TY - JOUR
T1 - A Bioartificial Liver Device Secreting Interleukin-1 Receptor Antagonist for the Treatment of Hepatic Failure in Rats
AU - Shinoda, Masahiro
AU - Tilles, Arno W.
AU - Kobayashi, Naoya
AU - Wakabayashi, Go
AU - Takayanagi, Atsushi
AU - Totsugawa, Toshinori
AU - Harada, Hirohisa
AU - Obara, Hideaki
AU - Suganuma, Kazuhiro
AU - Berthiaume, François
AU - Shimazu, Motohide
AU - Shimizu, Nobuyoshi
AU - Tanaka, Noriaki
AU - Kitajima, Masaki
AU - Tompkins, Ronald G.
AU - Toner, Mehmet
AU - Yarmush, Martin L.
N1 - Funding Information:
This work was partially supported by grants from Shriners Hospitals for Children, The Whitaker Foundation (Grant number: RG-01-0220), and National Institutes of Health (NIH) (Contract grant numbers: R01 DK43371 and K08 DK66040).
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - bio-artificial liver device
KW - fulminant hepatic failure
KW - immortalized human hepatocytes
KW - interleukin-1 receptor antagonist
KW - primary rat hepatocytes
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U2 - 10.1016/j.jss.2006.08.009
DO - 10.1016/j.jss.2006.08.009
M3 - Article
C2 - 17081566
AN - SCOPUS:33845392064
SN - 0022-4804
VL - 137
SP - 130
EP - 140
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -