State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
Invest Ophthalmol Vis Sci. 2018 Jun 1;59(7):2923-2931. doi: 10.1167/iovs.18-23942.
The purpose of this study was to explore the effects of pigment epithelium derived factor (PEDF) and PEDF-derived peptides Mer44 and Mer34 on the severity of herpetic simplex keratitis (HSK) in mice.
Adult C57BL/6 mice were infected ocularly with the herpes simplex virus type 1 (HSV-1, McKrae strain) and injected subconjunctivally with PEDF, Mer44, or Mer34. Corneal nerve degeneration, neovascularization, sensitivity, neutrophils, macrophages and CD4+ T-cell infiltration, virus contents, and expressions of VEGF, PEDF, and proinflammatory factors were evaluated during acute period. The direct inhibitory effect of PEDF on HSV-1 replication was further evaluated in cultured monkey Vero cells.
Following HSV-1 infection, corneal PEDF expression decreased at 3 and 7 days postinfection (dpi) but increased at 15 dpi, and returned to the similar level of normal mice at 45 dpi, which was accompanied with the progress of corneal nerve degeneration and neovascularization. Exogenous PEDF application attenuated corneal nerve degeneration and neovascularization and improved the impaired corneal sensitivity. Moreover, PEDF attenuated the neutrophils, but not macrophage or CD4+ T-cell infiltration, with the reduced expressions of IL-1β, IL-6, TNF-α, and VEGF. In addition, PEDF inhibited the replication of HSV-1 both in vitro and in mice. Mer44 attenuated corneal nerve degeneration more significantly than Mer34, whereas Mer34 inhibited corneal neovascularization.
PEDF and its derived peptides reduce the severity of herpetic simplex keratitis in mice, representing the potential therapeutic approach to control HSK lesions.
本研究旨在探讨色素上皮衍生因子（PEDF）及其衍生肽 Mer44 和 Mer34 对单纯疱疹性角膜炎（HSK）小鼠模型严重程度的影响。
成年 C57BL/6 小鼠通过眼部感染单纯疱疹病毒 1 型（HSV-1，McKrae 株），并通过结膜下注射 PEDF、Mer44 或 Mer34。在急性期评估角膜神经退行性变、血管新生、敏感性、中性粒细胞、巨噬细胞和 CD4+T 细胞浸润、病毒含量以及 VEGF、PEDF 和促炎因子的表达。进一步在培养的猴肾 Vero 细胞中评估 PEDF 对 HSV-1 复制的直接抑制作用。
HSV-1 感染后，角膜 PEDF 表达在感染后 3 天和 7 天降低，但在 15 天增加，在 45 天恢复到正常小鼠的相似水平，同时伴有角膜神经退行性变和血管新生的进展。外源性 PEDF 应用可减轻角膜神经退行性变和血管新生，并改善受损的角膜敏感性。此外，PEDF 可减轻中性粒细胞浸润，但不减轻巨噬细胞或 CD4+T 细胞浸润，同时降低 IL-1β、IL-6、TNF-α 和 VEGF 的表达。此外，PEDF 可抑制 HSV-1 的体外和体内复制。Mer44 对角膜神经退行性变的抑制作用比 Mer34 更显著，而 Mer34 抑制角膜血管新生。
PEDF 及其衍生肽可减轻 HSK 小鼠模型的严重程度，为控制 HSK 病变提供了潜在的治疗方法。
