Blockade of Endothelinergic Receptors Prevents Development of Proliferative Vitreoretinopathy in Mice

Abstract

Proliferative vitreoretinopathy (PVR) is characterized by severe glial remodeling. Glial activation and proliferation that occur in brain diseases are modulated by endothelin-1 (ET-1) and its receptor B (ETR-B). Because retinal astrocytes contain ET-1 and express ETR-B, we studied the changes of these molecules in an experimental mouse model of PVR and in human PVR. Both ET-1 and ETR-B immunoreactivities increased in mouse retina after induction of PVR with dispase. Epi-and subretinal outgrowths also displayed these immunoreactivities in both human and experimental PVR. Additionally, myofibroblasts and other membranous cell types showed both ET-1 and ETR-B immunoreactivities. In early stages of experimentally induced PVR, prepro-ET-1 and ETR-B mRNA levels increased in the retina. These mRNA levels also increased after retinal detachment (RD) produced by subretinal injection. Treatment of mice with tezosentan, an antagonist of endothelinergic receptors, reduced the histopathological hallmarks of dispase-induced PVR: retinal folding, epiretinal outgrowth, and gliosis. Our findings in human and in dispase-induced PVR support the involvement of endothelinergic pathways in retinal glial activation and the phenotypic transformations that underlie the growth of membranes in this pathology. Elucidating these pathways further will help to develop pharmacological treatments to prevent PVR. In addition, the presence of ET-1 and ETR-B in human fibrous membranes suggests that similar treatments could be helpful after PVR has been established.

In Vivo Gene Expression Profiling of Retina Postintravitreal Injections of Dexamethasone and Triamcinolone at Clinically Relevant Time Points for Patient Care

“…The scar acts as a barrier to neuronal growth, and prevents neural regeneration 55 , such as in proliferative vitreoretinopathy in the mouse 56 and Alexander disease 57 . Gfap also has a neuroprotective role and increases regeneration of neurons after an injury 58 .…”

The inhibitory effect of small interference RNA protein kinase C-alpha on the experimental proliferative vitreoretinopathy induced by dispase in mice

“…[22][23][24][25][26][28][29][30][31][32][33][34] Figure 7 Immunofluorescence analysis of GFAP and α-SMA at 4 weeks after siRNA-PKCα injection. Notes: There are faint expressions of GFAP (red) and (green) in normal retinas; these expressions seemed more pronounced in the epiretinal membranes in the negative control, as well as in the 250 nM, 500 nM, and 750 nM groups than in the 1000 nM and 1500 nM groups.…”

“…Sixty C57BL/6 mice PVR models were induced by dispase (Gibco ® , Life Technologies, Carlsbad, CA, USA), as previously described by both Cantó Soler et al and Iribarne et al 22,23 and our group. 24,25 Mice were anesthetized with 4.3% chloral hydrate (0.01 mL/g) (The Affiliated Ophthalmic Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China).…”

“…Because intravitreal hemorrhages and cataracts have often occurred in previous studies, 26 clinical PVR-like signs were defined as the presence of one of the following three symptoms: retinal folds, epiretinal membranes, and an uneven iris at 1 week, 2 weeks, and 4 weeks in our previous study and in this experiment. 24,25 This evaluation system was modified from Cantó Soler et al and Iribarne et al 22,23 Retinal PKCα levels after siRNA-PKCα injection…”

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

“…Eyes were fixed in 10% buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. To quantitate the extent of retinal folding in BALB/c and BALB(gld) mice, each section (5 or 6 sections per eye) was examined by a blinded observer who counted the number of retinal folds per 10-m section (5 or 6 sections per eye) (22,23). These sections were cut through or immediately adjacent to the optic nerve.…”