HGF Regulation Of RPE Proliferation In An Il-1-Beta/Retinal Hole-Induced Rabbit Model Of PVR

Abstract

Abstract: : Purpose: To understand molecular events that lead to RPE cell proliferation and migration during the early phases of proliferative vitreoretinopathy (PVR) in a rabbit model. Methods: Retinal holes were created and IL-1-beta was injected intravitreally. Animals were examined by indirect ophthalmoscopy and posterior segment tissues as well as vitreous samples were collected at different times after the surgery. RPE cell proliferation and migration were determined by immunohistochemistry. Tyrosine phosphorylation of ERK and HGF-receptor (c-met) was determined by Western blot analysis of vitreous-treated cultured ARPE-19 cells or retinal tissues. Matrix metalloproteinase (MMP) content in vitreous was assessed by zymography. Results: Indirect ophthalmoscopy identified formation of epiretinal membranes at 4 weeks post-surgery. At the same time immunohistochemistry identified proliferative and migratory cells including RPE cells in the area of retinal injury. Western blot analysis on injured retina including RPE cells identified tyrosine phosphorylation of ERK within 1/2 hour of surgery, and with a maximal c-met phosphorylation at 24 hours post-surgery. ARPE-19 cells treated with vitreous from the 24 hours post-surgical eyes showed morphological changes and phosphorylation of c-met. Zymographic analysis of vitreous identified MMP-9 in 12-72 hours post-surgery. Conclusion: These data suggest that the presence of retinal injury and Il-1-beta lead to the activation of HGF, MAPK and extracellular matrix remodelling that results in RPE proliferation and migratory cells in the wounded retina.

Keywords: 524 proliferative vitreoretinopathy • 316 animal model • 631 wound healing