Promotion of liver regeneration and anti‑fibrotic effects of the TGF‑β receptor kinase inhibitor galunisertib in CCl4‑treated mice

Abstract

The cytokine transforming growth factor-β (TGF-β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti-fibrogenic and regenerative effects of the TGF-β receptor type I kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl 4 )-induced liver cirrhosis and in vitro. Mice were intraperitoneally treated with CCl 4 for 8 weeks. At week 5, the mice were divided randomly into four treatment groups: Vehicle-treated; and treated with low-; middle-; and high-dose galunisertib, which was administered from weeks 5-8. The mice were sacrificed after 8 weeks of ccl 4 treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week 4-8 of ccl 4 treatment in the vehicle-treated mice. Galunisertib treatment dose-dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) after 8 weeks of ccl 4 treatment. The levels of active matrix metalloproteinase (MMP)-9 in galunisertib-treated livers were significantly increased compared with the vehicle-treated livers. In the high-dose group, the number of PCNA-positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription-quantitative PCR analysis verified that interleukin-6 and epiregulin expression levels were significantly increased in livers from the group treated with high-dose galunisertib compared with the vehicle-treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMP activity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF-β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF-β signaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.

Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis

“…Galunisertib is a highly selective inhibitor of TGFβR1 that has been demonstrated to completely inhibit phosphorylation and activation of SMAD2/3 [89]. Although the anti-fibrotic properties of galunisertib have not been widely explored, there is an emerging evidence for its therapeutic efficacy in liver fibrosis [26,27]. To date, the only report showing a potential benefit of galunisertib for the treatment of renal fibrosis in vivo is the study by Ding et al [90].…”

Lactiplantibacillus plantarum AR113 Exhibit Accelerated Liver Regeneration by Regulating Gut Microbiota and Plasma Glycerophospholipid

“…In addition, we found that TGF-β was increased in AR113+ PHx group at day 7 after PHx. TGF-β is produced principally in the hepatic stellate cells, and is a representative mitoinhibitory factor, which presumably induces the termination of liver regeneration (Masuda et al, 2020). Our study showed that whether probiotics are given before or after PHx will affect the expression of cytokine expression level.…”

The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF‐β receptor plus dual checkpoint inhibition maintains antitumor immune cells

“…We acknowledge that various TGF‐β receptor inhibitors (both antibody and small molecule) have various efficacies, benefits, and limitations. GAL dose schedules may be a limiting factor, as high doses of GAL are known to cause toxicity in animal models 51,52 . It is unlikely that GAL per se will be used in clinical trials but multiple other studies combining anti‐TGF‐β based therapy with immunotherapy are under investigation (http://clinicaltrials.gov) demonstrating value in this approach.…”