Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor beta 1

摘要

Severe hepatic insults can lead to acute liver failure and hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGF beta 1) has been shown to contribute to HE during acute liver failure; however, TGF beta 1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGF beta 1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess TSP-1 during acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1(-/-)) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurologic decline, and molecular analyses of TSP-1 and TGF beta 1 signaling were performed. AOM-treated mice had increased TSP-1 and TGF beta 1 mRNA and protein expression in the liver. TSP-1(-/-) mice administered AOM had reduced liver injury as assessed by histology and serum transaminase levels compared with C57Bl/6 AOM-treated mice. TSP-1(-/-) mice treated with AOM had reduced TGF beta 1 signaling that was associated with less hepatic cell death as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cleaved caspase 3 expression. TSP-1(-/-) AOM-treated mice had a reduced rate of neurologic decline, less cerebral edema, and a decrease in microglia activation in comparison with C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGF beta 1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.