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1、.Journal of Neuroimmunology 119 2001 175182 rlocaterjneuroim Bloodretinal barrier breakdown in experimental coronavirus retinopathy: association with viral antigen, inflammation, and VEGF in sensitive and resistant strains Stanley A. Vinores a,), Yun Wangb, Melissa A. Vinoresa, Nancy L. Derevjanika,
2、 Albert Shia, Diane A. Klein a, Barbara Detrickc, John J. Hooksb a 825 Maumenee Building, Wilmer Ophthalmologic Institute, Johns Hopkins Uniersity School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9289, USA b Immunology and Virology Section, Laboratory of Immunology, National Eye Institut
3、e, National Institutes of Health, Bethesda, MD, USA c Department of Pathology, Johns Hopkins Uniersity School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9289, USA Received 17 January 2001; received in revised form 23 June 2001; accepted 25 June 2001 Abstract .Intraocular coronavirus inocu
4、lation results in a biphasic retinal disease in susceptible mice BALBrc characterized by an acute .inflammatory response, followed by retinal degeneration associated with autoimmune reactivity. Resistant mice CD-1 , when similarly .inoculated, only develop the early phase of the disease. Bloodretina
5、l barrier BRB breakdown occurs in the early phase in both strains, coincident with the onset of inflammation. As the inflammation subsides, the extent of retinal vascular leakage is decreased, indicating .that BRB breakdown in experimental coronavirus retinopathyECORis primarily due to inflammation
6、rather than to retinal cell .destruction. Vascular endothelial growth factorVEGFis upregulated only in susceptible mice during the secondaryretinal .degeneration phase. q2001 Elsevier Science B.V. All rights reserved. Keywords: Coronavirus; Bloodretinal barrier; Vascular endothelial growth factor; R
7、etinopathy 1. Introduction .The neurotropic strainJHMof the mouse hepatitis . virus MHV is a murine coronavirus that induces a bipha- sic retinal disease when injected intraocularly into BALBrc .mice Robbins et al., 1990, 1991 . The early phase of the disease occurs from 1 to 7 days post-inoculation
8、 and involves a retinal vasculitis associated with the presence of infectious virus. The late phase of the disease begins at about day 10 post-inoculation and involves retinal degener- ation associated with the presence of autoantibodies di- rected against the neuroretina and the retinal pigmented .
9、epitheliumRPE . Infectious virus, viral antigens, and inflammatory cells are absent during the late phase and virus-neutralizing antibodies are produced during both phases. When CD-1 mice are similarly inoculated, only the ) Corresponding author. Tel.: q 1-410-955-4103; fax: q 1-410-502- 5382. .E-ma
10、il address: svinoresjhmi.edu S.A. Vinores . .early phase of the disease is induced Wang et al., 1996 ; antiviral antibodies are produced, but anti-retinal autoanti- .bodies are not Hooks et al., 1993 . .Vascular endothelial growth factorVEGFis well characterized as an angiogenic agent and a vascular
11、 perme- ability factorSenger et al., 1983, 1986; Roberts and .Palade, 1995; Dvorak et al., 1995; Ozaki et al., 1997 , but recent findings show that it is also involved with the recruitment and activation of inflammatory cells and their adhesion to the vascular endothelium Barleon et al., 1996; .Clau
12、ss et al., 1996; Melder et al., 1996; Lu et al., 1999 . A marked upregulation of VEGF occurs in the inner retinas of rats developing experimental autoimmune uveoretinitis . .EAULuna et al., 1997; Vinores et al., 1998a . In these rats, there is inflammatory cell infiltration and an autoim- .mune reac
13、tion with bloodretinal barrierBRBbreak- down, but no angiogenesis. Experimental coronavirus .retinopathy ECORof murine retinas provides a model with inflammatory cell infiltration in the early phase and an autoimmune reaction in the late phase, when BALBrc mice are used. In CD-1 mice, the autoimmune
14、 response is 0165-5728r01r$ - see front matter q2001 Elsevier Science B.V. All rights reserved. .PII: S0165-5728 01 00374-5 ()S.A. Vinores et al.rJournal of Neuroimmunology 119 2001 175182176 absent; therefore, differences that may be observed in BRB breakdown and the presence andror distribution of
15、 VEGF and its receptors, when comparing these two strains, are likely to relate to the development of retinal degenerative disease. This model will be used to determine at what phase BRB breakdown occurs, how extensive it is, and whether it is reversible. The immunohistochemical local- ization of ex
16、travasated albumin is an established method for visualizing the location and extent of sites of BRB breakdown Vinores, 1995; Vinores et al., 1989, 1990b, .1994, 1995a,b and it will be used to assess the integrity of the BRB. This model can also provide information as to whether VEGF may play a role in one or both of these phases. 2. Materials and methods Coronavirus retinopathy was induced with the murine coronavirus, MHV, strain JHMAmerican Type Culture wx.Collection ATCC , Rockville, MD . The
