Model of Liver Fibrosis Induction by Thioacetamide in Rats for Regenerative Therapy Studies

Overview

Journal Anal Cell Pathol (Amst)

Specialties Cell Biology
Oncology
Pathology

Date 2022 Nov 22

PMID 36411771

Authors

Nathaly Enciso

Jose Amiel

Fredy Fabian-Dominguez

Jhon Pando

Nancy Rojas

Carlos Cisneros-Huamani

Ernesto Nava

Javier Enciso

Affiliations

Soon will be listed here.

Abstract

Hepatic fibrosis is caused by chronic injury due to toxic, infectious, or metabolic causes, and it may progress to cirrhosis and hepatocellular carcinoma. There is currently no antifibrotic therapy authorized for human use; however, there are promising studies using cell therapies. There are also no animal models that exactly reproduce human liver fibrosis that can be used to better understand the mechanisms of its regression and identify new targets for treatment and therapeutic approaches. On the other hand, mesenchymal stem cells (MSC) have experimentally demonstrated fibrosis regression effects, but it is necessary to have an animal model of advanced liver fibrosis to evaluate the effect of these cells. The aim of this work was to establish a protocol for the induction of advanced liver fibrosis in rats using thioacetamide (TAA), which will allow us to perform trials using MSC as a possible therapy for fibrosis regression. For this purpose, we selected 24 female rats and grouped them into three experimental groups: the control group (G-I) without treatment and groups II (G-II) and III (G-III) that received TAA by intraperitoneal injection for 24 weeks. Then, 1 × 106/kg adipose mesenchymal stem cells (ASCs) were infused intravenously. Groups G-I and G-II were sacrificed 7 days after the last dose of ASC, and G-III was sacrificed 8 weeks after the last ASC infusion, all with xylazine/ketamine (40 mg/kg). The protocol used in this work established a model of advanced hepatic fibrosis as corroborated by METAVIR tests of the histological lesions; by the high levels of the markers -SMA, CD68, and collagen type I; by functional alterations due to elevated markers of the hepatic lesions; and by alterations of the leukocytes, lymphocytes, and platelets. Finally, transplanted cells in the fibrous liver were detected. We conclude that TAA applied using the protocol introduced in this study induces a good model of advanced liver fibrosis in rats.

Citing Articles

In Vivo and In Vitro Models of Hepatic Fibrosis for Pharmacodynamic Evaluation and Pathology Exploration.

Hu Y, Zhang Z, Adiham A, Li H, Gu J, Gong P Int J Mol Sci. 2025; 26(2).

PMID: 39859410 PMC: 11766297. DOI: 10.3390/ijms26020696.

Preliminary Exploration of the Protective Mechanism of Eugenol Against Acute Liver Injury Induced by Thioacetamide Based on Metabolomics.

Chen H, Li M, Yan H, Yan J, Wang G, Gao L Molecules. 2024; 29(22).

PMID: 39598677 PMC: 11596261. DOI: 10.3390/molecules29225288.

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.

LeFort K, Rungratanawanich W, Song B Cell Mol Life Sci. 2024; 81(1):34.

PMID: 38214802 PMC: 10786752. DOI: 10.1007/s00018-023-05061-7.

Anti-Fibrotic Efficacy of Apigenin in a Mice Model of Carbon Tetrachloride-Induced Hepatic Fibrosis by Modulation of Oxidative Stress, Inflammation, and Fibrogenesis: A Preclinical Study.

Melaibari M, AlKreathy H, Esmat A, Rajeh N, Shaik R, Alghamdi A Biomedicines. 2023; 11(5).

PMID: 37239014 PMC: 10216039. DOI: 10.3390/biomedicines11051342.

