We have previously reported (Arch Ophthal 2000;118:666) that astroglia
in the optic nerve head of glaucomatous eyes demonstrate increased expression
of the pro-inflammatory cytokine tumor necrosis factor-alpha. Using a
co-culture system, in which retinal ganglion cells and glial cells are grown on
different layers, but share the same culture medium, we studied influences of
glial cells on survival of retinal ganglion cells following exposure to
different stress conditions typified by simulated ischemia and elevated
hydrostatic pressure. Following exposure to these stressors, we observed that
glial cells secreted TNF-alpha as well as other noxious agents such as nitric
oxide into the co-culture media which facilitated apoptotic death of retinal
ganglion cells as assessed by morphology, terminal deoxynucleotidyl
transferase-mediated dUTP nick end labeling and caspase activity. The glial
origin of these noxious effects was confirmed by passive transfer experiments.
Since elevated intraocular pressure and ischemia are two prominent stress
factors identified in the eyes of patients with glaucoma, these findings reveal
a novel glia-initiated pathogenic mechanism for retinal ganglion cell death in
glaucoma. In addition, these findings suggest that inhibition of TNF-alpha
released by activated glial cells may provide a novel therapeutic target for
neuroprotection in the treatment of glaucomatous optic neuropathy.
(Supported by NIH RO-1 12314; Glaucoma Research Foundation, San
Francisco, American Health Assistance Foundation, Glaucoma Foundation, NYC and
Pharmacia)