Yamada Naoyuki, Yanai Ryoji, Inui Makoto, Nishida Teruo
Department of Biomolecular Recognition, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
Invest Ophthalmol Vis Sci. 2005 Mar;46(3):833-9. doi: 10.1167/iovs.04-0775.
Substance P (SP) is present in the sensory nerve fibers of the corneal epithelium. Various biological agents, including epidermal growth factor, fibronectin, interleukin-6, and the combination of SP and insulin-like growth factor (IGF)-1, promote the healing of corneal epithelial wounds. The role of SP in corneal epithelial migration was examined.
The effects of various agents on corneal epithelial migration were investigated with the rabbit cornea in an organ culture system.
An SP-derived tetrapeptide, FGLM-amide, shifted the dose-response relations for the induction of corneal epithelial migration not only by an IGF-1-derived peptide (C-domain peptide) but also by fibronectin or interleukin-6 to lower concentrations. This action of SP was prevented by inhibitors of phospholipase C, of the inositol 1,4,5-trisphosphate receptor-mediated release of Ca(2+) from intracellular stores, and of Ca(2+)- and calmodulin-dependent protein kinase II (CaM-PK II).
These results indicate that SP, acting at the neurokinin type 1 receptor, functions as an important modulator of corneal epithelial wound healing by activating CaM-PK II in epithelial cells and thereby sensitizing them to the induction of migration by various biological agents. They also provide important insight into a new strategy for the treatment of corneal wounds.
P物质（SP）存在于角膜上皮的感觉神经纤维中。多种生物制剂，包括表皮生长因子、纤连蛋白、白细胞介素-6以及SP与胰岛素样生长因子（IGF）-1的组合，均可促进角膜上皮伤口的愈合。本研究检测了SP在角膜上皮迁移中的作用。
在器官培养系统中，用兔角膜研究了多种制剂对角膜上皮迁移的影响。
一种源自SP的四肽FGLM-酰胺，不仅使源自IGF-1的肽（C结构域肽），而且使纤连蛋白或白细胞介素-6诱导角膜上皮迁移的剂量反应关系向更低浓度偏移。SP的这一作用被磷脂酶C抑制剂、肌醇1,4,5-三磷酸受体介导的细胞内钙库Ca(2+)释放抑制剂以及钙和钙调蛋白依赖性蛋白激酶II（CaM-PK II）抑制剂所阻断。
这些结果表明，SP作用于神经激肽1型受体，通过激活上皮细胞中的CaM-PK II，从而使它们对多种生物制剂诱导的迁移敏感，进而作为角膜上皮伤口愈合的重要调节剂发挥作用。它们还为角膜伤口治疗的新策略提供了重要见解。
