The present findings could have significant clinical importance.
Although sensitivity to oxidant-induced apoptosis by a mitochondrial
mechanism could increase because of life-long accumulation of genome
damage in the mitochondrial DNA, this sensitivity may not be readily
reversible by antioxidant treatments.
34 However, the
Fas-mediated pathway appears to be potentiated by increased FasL and
Fas expression, and this could be suppressed by antioxidants. In vitro
studies have demonstrated that many factors can induce FasL expression
and stimulate release of sFasL. These include T-cell activation,
phagocytosis, viral infection, metalloproteinase activation, and
oxidative stress.
14 15 35 36 37 38 A number of studies suggest
that oxidative damage in the RPE cells may contribute to the pathology
of ARMD.
18 24 25 26 27 Therefore, a mechanism for oxidative
injury of RPE cells in ARMD may involve upregulation of FasL in T cells
or other cell types. When cells with increased FasL infiltrate to the
subretinal space, they may facilitate oligomerization of Fas receptors
on RPE cells and kill them. In healthy, noninflamed eyes, Bruch’s
membrane may protect against cells infiltrating from the
choriocapillaris.
1 However, Bruch’s membrane function may
be impaired in inflamed eyes. Moreover, T cells and
monocyte/macrophages can also enter the subretinal space adjacent to
the RPE cells through retinal capillaries. Indeed, the presence of T
cells in the subretinal space has been found in the rat with
experimental autoimmune uveitis.
39 In exudative ARMD, a
choroidal neovascular membrane grows under or through the retinal
pigment epithelium through breaks in Brush’s membrane.
2 The endothelial cells of this neovascular net lack tight junctions, and
therefore fluid and blood leak into the subpigment epithelial layer of
the retina.
40 This could attract more cells that express
high FasL, such as activated T cells and activated macrophages, allow
access to FasL-bearing endothelial cells, or exposure to circulating
sFasL and thereby cause death of RPE cells. Thus, if Fas-mediated
apoptosis contributes to pathogenesis of ARMD, it may be involved both
in the initiation and progression of the disease.