IMR Press / FBL / Volume 27 / Issue 8 / DOI: 10.31083/j.fbl2708237
Open Access Original Research
Dynamics of Acute Liver Injury in Experimental Models of Hepatotoxicity in the Context of Their Implementation in Preclinical Studies on Stem Cell Therapy
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1 Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
2 Students Scientific Society, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
3 Department of Experimental Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
4 Department of Pathomorphology and Molecular Diagnostic, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
*Correspondence: pcz@sum.edu.pl (Piotr Czekaj)
These authors contributed equally.
Academic Editor: Gustavo Yannarelli
Front. Biosci. (Landmark Ed) 2022, 27(8), 237; https://doi.org/10.31083/j.fbl2708237
Submitted: 20 May 2022 | Revised: 2 July 2022 | Accepted: 22 July 2022 | Published: 10 August 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Background and Aims: Experimental models using carbon tetrachloride (CCl4) 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 CCl4 in mice (50 μL/100 g b.w.) and rats (200 μL/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 CCl4 injection, mouse livers showed moderate inflammatory infiltration and massive pericentral necrosis. In rats treated with CCl4, 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 CCl4-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.

Keywords
experimental models of hepatotoxicity
galactosamine
carbon tetrachloride
acute liver failure
stem cell therapy
Figures
Fig. 1.
Funding
KNW-1-103/N/8/0/ SUM Katowice
KNW-1- 100/K/9/0/ SUM Katowice
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