A Bioartificial Liver Device Secreting Interleukin-1 Receptor Antagonist for the Treatment of Hepatic Failure in Rats

Masahiro Shinoda, Arno W. Tilles, Naoya Kobayashi, Go Wakabayashi, Atsushi Takayanagi, Toshinori Totsugawa, Hirohisa Harada, Hideaki Obara, Kazuhiro Suganuma, François Berthiaume, Motohide Shimazu, Nobuyoshi Shimizu, Noriaki Tanaka, Masaki Kitajima, Ronald G. Tompkins, Mehmet Toner, Martin L. Yarmush

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Abstract

Background: Liver transplantation is the treatment of choice for many patients with fulminant hepatic failure (FHF). A major limitation of this treatment is the lack of available donors. An optimally functioning bio-artificial liver (BAL) device has the potential to provide critical hepatic support to patients with FHF. In this study, we examined the efficacy of combining interleukin-1 (IL-1) receptor blockade with the synthetic function of hepatocytes in a BAL device for the treatment of FHF. Materials and methods: We injected an adenoviral vector encoding human IL-1 receptor antagonist (AdIL-1Ra) into the liver of D-galactosamine (GalN) intoxicated rats via the portal vein. We also transfected primary rat hepatocytes and reversibly immortalized human hepatocytes (TTNT cells) with AdIL-1Ra, and incorporated these transfected hepatocytes into our flat-plate BAL device and evaluated their efficacy in our GalN-induced FHF rat model after 10 h of extracorporeal perfusion. Results: Rats injected with AdIL-1Ra showed significant reductions in the plasma levels of hepatic enzymes. Primary rat hepatocytes transfected with AdIL-1Ra secreted IL-1Ra without losing their original synthetic function. Incorporating these cells into the BAL device and testing in a GalN-induced FHF rat model resulted in significant reductions in plasma IL-6 levels and significantly improved animal survival. Incorporating the AdIL-1Ra transfected TTNT cells in the BAL device and testing in the GalN-induced FHF rat model resulted in significantly reduced plasma IL-6 levels, and a trend toward improved survival was seen. Conclusion: Hepatocytes producing IL-1Ra are a promising cell source for BAL devices in the treatment of GalN-induced FHF.

Original languageEnglish
Pages (from-to)130-140
Number of pages11
JournalJournal of Surgical Research
Volume137
Issue number1
DOIs
Publication statusPublished - 2007 Jan 1

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Keywords

  • bio-artificial liver device
  • fulminant hepatic failure
  • immortalized human hepatocytes
  • interleukin-1 receptor antagonist
  • primary rat hepatocytes

ASJC Scopus subject areas

  • Surgery

Cite this

Shinoda, M., Tilles, A. W., Kobayashi, N., Wakabayashi, G., Takayanagi, A., Totsugawa, T., Harada, H., Obara, H., Suganuma, K., Berthiaume, F., Shimazu, M., Shimizu, N., Tanaka, N., Kitajima, M., Tompkins, R. G., Toner, M., & Yarmush, M. L. (2007). A Bioartificial Liver Device Secreting Interleukin-1 Receptor Antagonist for the Treatment of Hepatic Failure in Rats. Journal of Surgical Research, 137(1), 130-140. https://doi.org/10.1016/j.jss.2006.08.009