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Liver models

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Inflammation

Autoimmunity models Dermal models Gut models Kidney models Liver models Lung models Systemic Inflammation Models

Preclinical CRO Services for Inflammatory Diseases of the Liver

 

Acute and chronic inflammatory diseases of the liver tract can be triggered by several causes such as exposure to toxic chemicals, diet or immune dysregulation. Rodent models of liver inflammation are helpful to decipher the disease triggering or sustaining mechanisms observed in patients.

Oncodesign Services offers CRO services for several preclinical models addressing a variety of liver diseases, and provides CRO support for de novo development of new research models recently described in literature

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Typical readouts in liver inflammation

  • Steatosis
  • Fibrosis
  • NASH score
  • Neutrophil infiltration
  • Serum markers of liver injury: LDH, ALT, AST
  • Inflammation markers
  • Immune cell infiltrates
  • Ballooning degeneration of hepatocytes
  • Apoptosis markers or necrotic histology
  • Gene expression in liver, by qPCR/dPCR
  • Biomarker / drug monitoring

Discover Oncodesign Services offers for liver inflammation diseases

Integrated Drug Discovery Services by Oncodesign

Case studies in liver inflammation

The CCl4 model of liver fibrosis is a classic model widely used in industry.  Juvenile mice are given repeated doses of CCl4.Liver fibrosis then typically appears at 6 weeks old.

This model is useful for therapies aiming to modulate collagen depositions and expression of metalloproteases.  ALK5 (TGFb receptor I) inhibition, a well-known anti-fibrotic mechanism, decreases collagen induction and is used as a reference compound.

 

Liver - CCl4 liver fibrosis biomarker results
Liver - CCl4 liver fibrosis model gene expression ALK5 inhibitor response

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  • References

    (1) Acute liver injury models in mice

    FasL:

    Shao R, Yang Y, Fan K, Wu X, Jiang R, Tang L, Li L, Shen Y, Liu G, Zhang L. REV-ERBα Agonist GSK4112 attenuates Fas-induced Acute Hepatic Damage in Mice. Int J Med Sci. 2021 Oct 25;18(16):3831-3838. doi: 10.7150/ijms.52011. PMID: 34790059; PMCID: PMC8579287. https://www.medsci.org/v18p3831.htm

    Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806-9. doi: 10.1038/364806a0. Erratum in: Nature 1993 Oct 7;365(6446):568. PMID: 7689176 https://www.nature.com/articles/364806a0

    Lesnikov V, Gorden N, Fausto N, Spaulding E, Campbell J, Shulman H, Fleming RE, Deeg HJ. Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2. Apoptosis. 2008 Aug;13(8):1005-12. doi: 10.1007/s10495-008-0233-6. PMID: 18561026; PMCID: PMC2574612. https://link.springer.com/article/10.1007/s10495-008-0233-6

    Ohtaki Y, Yamaguchi K, Yu Z, Kumamoto H, Shimauchi H, Iwakura Y, Sugawara S, Endo Y. Hepatic platelet accumulation in Fas-mediated hepatitis in mice. Int Immunopharmacol. 2009 Aug;9(9):1071-8. doi: 10.1016/j.intimp.2009.04.016. Epub 2009 May 9. PMID: 19439197. https://www.sciencedirect.com/science/article/pii/S1567576909001659?via%3Dihub

    Donthamsetty S, Mars WM, Orr A, Wu C, Michalopoulos GK. Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice. Comp Hepatol. 2011 Nov 21;10:11. doi: 10.1186/1476-5926-10-11. PMID: 22104495; PMCID: PMC3228663. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228663/

     

    Acetaminophen:

    • Mechanism:

    Ni HM, McGill MR, Chao X, Du K, Williams JA, Xie Y, Jaeschke H, Ding WX. Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol. 2016 Aug;65(2):354-62. doi: 10.1016/j.jhep.2016.04.025. Epub 2016 May 2. PMID: 27151180; PMCID: PMC4955750. https://www.journal-of-hepatology.eu/article/S0168-8278(16)30169-6/fulltext

    Groeneveld D, Cline-Fedewa H, Baker KS, Williams KJ, Roth RA, Mittermeier K, Lisman T, Palumbo JS, Luyendyk JP. Von Willebrand factor delays liver repair after acetaminophen-induced acute liver injury in mice. J Hepatol. 2020 Jan;72(1):146-155. doi: 10.1016/j.jhep.2019.09.030. Epub 2019 Oct 10. PMID: 31606553; PMCID: PMC6941657. https://www.journal-of-hepatology.eu/article/S0168-8278(19)30600-2/fulltext

     

    • Review:

    Mossanen JC, Tacke F. Acetaminophen-induced acute liver injury in mice. Lab Anim. 2015 Apr;49(1 Suppl):30-6. doi: 10.1177/0023677215570992. PMID: 25835736. https://journals.sagepub.com/doi/10.1177/0023677215570992?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

    osner I, Romero-Ferret C, Mottot G. Letter: Treatment of acute paracetamol poisoning. Lancet. 1973 Dec 1;2(7840):1273-4. doi: 10.1016/s0140-6736(73)91024-6. PMID: 4128608 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(73)91024-6/fulltext

     

    • Testing compounds :

