Hedgehog Signaling is Associated with Liver Response to Fractionated Irradiation in Mice

Abstract

Background/Aims: Radiation-induced liver disease (RILD) is a major obstacle in treating liver cancer; however, the mechanisms underlying RILD development remain unclear. Hedgehog (Hh) orchestrates liver response to injury. Herein, we investigated the liver response with Hh to fractionated irradiation (FI) using a small murine model for RILD. Methods: Male mice exposed to liver-targeted FI with 6Gy in 5 consecutive weekly fractions were sacrificed at one day after weekly irradiation and 6 or 10 weeks post 5th FI for the acute and late response model, respectively. Results: The levels of ALT/AST and apoptosis were elevated in all radiation groups. The expression of Hh ligand, Sonic and Indian Hh, and Hh activator, smoothened and gli2, was higher in the acute groups than the control group. Pro-fibrogenic markers were also up-regulated in this model compared with the control group. Histomorphological changes and ballooned hepatocytes were observed in the late response model. Both the expression of Hh and profibrotic genes and the fibrosis level increased in this model compared with the control groups. Conclusion: Enhanced Hedgehog signaling and liver injury with fibrosis in RILD murine model suggests hedgehog as the potential regulator in RILD progression and the suitability of this model for studying RILD.