Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus.
In this report, we demonstrate that herpes simplex virus (HSV) infection of the cornea results in the upregulation of the matrix-degrading metalloproteinase enzyme MMP-9. This enzyme was shown to contribute to the neovascularization process that occurs in the corneal stroma in response to HSV infection. The likely source of MMP-9, at least initially after infection, was neutrophils that were signaled to invade the cornea soon after infection. Corneal infiltrating neutrophils were shown to express MMP-9, and preventing the neutrophil response with specific mAb diminished MMP-9 expression as well as the extent of angiogenesis. Further supporting a role for MMP-9 in HSV-induced corneal angiogenesis was the observation that inhibition of MMP-9 with the specific inhibitor TIMP-1 resulted in reduced angiogenesis. In addition, angiogenesis was diminished in ocularly infected MMP-9 knockout mice. Our results demonstrate that MMP-9 is involved in angiogenesis caused by HSV. Since angiogenesis appears to represent a vital step in the pathogenesis of herpetic stromal keratitis, these results indicate that targeting MMP-9 for inhibition should prove useful for the therapy of herpetic stromal keratitis.
Lee
Sujin
S
Department of Microbiology, The University of Tennessee, Knoxville, Tennessee 37996-0845, USA.
Zheng
Mei
M
Kim
Bumseok
B
Rouse
Barry T
BT
D000818:Animals; D004247:DNA / Q000187:drug effects / Q000235:genetics; D016228:Endothelial Growth Factors / Q000494:pharmacology; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D016849:Keratitis, Herpetic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008212:Lymphocyte Depletion; D008222:Lymphokines / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D009504:Neutrophils / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004247:DNA; D020780:Matrix Metalloproteinase 9