title: An anti-inflammatory role of VEGFR2/Src kinase inhibitor in herpes simplex virus 1-induced immunopathology.
abstract: 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.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 1414 Cumberland Avenue, Knoxville, TN 37996-0845, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Sharma
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003315:Cornea / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005260:Female; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C529233:4-chloro-3-(5-methyl-3-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)-1,2,4-benzotriazin-7-yl)phenol; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010636:Phenols; D014227:Triazines; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases