title: Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.
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 (TRAILPEG ) 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.
  
  
  
  TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology 2016;64:209-223).
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.|Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Swierczewska
authors.affiliation: Divison of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sung-Mook
authors.initials: SM
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Eom
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Dong Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Biological Science, Sungkyunkwan University, Suwon, Korea.
authors.forename: Choong-Eun
authors.initials: CE
authors.lastname: Lee
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Raouf
authors.initials: R
authors.lastname: Kechrid
authors.affiliation: The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Materials Science and Engineering, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Sei Kwang
authors.initials: SK
authors.lastname: Hahn
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.|The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD.|Therapy Pharmaceuticals, Inc., Baltimore, MD.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride; D004353:Drug Evaluation, Preclinical; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D015854:Up-Regulation
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D002251:Carbon Tetrachloride