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. Conclusion: 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. (HEPATOLOGY 2011:53:618‐627)