Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 1414 Cumberland Avenue, Knoxville, TN 37996-0845, USA.
J Virol. 2011 Jun;85(12):5995-6007. doi: 10.1128/JVI.00034-11. Epub 2011 Apr 6.
Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4(+) T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world.
角膜新生血管是单纯疱疹病毒（HSV）引起眼部感染导致致盲性炎症性基质角膜炎（SK）的关键步骤。在本报告中，我们描述了一种限制 HSV 感染小鼠眼血管生成的新方法。我们发现，局部或全身给予Src 激酶抑制剂（TG100572）可抑制血管内皮生长因子（VEGF）信号通路的下游分子，导致 HSV 诱导的血管生成水平明显降低，并显著减轻 SK 病变的严重程度。多种机制参与了抑制作用。这些机制包括阻断白细胞介素-8（IL-8）/趋化因子（CXCL1），IL-8/CXCL1 参与招募炎症细胞，而炎症细胞是 VEGF 的来源，减少角膜中的细胞浸润，以及减少 CD4（+）T 细胞向角膜的增殖和迁移。由于多种血管生成因子（VEGF 和碱性成纤维细胞生长因子[bFGF]）在促进 SK 期间的血管生成中发挥作用，并且 Src 激酶参与其中许多因子的信号转导，因此抑制 Src 激酶代表了一种有前途的方法，可以限制 SK 病变的严重程度，SK 病变是西方世界感染性失明的最常见原因。
