Systemic PEGylated TRAIL Treatment Ameliorates Liver Cirrhosis in Rats by Eliminating Activated Hepatic Stellate Cells
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SCOPUS
- Title
- Systemic PEGylated TRAIL Treatment Ameliorates Liver Cirrhosis in Rats by Eliminating Activated Hepatic Stellate Cells
- Authors
- Oh, YM; Park, O; Swierczewska, M; Hamilton, JP; Park, JS; Kim, TH; Lim, SM; Eom, H; Jo, DG; Lee, CE; Kechrid, R; Mastorakos, P; Zhang, C; Hahn, SK; Jeon, OC; Byun, Y; Kim, K; Hanes, J; Lee, KC; Pomper, MG; Gao, B; Lee, S
- Date Issued
- 2016-07
- Publisher
- WILEY-BLACKWELL
- Abstract
- Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAIL(PEG)) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. Conclusion: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/36513
- DOI
- 10.1002/HEP.28432
- ISSN
- 0270-9139
- Article Type
- Article
- Citation
- HEPATOLOGY, vol. 64, no. 1, page. 209 - 223, 2016-07
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- There are no files associated with this item.
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