Injury Resistance in the Setting of Liver Fibrosis Is Accompanied by the Inhibition of High-Mobility Group Box-1 Translocation and Release

Abstract

Background: Injury resistance occurring in the setting of liver fibrosis is an interesting phenomenon not yet well characterized. In the present study, we investigated dynamically the injury resistance against acute challenge using animal models of hepatic fibrosis and spontaneous resolution, and focused on high-mobility group box-1 (HMGB1), an important proinflammatory mediator. Methods: The hepatic damage of control, fibrosis (CCl4, 6 weeks), and regressive mice with or without CCl4 challenge was dynamically observed and compared. The translocation and release of HMGB1 were assessed by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. The gene expression of proinflammatory mediators was detected by real-time PCR. Results: Our data showed that the fibrotic mice were invulnerable to acute CCl4 insult. The injury resistance diminished along with the resolution of liver fibrosis. Acute insult triggered the translocation and release of HMGB1 in control mice, which were remarkably inhibited in fibrotic mice, even under acute challenge. Nevertheless, regressive mice exhibited obvious translocation upon insult, especially for R12d mice. HMGB1-related proinflammatory immune responses were suppressed in fibrotic mice; however, they were restored in regressive mice upon insult. Conclusion: The injury resistance in the setting of liver fibrosis is accompanied by the inhibition of HMGB1 translocation and release as well as the suppression of HMGB1-related proinflammatory immune responses.