Heme-Inducing Endothelial Pyroptosis Plays a Key Role in Radiofrequency Ablation of Hepatic Hemangioma Leading to Systemic Inflammatory Response Syndrome

Abstract

Purpose

Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear.

Methods

We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1β and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD ^−/− mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins.

Results

The levels of heme, IL-1β, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1β and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS.

Conclusion

Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA.

Graphical Abstract