NINTEDANIB AND GREEN TEA EXTRACTS (ELLAGIC ACID AND EPIGALLOCATECHIN GALLATE): A COST-EFFECTIVE, COMBINATION THERAPY TO REDUCE PULMONARY FIBROSIS IN HUMAN TGF-BETA STIMULATED FIBROBLASTS

Abstract

SESSION TITLE: Tuesday Electronic Posters 1 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: Cost-effective, combination therapies are sorely needed for idiopathic pulmonary fibrosis (IPF). Current FDA approved therapies are limited to nintedanib and pirfenidone, drugs which only slow FEV1 decline but with significant costs, exceeding $100,000 per year [1]. These monotherapies may have only tempering effects on IPF clinically because of the multiple pathways of lung injury involved [2]. Ellagic Acid (EA) and Epigallocatechin Gallate (EGCG) are naturally occurring, low cost polyphenol compounds found abundantly in fruits, nuts, and green tea. As strong anti-oxidants, they have clinical benefits in pulmonary toxicity from chemotherapy, radiation induced lung fibrosis, and inflammation in asthma [3, 4]. Recently, EA and EGCG were shown to have pulmonary anti-fibrotic effect in vitro and in vivo. Bleomycin mice fed with extract rich EA showed markedly lower levels of lung collagen, fibronectin, Snail1, and p-Smad3 [4]. METHODS: The objective of this study was to demonstrate whether the combination of EA or EGCG and low dose nintedanib can reduce fibrosis in vitro. Human IPF fibroblasts were incubated with 2uM EA, 1uM EA, 2uM EGCG, and 1uM EGCG. Cells were then stimulated with TGF-β, a key cytokine in the development of pulmonary fibrosis, for 24 hours. ELISAs (enzyme-linked immunosorbent assays) were performed for fibronectin protein production quantification. Cellular fibronectin is one of first extracellular matrix proteins to be deposited in fibroblasts upon TGFβ stimulation. RESULTS: Pooled ELISA analysis confirmed the anti-fibrotic effect of both EA and EGCG. 1uM EA lowered fibronectin levels to average 49.0% (+/- 17.13, p=0.01) of the TGF-β stimulated fibroblasts. 2uM EGCG and 1uM EGCG lowered fibronectin levels to average 42.6% (+/- 3.3, p=0.0002) and 63.9% (+/-13.5,p=0.06) respectively of the unstimulated fibroblasts. When combined with 0.5uM and 0.25 uM nintedanib, 1uM EA lowered fibronectin levels to an average 0.04% (+/-26.4) and 9.19% (+/-12.9) respectively of the TGF-β stimulated fibroblasts. This was an increased effect from 0.5uM and 0.25 uM nintedanib alone, which lowered fibronectin levels to an average of 26.3% and 39.7% respectively. 1uM EGCG, when combined with 0.5uM and 0.25 uM nintedanib also showed a fibronectin lowering effect, to an average of 47.7% (+/-3.6, p=0.03) and 49.6% (+/-6.09, p=0.09) respectively of the unstimulated fibroblasts. This was higher than the combined effect of either drug alone. CONCLUSIONS: Polyphenol compounds with natural anti-oxidant properties, such as Ellagic Acid and Epigallocatechin Gallate, have been shown to have pulmonary anti-fibrotic effect and demonstrate potential as novel therapies for IPF. CLINICAL IMPLICATIONS: With additional research, perhaps these widely available compounds could be added to current standard therapies to offset their significant costs to patients. DISCLOSURES: no disclosure on file for Theodore Kottom; No relevant relationships by Andrew Limper, source=Web Response No relevant relationships by Kyle Schaefbauer, source=Web Response No relevant relationships by Ann Vu, source=Web Response