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S.W. Cousins, D.G. Espinosa–Heidmann, S. Pereira–Simon, D.M. Miller, R.D. Dix; Macrophage Activation Associated With Persistent Cytomegalovirus Infection Causes More Severe Experimental Choroidal Neovascularization (CNV) . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3508. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have previously shown that macrophages are important in experimental CNV, and that anti–macrophage therapy can limit severity. Second, patients with wet age–related macular degeneration (AMD) have macrophages with higher level of pro–inflammatory activity. Third, we have found much higher frequency of elevated cytomegalovirus–specific IgG titers in the serum of patients with wet AMD compared to patients with dry ARMD. Therefore, we hypothesize that wet AMD may be associated with macrophage activation in response to persistent infection with cytomegalovirus. We sought to test this idea in a mouse model of experimental CNV. Methods: C57BL/6 mice were injected with UV inactivated virus or infected with non–lethal doses of the Smith strain of murine cytomegalovirus. At various times after infection (6 days, 6 weeks and 12 weeks), laser–induced CNV was performed. CNV severity was determined 4 weeks later by analysis of choroidal flatmount. Splenic macrophages were recovered and mRNA isolated for RT–PCR for various pro–inflammatory factors. The choroids of eyes with CNV were recovered to document the presence of virus–associated ie2 or glycoprotein B. Results: Mice receiving UV inactivated virus demonstrated typically small CNV (1.8 +/–0.3 disc areas). In comparison, all mice infected with live virus demonstrated more severe CNV. The most severe CNV developed in mice with the most chronic infection (12 weeks post–infection = 4.3 +/– 1.2 disc areas, p<0.0001 versus UV inactivated virus). CNV and choroid from acutely infected mice demonstrated productive virus infection (i.e., gB mRNA), but CNV from chronically infected mice did not. Macrophages isolated from mice with chronic infection, compared to those from mice with acute infection, expressed significantly greater levels of mRNA for TNF–a, MMP–9, VEGF, COX–2 and beta 3 integrin. Conclusions: These studies indicate that chronic cytomegalovirus infection promotes increased CNV size and severity. Although the mechanism is uncertain, chronic virus–mediated pro–inflammatory activation of circulating macrophages seems more likely than direct virus infection of the choroid.
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