|Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Background and Aims : Kupffer cells, resident tissue macrophages of the liver, play a key role in the regulation of hepatic inflammation, hepatocyte death, and fibrosis that characterize liver diseases. However, it is controversial whether Kupffer cell promotes or protects from liver injury. To explore this issue, we examined the role of Kupffer cell in liver injury, cell death, regeneration, and fibrosis on cholestatic liver injury. Methods : A model of partial bile duct ligation (PBDL) was developed. The left hepatic duct of wild-type C57BL/6 male mice was ligated with 6-0 silk, and the animals were sacrificed 10 days after the surgery. Liver injury, regeneration, and fibrosis were compared between the ligated left and non-ligated right lobes. Hepatocyte apoptosis was induced by administration of D-galactosamine and TNF-alpha to the PBDL mice. The effects of Kupffer cell depletion by alendronate liposomes, or inhibition of AKT by adenovirus expressing dominant-negative AKT were investigated. Results : In the cholestatic liver injury, remaining viable cells represented tolerance for tumor necrosis factor (TNF)-α-induced hepatocyte apoptosis and regenerative features along with AKT activation. Inhibition of AKT abolished the survival and regenerative properties in hepatocytes. Moreover, Kupffer cell depletion increased hepatocyte damage and the sensitivity of TNF-α-induced hepatocyte apoptosis in ligated lobes. Kupffer cell depletion decreased hepatocyte regeneration and liver fibrosis with reduced AKT activation. Conclusion: Kupffer cell has a protective role for hepatocyte damage, and promotes cell survival, liver regeneration, and fibrosis in cholestatic liver disease. Kupffer cell is crucial for AKT activation of hepatocytes that is required for the survival and regenerative responses.