Investigation on the pathology of neurotrophic keratopathy and development of new drugs

我们的临床经验表明，感觉神经系统可能在角膜上皮损伤愈合中起重要作用。本研究的最终目的是了解神经营养性角膜病变的病理机制，并开发新的治疗模式。为此，我们研究了P物质和ICF- 1对角膜上皮的协同作用的作用机制。利用角膜器官培养系统，我们发现P物质和IGF- 1协同作用的信号转导系统中有蛋白激酶C和酪氨酸激酶参与。此外，我们发现，在物质P，FGLM的C-末端的四个氨基酸序列，是与ICE-1在体外和体内对角膜上皮伤口愈合的协同作用的最小氨基酸序列。这种协同作用通过激活整合素α 5 β 1、粘着斑激酶和桩蛋白系统来表达。在临床情况下，局部应用P物质+ IGF-1滴眼液或FCLM + IGF-1滴眼液治疗严重的神经营养性角膜病变是有效的。这些结果表明，含有P物质+ ICF-1或FCLM + IGF-1滴眼液的治疗可能为未来的治疗神经营养性角膜病变的方法提供了线索。

Our clinical experience that lost corneal sensation often induces persistent corneal epithelial defects or delay epitheliat wound healing suggested that sensory nerve system might play an important role in corneal epithelial wound healing. The ultimate purpose of the present study is to understand the pathology and to develop the new mode of treatment of neurotrophic keratopathy. For this end, we investigated the action mechanisms of the synergistic effects of substance P and ICF- 1 on corneal epithelium. Using an organ culture system of the cornea, we found that protein kinase C and tyrosine kinase, signal tansduction systems are involved in the synergistic effect of substance P and IGF- 1 . In addition, we found that a four amino acid sequence at the C-terminus of substance P, FGLM, was the minimum amino acid sequence for the synergistic effect with ICE-1 on corneal epithelial wound healing in vitro and in vivo. This synergism is expressed through the activation of integrin alpha5beta1, focal adhesion kinase, and paxillin system. In clinical situations, topical application of substance P + IGF-1 eye drops or FCLM + IGF-1 eye drops was effective in the treatment of severe neurotrophic keratopathy These results suggested that the treatment with eye drops containing substance P + ICF-1 or FCLM + IGF-1 may shed light on future approaches to the treatment of neurotrophic keratopathy.