Abstract
Purpose :
PPS is a low molecular weight heparin-like molecule used in the treatment of interstitial cystitis. Recently, long-term use of PPS has been associated with a bilateral progressive maculopathy, characterized by hyper-pigmented lesions, subretinal deposits and speckled parafoveal RPE atrophy and can even progress after PPS discontinuation. There is growing clinical evidence supporting the association between PPS use and maculopathy development, but no pathophysiological mechanism has been described yet. In this setting, we investigated PPS toxicity on cell lines representing the outer retina / choroid complex. We also explored the effects of PPS on RPE proliferation and migration, as well as its potential interference with a heparin-binding EGF-like growth factor (HB-EGF) signaling.
Methods :
Retinal pigment epithelial cell line (ARPE-19), photoreceptor cell line (661W), primary human retinal microvascular endothelial cell (HRMEC), and human endothelial cell line (HUVEC) were cultured with PPS for 24h and 72h after confluency, in 96 well plates. Toxicity was assessed with the CCK-8 cell counting kit and the LDH release kit. The effect of PPS on HB-EGF-induced RPE proliferation and migration was assessed by the CCK-8 kit and the scratch-wound assay.
Results :
PPS was not toxic to RPE or photoreceptor cells with doses up to 1mg/ml. PPS was toxic to HUVEC at doses greater than or equal to 7.9 µg/ml, and reduced 79% of cell viability at 1mg/ml after 72h. PPS was also toxic to HRMEC at doses greater than or equal to 31.25 µg/ml and reduced 38% of cell viability at 1mg/ml after 72h. PPS at 1mg/ml completely prevented HB-EGF-induced proliferation and migration of ARPE-19 cells.
Conclusions :
Our data suggest a pathophysiological mechanism for PPS maculopathy that implicates vascular endothelial cells more than RPE and significantly impaired the HB-EGF-induced wound repair in RPE cells. Chronic exposure to PPS could damage the choroidal vessels and disrupt the wound-healing response of the RPE, potentially predisposing to RPE atrophy. These findings are aligned with the clinical presentation of PPS maculopathy, and recent angiographic findings suggesting that choroidal injury precedes the pigmentary changes in the disease’s natural history.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.