title: Treatment of fulminant hepatic failure in rats using a bioartificial liver device containing porcine hepatocytes producing interleukin-1 receptor antagonist.
abstract: 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.
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinoda
authors.forename: Arno W
authors.initials: AW
authors.lastname: Tilles
authors.forename: Go
authors.initials: G
authors.lastname: Wakabayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takayanagi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Harada
authors.forename: Hideaki
authors.initials: H
authors.lastname: Obara
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suganuma
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Motohide
authors.initials: M
authors.lastname: Shimazu
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitajima
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: 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
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins