title: Human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers.
abstract: Acute liver failure (ALF) is a rare syndrome with a difficult clinical management and a high mortality rate. During ALF, several molecular pathways governing oxidative stress and apoptosis are activated to induce massive tissue injury and suppress cell proliferation. There are few anti-ALF drug candidates, among which is the C-type lectin Reg3α, or human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), which displayed promising properties for tissue regeneration and protection against cellular stress in transgenic mice. We report on substantial preclinical and clinical advances in the development of a recombinant (rc) full-length human HIP/PAP protein as an anti-ALF drug. The curative effects and mechanisms of action of rcHIP/PAP were investigated in murine Fas-induced ALF. Primary hepatocytes were cultured with cytotoxic doses of tumor necrosis factor α/actinomycin-D, transforming growth factor β, agonistic Fas antibody or hydrogen peroxide, and various concentrations of rcHIP/PAP. Cell viability, proliferation index, apoptosis, and oxidation were monitored. We found that rcHIP/PAP significantly improved survival in Fas-intoxicated mice in a dose-dependent and time-dependent manner, with optimum effects when it was injected at advanced stages of ALF. Primary hepatocytes were efficiently protected against multiple cell death signals by rcHIP/PAP. This survival benefit was linked to a depletion of oxidized biomolecules in injured liver cells due to a strong reactive oxygen species scavenging activity of rcHIP/PAP. Clinically, an escalating dose phase 1 trial demonstrated a good tolerability and pharmacokinetic profile of rcHIP/PAP in healthy subjects.
  
  
  CONCLUSIONS
  The rcHIP/PAP protein exhibited significant curative properties against ALF in mice. It is a free-radical scavenger that targets a broad spectrum of death effectors and favors liver regeneration. The good safety profile of rcHIP/PAP during a phase 1 trial encourages evaluation of its efficacy in patients with ALF.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U785, Centre Hépatobiliaire, Villejuif, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moniaux
authors.forename: Haiyan
authors.initials: H
authors.lastname: Song
authors.forename: Marion
authors.initials: M
authors.lastname: Darnaud
authors.forename: Kévin
authors.initials: K
authors.lastname: Garbin
authors.forename: Michelle
authors.initials: M
authors.lastname: Gigou
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Laure
authors.initials: L
authors.lastname: Jamot
authors.forename: Paul
authors.initials: P
authors.lastname: Amouyal
authors.forename: Gilles
authors.initials: G
authors.lastname: Amouyal
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016166:Free Radical Scavengers / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005609:Free Radicals / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D037181:Lectins, C-Type / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult; D019014:fas Receptor / Q000009:adverse effects*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C491899:Fas protein, mouse; D016166:Free Radical Scavengers; D005609:Free Radicals; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D011994:Recombinant Proteins; D019014:fas Receptor