Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells

Yumin Oh, Ogyi Park, Magdalena Swierczewska, James P. Hamilton, Jong Sung Park, Tae Hyung Kim, Sung Mook Lim, Hana Eom, Dong Gyu Jo, Choong Eun Lee, Raouf Kechrid, Panagiotis Mastorakos, Clark Zhang, Sei Kwang Hahn, Ok Cheol Jeon, Youngro Byun, Kwang Meyung Kim, Justin Hanes, Kang Choon Lee, Martin G. PomperBin Gao, Seulki Lee

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 TRAIL PEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAIL PEG 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. (Hepatology 2016;64:209–223).

Original languageEnglish
Pages (from-to)209-223
Number of pages15
JournalHepatology
Volume64
Issue number1
DOIs
Publication statusPublished - 2016 Jul 1
Externally publishedYes

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Hepatic Stellate Cells
Liver Cirrhosis
Half-Life
Fibrosis
Therapeutics
Apoptosis
Death Domain Receptors
Carbon Tetrachloride
Gastroenterology
Intravenous Injections
Primates
Liver Diseases
Hepatocytes
Hepatocellular Carcinoma
Rodentia
Chronic Disease
Cell Death
Necrosis
Ligands
Food

ASJC Scopus subject areas

  • Hepatology

Cite this

Oh, Y., Park, O., Swierczewska, M., Hamilton, J. P., Park, J. S., Kim, T. H., ... Lee, S. (2016). Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology, 64(1), 209-223. https://doi.org/10.1002/hep.28432

Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. / Oh, Yumin; Park, Ogyi; Swierczewska, Magdalena; Hamilton, James P.; Park, Jong Sung; Kim, Tae Hyung; Lim, Sung Mook; Eom, Hana; Jo, Dong Gyu; Lee, Choong Eun; Kechrid, Raouf; Mastorakos, Panagiotis; Zhang, Clark; Hahn, Sei Kwang; Jeon, Ok Cheol; Byun, Youngro; Kim, Kwang Meyung; Hanes, Justin; Lee, Kang Choon; Pomper, Martin G.; Gao, Bin; Lee, Seulki.

In: Hepatology, Vol. 64, No. 1, 01.07.2016, p. 209-223.

Research output: Contribution to journalArticle

Oh, Y, 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, KM, Hanes, J, Lee, KC, Pomper, MG, Gao, B & Lee, S 2016, 'Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells', Hepatology, vol. 64, no. 1, pp. 209-223. https://doi.org/10.1002/hep.28432
Oh, Yumin ; Park, Ogyi ; Swierczewska, Magdalena ; Hamilton, James P. ; Park, Jong Sung ; Kim, Tae Hyung ; Lim, Sung Mook ; Eom, Hana ; Jo, Dong Gyu ; Lee, Choong Eun ; Kechrid, Raouf ; Mastorakos, Panagiotis ; Zhang, Clark ; Hahn, Sei Kwang ; Jeon, Ok Cheol ; Byun, Youngro ; Kim, Kwang Meyung ; Hanes, Justin ; Lee, Kang Choon ; Pomper, Martin G. ; Gao, Bin ; Lee, Seulki. / Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. In: Hepatology. 2016 ; Vol. 64, No. 1. pp. 209-223.
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