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A bioartificial liver device secreting interleukin-1 receptor antagonist for the treatment of hepatic failure in rats.

Research paper by Masahiro M Shinoda, Arno W AW Tilles, Naoya N Kobayashi, Go G Wakabayashi, Atsushi A Takayanagi, Toshinori T Totsugawa, Hirohisa H Harada, Hideaki H Obara, Kazuhiro K Suganuma, François F Berthiaume, Motohide M Shimazu, Nobuyoshi N Shimizu, Noriaki N Tanaka, Masaki M Kitajima, Ronald G RG Tompkins, et al.

Indexed on: 04 Nov '06Published on: 04 Nov '06Published in: Journal of Surgical Research



Abstract

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.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.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.Hepatocytes producing IL-1Ra are a promising cell source for BAL devices in the treatment of GalN-induced FHF.

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