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- Title
Inhibition of TGFβ type I receptor activity facilitates liver regeneration upon acute CCl intoxication in mice.
- Authors
Karkampouna, Sofia; Goumans, Marie-José; Dijke, Peter; Dooley, Steven; Kruithof-de Julio, Marianna
- Abstract
Liver exhibits a remarkable maintenance of functional homeostasis in the presence of a variety of damaging toxic factors. Tissue regeneration involves cell replenishment and extracellular matrix remodeling. Key regulator of homeostasis is the transforming growth factor-β (TGFβ) cytokine. To understand the role of TGFβ during liver regeneration, we used the single-dose carbon tetrachloride (CCl) treatment in mice as a model of acute liver damage. We combined this with in vivo inhibition of the TGFβ pathway by a small molecule inhibitor, LY364947, which targets the TGFβ type I receptor kinase [activin receptor-like kinase 5 (ALK5)] in hepatocytes but not in activated stellate cells. Co-administration of LY364947 inhibitor and CCl toxic agent resulted in enhanced liver regeneration; cell proliferation (measured by PCNA, phosphorylated histone 3, p21) levels were increased in CCl + LY364947 versus CCl-treated mice. Recovery of CCl-metabolizing enzyme CYP2E1 expression in hepatocytes is enhanced 7 days after CCl intoxication in the mice that received also the TGFβ inhibitor. In summary, a small molecule inhibitor that blocks ALK5 downstream signaling and halts the cytostatic role of TGFβ pathway results in increased cell regeneration and improved liver function during acute liver damage. Thus, in vivo ALK5 modulation offers insight into the role of TGFβ, not only in matrix remodeling and fibrosis, but also in cell regeneration.
- Subjects
LIVER regeneration; TRANSFORMING growth factors-beta; HOMEOSTASIS; PHYSIOLOGICAL effects of cytokines; CARBON tetrachloride
- Publication
Archives of Toxicology, 2016, Vol 90, Issue 2, p347
- ISSN
0340-5761
- Publication type
Article
- DOI
10.1007/s00204-014-1436-y