tretinoin and cenicriviroc

Cholestatic liver injury is mediated by bile acid-induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation.. All-trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the atRA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro-inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in Mdr2. Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with atRA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Bile Acids and Salts; Cholestasis; Disease Models, Animal; Drug Therapy, Combination; Imidazoles; Ligation; Liver; Liver Diseases; Male; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptors, Cytokine; Sulfoxides; Tretinoin

Topics: Animals; Imidazoles; Liver Diseases; Receptors, Cytokine; Rodentia; Sulfoxides; Tretinoin