但对上皮和基质愈合的影响不如用Smad7处理的角膜明显。这些数据共同表明，Smad7的过表达可能具有超出简单阻断Smad3/TGF-β信号传导的作用，可能代表一种治疗眼烧伤的有效新策略。
