Treatment of fulminant hepatic failure in rats using a bioartificial liver device containing porcine hepatocytes producing interleukin-1 receptor antagonist.
Fulminant hepatic failure (FHF) is a serious clinical condition that is associated with high mortality. There is evidence that FHF is an inflammatory disease, which is supported clinically by elevated serum levels of cytokines. In an effort to develop hepatocytes with additional functions for use in our bioartificial liver (BAL) device, we focused on interleukin-1 (IL-1) blockade as a therapeutic modality. Primary porcine hepatocytes were isolated from the livers of miniature swine and then transfected with an adenoviral vector encoding human interleukin-1 receptor antagonist (AdIL-1Ra). The transfected hepatocytes secreted human IL-1Ra. These transfected hepatocytes were incorporated into a flat-plate BAL device to evaluate their efficacy in treating D-galactosamine (GalN)- induced FHF in a rat model. After extracorporeal perfusion with the BAL device containing the transfected hepatocytes, there were significant reductions in the plasma levels of hepatic enzymes (aspartate aminotransferase and alanine aminotransferase) and cytokines (IL-1 and IL-6), indicating a beneficial effect. Animal survival was significantly improved in the treated group compared to the control group. These experiments demonstrate that combining inflammatory cytokine blockade with a functional BAL device may be an effective therapeutic option in the treatment of FHF.
Shinoda
Masahiro
M
Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Tilles
Arno W
AW
Wakabayashi
Go
G
Takayanagi
Atsushi
A
Harada
Hirohisa
H
Obara
Hideaki
H
Suganuma
Kazuhiro
K
Berthiaume
François
F
Shimazu
Motohide
M
Shimizu
Nobuyoshi
N
Kitajima
Masaki
M
Tompkins
Ronald G
RG
Toner
Mehmet
M
Yarmush
Martin L
ML
D000256:Adenoviridae; D000818:Animals; D006464:Hemoperfusion; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D017114:Liver Failure, Acute / Q000628:therapy*; D019164:Liver, Artificial; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature; D014161:Transduction, Genetic; D020298:U937 Cells
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins