Abstract
Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.
Highlights
Radiation retinopathy (RR) is a chronic degenerative disease that leads to significant visual impairment [1,2]
Digital analysis of U937 cell adhesion to the retinal endothelial cell (REC) monolayer revealed significant increases following radiation compared to unirradiated RECs (Fig. 2b, 262 vs. 87618 adhered cells; *P,0.05)
Studies have emphasized the primary mechanism of retinal injury involves leukocyte entrapment and accumulation within microvascular circulation with resultant capillary closure and subsequent ischemia [45]
Summary
Radiation retinopathy (RR) is a chronic degenerative disease that leads to significant visual impairment [1,2]. RR results from exposure of the eye to various directed radiotherapy interventions such as external beam, plaque brachytherapy, and gamma knife [3,4,5]. Radiotherapy is used to treat uveal melanoma since it provides both equivalent local tumor control and survival enucleation (eye removal) [6,7]. The incidence of RR in patients with uveal melanoma treated with plaque brachytherapy has been estimated at 20% with a subset of these patients developing proliferative neovascularization [8,9,10]. Radiation-induced damage to the vascularized retina triggers an exuberant pro-inflammatory response resulting in leukocyte adhesion and stasis, vessel occlusion, retinal endothelial cell (REC) death, and subsequent hypoxia [12,13]. Studies inhibiting adhesive interactions using antibodies against ICAM-1 prevented retinal endothelial cell dysfunction, death and subsequent tissue ischemia, in turn, preventing compensatory retinal neovascularization (Fig. 1) [15]
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