Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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DNA / drug effects
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DNA / genetics
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Endothelial Growth Factors / pharmacology
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Female
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Intercellular Signaling Peptides and Proteins / pharmacology
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Keratitis, Herpetic / enzymology*
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Keratitis, Herpetic / genetics
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Keratitis, Herpetic / pathology*
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Keratitis, Herpetic / physiopathology
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Lymphocyte Depletion
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Lymphokines / pharmacology
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Matrix Metalloproteinase 9 / deficiency
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / physiology*
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Matrix Metalloproteinase Inhibitors
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Neovascularization, Pathologic / enzymology*
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Neovascularization, Pathologic / etiology
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Neovascularization, Pathologic / prevention & control
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Neutrophils / physiology
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Protease Inhibitors / pharmacology
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Tissue Inhibitor of Metalloproteinase-1
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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DNA
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Matrix Metalloproteinase 9