References

Fouts D, Torralba M, Nelson K, Brenner D, Schnabl B . Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol. 2012; 56(6):1283-92. PMC: 3357486. DOI: 10.1016/j.jhep.2012.01.019. View

Bedossa P, Poynard T . An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996; 24(2):289-93. DOI: 10.1002/hep.510240201. View

. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020; 5(3):245-266. PMC: 7026710. DOI: 10.1016/S2468-1253(19)30349-8. View

Ipsen D, Lykkesfeldt J, Tveden-Nyborg P . Animal Models of Fibrosis in Nonalcoholic Steatohepatitis: Do They Reflect Human Disease?. Adv Nutr. 2020; 11(6):1696-1711. PMC: 7666900. DOI: 10.1093/advances/nmaa081. View

McQuitty C, Williams R, Chokshi S, Urbani L . Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment. Front Immunol. 2020; 11:574276. PMC: 7686550. DOI: 10.3389/fimmu.2020.574276. View

Delire B, Starkel P, Leclercq I . Animal Models for Fibrotic Liver Diseases: What We Have, What We Need, and What Is under Development. J Clin Transl Hepatol. 2015; 3(1):53-66. PMC: 4542084. DOI: 10.14218/JCTH.2014.00035. View

Maes M, Vinken M, Jaeschke H . Experimental models of hepatotoxicity related to acute liver failure. Toxicol Appl Pharmacol. 2015; 290():86-97. PMC: 4691574. DOI: 10.1016/j.taap.2015.11.016. View

Reif S, Aeed H, Shilo Y, Reich R, Kloog Y, Kweon Y . Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. J Hepatol. 2004; 41(2):235-41. DOI: 10.1016/j.jhep.2004.04.010. View

Matsuo M, Murata S, Hasegawa S, Hatada Y, Ohtsuka M, Taniguchi H . Novel liver fibrosis model in Macaca fascicularis induced by thioacetamide. Sci Rep. 2020; 10(1):2450. PMC: 7016167. DOI: 10.1038/s41598-020-58739-4. View

10.

Harn H, Lin S, Hung S, Subeq Y, Li Y, Syu W . Adipose-derived stem cells can abrogate chemical-induced liver fibrosis and facilitate recovery of liver function. Cell Transplant. 2012; 21(12):2753-64. DOI: 10.3727/096368912X652959. View

11.

Yeh C, Maitra A, Lee K, Jan Y, Chen M . Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis. 2003; 25(4):631-6. DOI: 10.1093/carcin/bgh037. View

12.

FITZHUGH O, Nelson A . Liver Tumors in Rats Fed Thiourea or Thioacetamide. Science. 1948; 108(2814):626-8. DOI: 10.1126/science.108.2814.626. View

13.

Al-Dhamin Z, Liu L, Li D, Zhang S, Dong S, Nan Y . Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of studies. World J Gastroenterol. 2021; 26(47):7444-7469. PMC: 7754546. DOI: 10.3748/wjg.v26.i47.7444. View

14.

Li X, Benjamin I, Alexander B . Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality. J Hepatol. 2002; 36(4):488-93. DOI: 10.1016/s0168-8278(02)00011-9. View

15.

Wallace M, Hamesch K, Lunova M, Kim Y, Weiskirchen R, Strnad P . Standard operating procedures in experimental liver research: thioacetamide model in mice and rats. Lab Anim. 2015; 49(1 Suppl):21-9. DOI: 10.1177/0023677215573040. View

16.

Yang J, Han D, Xie C, Zhao Y, Ma X . Endotoxins enhance hepatocarcinogenesis induced by oral intake of thioacetamide in rats. World J Gastroenterol. 2002; 4(2):128-132. PMC: 4688633. DOI: 10.3748/wjg.v4.i2.128. View

17.

Roehlen N, Crouchet E, Baumert T . Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells. 2020; 9(4). PMC: 7226751. DOI: 10.3390/cells9040875. View

18.

Weber L, Boll M, Stampfl A . Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003; 33(2):105-36. DOI: 10.1080/713611034. View

19.

Fortea J, Fernandez-Mena C, Puerto M, Ripoll C, Almagro J, Banares J . Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats - Improving Yield and Reproducibility. Sci Rep. 2018; 8(1):9163. PMC: 6003930. DOI: 10.1038/s41598-018-27427-9. View

20.

Horowitz J, Venkatesh S, Ehman R, Jhaveri K, Kamath P, Ohliger M . Evaluation of hepatic fibrosis: a review from the society of abdominal radiology disease focus panel. Abdom Radiol (NY). 2017; 42(8):2037-2053. PMC: 5994771. DOI: 10.1007/s00261-017-1211-7. View