The TGFβ1 receptor antagonist GW788388 reduces JNK activation and protects against acetaminophen hepatotoxicity in mice.
McMillin M , Grant S , Frampton G , Petrescu AD , Williams E , Jefferson B , DeMorrow S
Toxicological sciences : an official journal of the Society of Toxicology
Acute liver failure is a serious consequence of acetaminophen (APAP)-induced hepatotoxic liver injury with high rates of morbidity and mortality. TGFβ1 is elevated during liver injury and influences hepatocyte senescence during APAP-induced hepatotoxicity. The current study investigated TGFβ1 signaling in the context of inflammation, necrotic cell death and oxidative stress during APAP-induced liver injury. Male C57Bl/6 mice were injected with 600 mg/kg APAP to generate liver injury in the presence or absence of the TGFβ receptor 1 inhibitor, GW788388, 1 hour prior to APAP administration. APAP-induced liver injury was characterized using histological and biochemical measures. TGFβ1 expression and signal transduction were assessed using immunohistochemistry, western blotting and ELISA assays. Hepatic necrosis, liver injury, cell proliferation, hepatic inflammation and oxidative stress were assessed in all mice. APAP administration significantly induced necrosis and elevated serum transaminases compared to control mice. TGFβ1 staining was observed in and around areas of necrosis with phosphorylation of SMAD3 observed in hepatocytes neighboring necrotic areas in APAP-treated mice. Pretreatment with GW788388 prior to APAP administration in mice reduced hepatocyte cell death and stimulated regeneration. Phosphorylation of SMAD3 was reduced in APAP mice pretreated with GW788388 and this correlated with reduced hepatic cytokine production and oxidative stress. These results support that TGFβ1 signaling plays a significant role in APAP-induced liver injury by influencing necrotic cell death, inflammation, oxidative stress and hepatocyte regeneration,. In conclusion, targeting TGFβ1 or downstream signaling may be a possible therapeutic target for the management of APAP-induced liver injury.
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