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Thrombospondin-1 exacerbates acute liver failure and hepatic encephalopathy pathology in mice by activating transforming growth factor beta 1.

著者 Jefferson B , Ali M , Grant S , Frampton G , Ploof M , Andry S , DeMorrow S , McMillin M
Am J Pathol.2019 Nov 14 ; ():.
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Severe hepatic insults can lead to acute liver failure and the development of hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGFβ1) has been demonstrated to contribute to HE from acute liver failure; however, TGFβ1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFβ1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess the role of TSP-1 in 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, neurological decline, and molecular analyses of TSP-1 and TGFβ1 signaling were performed. AOM-treated mice had elevated TSP-1 and TGFβ1 mRNA and protein expression in the liver. TSP-1 mice administered AOM had reduced liver injury as assessed by histology and serum transaminases compared to C57Bl/6 AOM-treated mice. TSP-1 mice treated with AOM had reduced TGFβ1 signaling which was associated with less hepatic cell death as assessed by TUNEL staining and cleaved caspase 3 expression. TSP-1 AOM-treated mice had a reduced rate of neurological decline, less cerebral edema and a decrease in microglia activation in comparison to C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGFβ1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.
PMID: 31734229 [PubMed - as supplied by publisher]
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