Background and Aims: Experimental models using carbon tetrachloride
(CCl) and D-galactosamine (D-GalN) can be used in preclinical assessment of
acute liver failure (ALF) therapies. Unfortunately, these models are
characterized by different dynamics of liver injury depending on the animal
strain, administered hepatotoxin, and its dose. The aim of this study was to
compare known rat and mouse models of ALF with a view to their future
introduction into preclinical cell therapy experiments. In particular, based on
histopathological and molecular changes, we suggested experimental time cut-off
points for an effective stem cell therapeutic intervention. Methods: ALF
was induced by a single intraperitoneal injection of CCl in mice (50
L/100 g b.w.) and rats (200 L/100 g b.w.) and D-GalN
in mice (150 mg/100 g b.w.) and rats (50 mg/100 g b.w.). Blood and liver samples
were collected 12 h, 24 h, 48 h and 7 days after intoxication. Blood morphology,
liver function blood tests, histopathological changes, proliferation activity,
apoptosis, fibrosis, and gene expression were analysed to assess liver damage.
Results: At 12 h, 24 h, and 48 h after CCl injection, mouse livers
showed moderate inflammatory infiltration and massive pericentral necrosis. In
rats treated with CCl, minor lymphocytic infiltration in the liver
parenchyma was seen at 12 h, followed by necrosis that appeared around central
veins at 24 h and persisted to 48 h. In D-GalN-injected mice, the first
histopathological signs of liver injury appeared at 48 h. In the livers of
D-GalN-treated rats, moderate pericentral inflammatory infiltration occurred
after 12 h, 24 h, and 48 h, accompanied by increased proliferation and apoptosis.
All histological changes were accompanied by decreasing expression of certain
genes. In most experimental groups of rats and mice, both histological and
molecular parameters returned to the baseline values between 48 h and 7 days
after intoxication. Conclusions: In mice and rats with CCl-induced
ALF, signs of liver failure can be seen as early as 12 h and develop to 48 h. In
the D-GalN-induced model, mice are more resistant to the hepatotoxic effect than
rats (after 12 h), and the early hepatitis phase can be observed much later,
after 48 h. These cut-off points seem to be optimal for suppressing inflammation
and applying effective stem cell therapy for acute liver injury.