Abstract
Degenerative-dystrophic retinal diseases, particularly age-related macular degeneration (AMD), are now considered to be the lead cause of blindness and low vision in developed countries, with a steadily increasing trend. Recent publications provide evidence for the involvement of inflammatory mechanisms in TMD development and progression unveiled due to advances in innate and adaptive immunity research. However, the immunopathogenesis of atrophic AMD form, “geographic atrophy” (GA) remains largely unstudied. Objective: to investigate local mRNA expression of inflammatory cytokines IL-1β, IL-18, CCL2/MCP-1 in a model of RPE atrophy induced after subretinal injection of 0.9% sodium chloride solution in experimental rabbits. The investigation was carried out in tissue complex retina-RPE-choroid (TC) samples isolated from eyes of 23 albino New Zealand rabbits after modeling RPE atrophy by subretinal injection of 0.9% sodium chloride solution and 5 healthy rabbits lacking eye lesions. Animals in the experimental group (one week before surgical intervention, in the early period, and in the period of sustained RPE atrophy formation) and controls were subjected to optical coherence tomography (OCT) and ocular fundus autofluorescence (FAF). Evaluation of proinflammatory cytokine gene expression levels in TC was performed by RT-PCR. Results. Subretinal injection of 0.01 ml of 0.9% sodium chloride solution induced experimental RPE atrophy development in rabbits vs. control that was associated with multidirectional changes of IL-1β, IL-18, MCP-1/CCL2 gene mRNA expression. Three types of response in the TC, formed during development of atrophic changes and determined by the value of local cytokine gene expression were characterized: 1) hypo/ no response – decreased/no expression; 2) normal response – moderate increase; 3) hyper response – overexpression. 69.6% of animals with persistent atrophy had a moderate to hypertrophic increase in locally expressed mRNA MCP-1/CCL2, whereas 30% cases had significantly increased IL-1β mRNA expression – factors damaging the blood-retinal barrier and contributing to posterior segment immune privilege. It should be taken into account while developing new strategies for treatment of ophthalmic pathology, in particular the currently actively studied and tested options for RPE stem cell transplantation into subretinal space. The data obtained may be useful to investigate various types of RPE atrophy and develop new strategies of ophthalmopathology treatment in preclinical studies.
Highlights
Degenerative-dystrophic retinal diseases are currently considered as the lead cause of blindness and low vision in developed countries and have a steadily increasing trend
Between 2 and 7 days after surgery, changes in the rabbit fundus were determined as neurosensory reti nal detachment with hyporeflective content under neath, retinal tear with elevated edges according to the cannula injection site, disorganization of retinal layers, irregular hyperfluorescence was determined on FAF indicating Retinal pigment epithelium damage (RPE) lesion
The early post-operative period was trended to increased local expression of MCP-1/CCL-1 gene mRNA: special attention was paid to its wide range of upward shifts relative to normal: from a slight/ moderate increase (0.05 rel. units) to a hyperreactive response – a 4000-fold increase in expression com pared to healthy eye tissue (Figure 1)
Summary
Degenerative-dystrophic retinal diseases are currently considered as the lead cause of blindness and low vision in developed countries and have a steadily increasing trend. Retinal pigment epithelium damage (RPE) is the initial step in the development of degenerative changes in age-related macular degeneration, leading to photoreceptor death and irreversible loss of central vision. RPE is formed by a single layer of hexagonal polarized pigmented epithelial cells and located between the choroid and the neurosensory retina [10]. RPE plays an important role in ocular immune privilege by forming the outer part of the haematoretinal bar rier and secreting membrane-bound and soluble immunosuppressive and apoptotic factors into the subretinal space [3, 5]. PPE cells are incapable of regeneration, and their damage is irreversible [9]
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