Fibroblast growth factor 9 attenuates sepsis-induced fulminant hepatitis in mice.

ABSTRACT

Sepsis-induced fulminant hepatitis (FH) is a fatal syndrome that has a worse prognosis in clinical practice. Hence, seeking effective agents for sepsis-induced FH treatment is urgently needed. Fibroblast growth factors (FGFs) are vital for tissue homeostasis and damage repair in various organs including the liver. Our study aims to investigate the protective effects and potential mechanisms of FGF9 on lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced FH in mice. We found that pre-treatment with FGF9 exhibited remarkable hepaprotective effects on liver damage caused by LPS/D-Gal, as manifested by the concomitant decrease in mortality and serum aminotransferase activities, and the attenuation of hepatocellular apoptosis and hepatic histopathological abnormalities in LPS/D-Gal-intoxicated mice. We further found that FGF9 alleviated the infiltration of neutrophils into the liver, and decreased the serum levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS/D-Gal-challenged mice. These effects can be explained at least in part by the inhibition of NF-κB signaling pathway. Meanwhile, FGF9 enhanced the antioxidative defense system in mice livers by upregulating the expression of NRF-2-related antioxidative enzymes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase-1 (HO-1). These data indicate that FGF9 represents a promising therapeutic drug for ameliorating sepsis-induced FH via its anti-apoptotic and anti-inflammatory capacities.