    Jaeschke H, Akakpo JY, Umbaugh DS, Ramachandran A. Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure. Toxicol Sci. 2020 Apr 1;174(2):159-167. doi: 10.1093/toxsci/kfaa002. PMID: 31926003; PMCID: PMC7098369. https://academic.oup.com/toxsci/article/174/2/159/5700748?login=false

    Niu B, Lei X, Xu Q, Ju Y, Xu D, Mao L, Li J, Zheng Y, Sun N, Zhang X, Mao Y, Li X. Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury. Cell Biol Toxicol. 2022 Jun;38(3):505-530. doi: 10.1007/s10565-021-09624-x. Epub 2021 Aug 17. PMID: 34401974. https://link.springer.com/article/10.1007/s10565-021-09624-x

     

    Schneider KM, Elfers C, Ghallab A, Schneider CV, Galvez EJC, Mohs A, Gui W, Candels LS, Wirtz TH, Zuehlke S, Spiteller M, Myllys M, Roulet A, Ouzerdine A, Lelouvier B, Kilic K, Liao L, Nier A, Latz E, Bergheim I, Thaiss CA, Hengstler JG, Strowig T, Trautwein C. Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury. Cell Mol Gastroenterol Hepatol. 2021;11(4):909-933. doi: 10.1016/j.jcmgh.2020.11.002. Epub 2020 Nov 12. PMID: 33189892; PMCID: PMC7900526 https://www.cmghjournal.org/article/S2352-345X(20)30181-8/fulltext

     

    (2) Chronic liver injury models in mice

    • Review :

    Ravichandra A, Schwabe RF. Mouse Models of Liver Fibrosis. Methods Mol Biol. 2021;2299:339-356. doi: 10.1007/978-1-0716-1382-5_23. PMID: 34028753. https://link.springer.com/protocol/10.1007/978-1-0716-1382-5_23

     

    • CCl4 fibrosis

    Scholten D, Trebicka J, Liedtke C, Weiskirchen R. The carbon tetrachloride model in mice. Lab Anim. 2015 Apr;49(1 Suppl):4-11. doi: 10.1177/0023677215571192. PMID: 25835733.

    https://journals.sagepub.com/doi/10.1177/0023677215571192?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

     

    Chang J, Lan T, Li C, Ji X, Zheng L, Gou H, Ou Y, Wu T, Qi C, Zhang Q, Li J, Gu Q, Wen D, Cao L, Qiao L, Ding Y, Wang L. Activation of Slit2-Robo1 signaling promotes liver fibrosis. J Hepatol. 2015 Dec;63(6):1413-20. doi: 10.1016/j.jhep.2015.07.033. Epub 2015 Aug 8. PMID: 26264936. https://www.journal-of-hepatology.eu/article/S0168-8278(15)00536-X/fulltext

    Arroyo N, Villamayor L, Díaz I, Carmona R, Ramos-Rodríguez M, Muñoz-Chápuli R, Pasquali L, Toscano MG, Martín F, Cano DA, Rojas A. GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells. JCI Insight. 2021 Dec 8;6(23):e150059. doi: 10.1172/jci.insight.150059. PMID: 34699385; PMCID: PMC8675192. https://insight.jci.org/articles/view/150059

    Shrestha N, Chand L, Han MK, Lee SO, Kim CY, Jeong YJ. Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial-mesenchymal transition in mouse hepatocytes. Food Chem Toxicol. 2016 Jul;93:129-37. doi: 10.1016/j.fct.2016.04.024. Epub 2016 Apr 29. PMID: 27137983. https://www.sciencedirect.com/science/article/abs/pii/S0278691516301302?via%3Dihub

    Wu H, Chen G, Wang J, Deng M, Yuan F, Gong J. TIM-4 interference in Kupffer cells against CCL4-induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway. Cell Prolif. 2020 Jan;53(1):e12731. doi: 10.1111/cpr.12731. Epub 2019 Nov 22. PMID: 31755616; PMCID: PMC6985653. https://onlinelibrary.wiley.com/doi/10.1111/cpr.12731

     

    • NASH MODELS : STZ+HFD NASH / CCl4+HFD NASH / Long term NASH-HCC

    Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today. 2017 Nov;22(11):1707-1718. doi: 10.1016/j.drudis.2017.06.007. Epub 2017 Jul 4. PMID: 28687459 https://www.sciencedirect.com/science/article/pii/S1359644617300272?via%3Dihub

    Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, Hashiguchi T, Plato C, Poulin D, Richards T, Yoneyama H, Jenkins H, Wolfgang G, Friedman SL. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016 Jun 27;11(6):e0158156. doi: 10.1371/journal.pone.0158156. PMID: 27347680; PMCID: PMC4922569. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158156

    Klein T, Fujii M, Sandel J, Shibazaki Y, Wakamatsu K, Mark M, Yoneyama H. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med Mol Morphol. 2014 Sep;47(3):137-49. doi: 10.1007/s00795-013-0053-9. Epub 2013 Sep 19. PMID: 24048504. https://link.springer.com/article/10.1007/s00795-013-0053-9

    Orime K, Shirakawa J, Togashi Y, Tajima K, Inoue H, Nagashima Y, Terauchi Y. Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model. Eur J Pharmacol. 2016 Feb 5;772:22-32. doi: 10.1016/j.ejphar.2015.12.043. Epub 2015 Dec 24. PMID: 26724391. https://www.sciencedirect.com/science/article/abs/pii/S0014299915304398