Inhibitory effect of nintedanib on VEGF secretion in retinal pigment epithelial cells induced by exposure to a necrotic cell lysate

Abstract

Necrosis is a form of cell death that results in rupture of the plasma membrane and the release of cellular contents, and it can give rise to sterile inflammation in the retina and other tissues. The secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells contributes to retinal homeostasis as well as to pathological angiogenesis. We have now examined the effect of a necrotic cell lysate prepared from human RPE cells (NLR) on the release of VEGF by healthy RPE cells. We found that NLR markedly increased the release of VEGF from RPE cells and that this effect was attenuated by nintedanib, a multiple receptor tyrosine kinase inhibitor, whereas it was unaffected by inhibitors of NF-κB signaling or of caspase-1. NLR also induced the phosphorylation of extracellular signal–regulated kinase (Erk) and signal transducer and activator of transcription 3 (Stat3) in a manner sensitive to inhibition by nintedanib, although inhibitors of Erk and Stat3 signaling pathways did not affect NLR-induced VEGF secretion. In addition, nintedanib attenuated the development of choroidal neovascularization in mice. Our results have thus shown that a necrotic lysate of RPE cells induced VEGF secretion from healthy RPE cells and that this effect was mediated by receptor tyrosine kinase signaling. They therefore suggest that VEGF secretion by healthy RPE cells is a potential therapeutic target for retinal diseases associated with sterile inflammation and pathological angiogenesis.

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells

“…Neutrophil infiltration has been shown to induce VEGF release in the cornea of mice (Gong et al, 2010). In addition, injured or necrotic RPE cells are able to trigger VEGF release from adjacent healthy RPE cells (Hatano et al, 2019). In RPE cells, TNF‐α contributed to neovascularization independently of NF‐κB, and VEGF levels increased concurrently with increased ROS production (Wang, Han, et al, 2016).…”

Potential of Stimuli-Responsive In Situ Gel System for Sustained Ocular Drug Delivery: Recent Progress and Contemporary Research

“…The use of thermosensitive in situ gelling systems in the treatment of other diseases including corneal neovascularization, ocular allergy, and cataract has been studied [ 37 , 38 , 49 , 50 , 51 , 52 ]. Corneal neovascularization is related to the invasion of new blood vessels into the cornea from the limbus because of an imbalance between angiogenic and antiangiogenic factors, which can be caused by ocular injury and diseases [ 52 ].…”

“…Corneal neovascularization is related to the invasion of new blood vessels into the cornea from the limbus because of an imbalance between angiogenic and antiangiogenic factors, which can be caused by ocular injury and diseases [ 52 ]. Recently, a nintedanib eye drop has been shown to have potential in reducing the development of choroidal neovascularization in mice, but it may not provide a long-lasting effect, owing to rapid elimination [ 49 ]. Henceforth, Gong et al prepared a nintedanib thermosensitive hydrogel (NTH) utilizing poloxamer 407 tested on the alkali burn rat model [ 37 ].…”

Effect of a novel tyrosine kinase inhibitor nintedanib on bFGF and VEGF concentrations in a rabbit retinal vein occlusion model

“…16, No. 9, Sep.18, 2023 www.ijo.cn Tel: 8629-82245172 8629-82210956 Email: ijopress@163.com 3 (VEGFR 1, 2, 3) [19][20][21][22] . Oral administration of nintedanib has been approved by Food and Drug Administration (FDA) for idiopathic pulmonary fibrosis in clinic.…”