Background: In humans, chronic liver disease (CLD) is a
serious clinical condition with many life-threatening complications. Currently,
there is no therapy to stop or slow down the progression of liver fibrosis.
Experimental mouse models of CLD, induced by repeated intraperitoneal injections
of carbon tetrachloride (CCL) and D-galactosamine (D-GalN), can be used to
evaluate therapies that cannot be performed in humans. A major drawback of these
animal models is the different dynamics of liver fibrosis progression depending
on the animal strain, administered hepatotoxin, its dose, duration of
intoxication, and frequency of injections. The aim of this study was to describe
and compare the dynamics of progression of pathological changes in the BALB/c
mouse and Sprague Dawley rat models of CLD induced by CCl and D-GalN. We
defined the onset and duration of these changes and suggested the optimal time
for therapeutic intervention in the analyzed CLD models. Methods: CLD
was induced by repeated intraperitoneal injection of CCl in mice
(12.5 L/100 g bw every 5 days) and rats
(25–100 L/100 g bw twice a week) and D-GalN in mice (75 mg/100
g bw twice a week) and rats (25 mg/100 g bw twice a week). Blood and liver
samples were collected at weeks 2, 4, 6, 8, 10, and 12 of intoxication. Liver
injury and its progression were assessed by using complete blood count and liver
function blood tests as well as by analyzing histopathological changes, including
fibrosis, proliferation activity, apoptosis, stellate cell activation, and gene
expression. Results: In mice and rats treated with CCl, early
fibrosis was observed in most pericentral areas from week 2 to 4 of intoxication.
Established fibrosis developed in both rats and mice at week 6 of intoxication.
Incomplete cirrhosis, defined as the presence of occasional cirrhotic nodules,
was observed in rats at week 12 of intoxication. The dynamics of liver fibrosis
in CCl-treated animals were greater than in the D-GalN groups. In
D-GalN-intoxicated rats and mice, the first signs of liver fibrosis were observed
at weeks 4 and 10 of intoxication, respectively. The rats developed early
fibrosis after 8 weeks of D-GalN intoxication. The progression of collagen
deposition was accompanied by histological changes and alteration of certain
genes and blood liver parameters. Conclusions: The dynamics of liver
fibrosis in CCl treated rodents is greater than in the D-GalN treated ones.
In the CCl models, two appropriate times for therapeutic intervention are
indicated, which to varying degrees reflect the real clinical situation and may
potentially differ in the obtained results: early intervention before week 4 of
intoxication (early fibrosis) and late intervention after week 8 of intoxication
(when signs of established fibrosis are present). Rodent models of D-GalN-induced
fibrosis are not recommended due to the long incubation period and weak toxic
effect.