Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612685
Poster Visit Session I Fibrogenesis and Nonparenchymal Cells – Friday, January 26, 2018, 12:30pm – 1:15pm, Room 121
Georg Thieme Verlag KG Stuttgart · New York

Inhibition of TGF-β1 pathway reduces fibrosis in ABCB4-/- mouse model

J Werle
1   II. Medizinische Klinik, Universitätsmedizin Mannheim, Molekulare Hepatologie, AG Dooley, Mannheim
,
S Hammad
1   II. Medizinische Klinik, Universitätsmedizin Mannheim, Molekulare Hepatologie, AG Dooley, Mannheim
,
G Gianelli
2   IRCCS Saverio de Bellis, Gastroenterology, Castellana Grotte BA
,
S Dooley
1   II. Medizinische Klinik, Universitätsmedizin Mannheim, Molekulare Hepatologie, AG Dooley, Mannheim
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2018 (online)

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Background and aims:

Since the only therapy of end-stage liver disease still is transplantation, the need for an early treatment in the stage of fibrosis is becoming more important.

The concept of reversing chronic liver disease (CLD) has been intensively studied for many years now. The transforming growth factor (TGF)-β has been identified as a master regulator of liver fibrogenesis.

In our experiments we targeted TGF-β1 pathway via a small molecule, Galunisertib, which is inhibiting ALK5 intracellularly and thereby the phosphorylation of SMAD2. The inhibitor is already in clinical trials phase II to treat the hepatocellular carcinoma patients (NCT02423343).

Methods:

MDR2 KO mice, a well-established model for CLD, were treated at the age of 6 months. Twice a day the animals were fed via oral gavage with Galunisertib, 150 mg/kg body weight. Two days after the last dosage, blood plasma and livers were harvested for standard CLD assessments.

Results:

No changes were observed in body weight of Galunisertib-exposed mice compared to vehicle treated or untreated group. pSMAD2 immunostaining showed a significant reduction in the number of positive stained hepatocytes after Galunisertib administration as well as analysis of TGF- pathway genes indicate the efficacy of the treatment.

Liver transaminases, namely ALT and AST were slightly reduced in the treated group. Moreover, Galunisertib reduced the level of collagen expression as tested by Picro Sirius Red staining and Hydroxyproline analysis.

Next step will be examining in which cell type/s the impact of Galunisertib is the strongest and leads to the reduction of the fibrosis in the treated livers. This we show by co-staining of pSMAD2 with markers for hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells and bile duct cells. To confirm our findings here we plan to treat primary cells with Galunisertib in vitro.

Conclusion:

We can conclude that Galunisertib shows a trend in the direction of CLD regression. Further experiments are ongoing to determine which mechanisms lay beyond the effect of the ALK5 inhibtor.