gw-799388 and Hepatic-Encephalopathy

Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFβ1) is upregulated due to liver failure in mice and inhibiting circulating TGFβ reduced HE progression. However, the specific contributions of TGFβ1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFβ1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches.. TGFβ1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFβ1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFβR2. Increased circulating TGFβ1 following acute liver failure results in activation of neuronal TGFβR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.

Topics: Animals; Antibodies; Azoxymethane; Benzamides; Carcinogens; Cell Line, Transformed; Cerebral Cortex; Disease Models, Animal; Hepatic Encephalopathy; Inflammation; Isoquinolines; Liver; Liver Failure, Acute; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurons; Phagocytosis; Pyrazoles; Pyridines; Pyrroles; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Transforming Growth Factor beta1; Up-Regulation