Sulforaphane regulates hepatic autophagy and apoptosis by modulating Kupffer cells' polarization via Nrf2/HO-1 pathway in the murine hemorrhagic shock/resuscitation model.

PURPOSE

The aim of this study was to explore how sulforaphane (SFN), a well-known nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activator, regulates hepatic autophagy and apoptosis by modulating the polarization of Kupffer cells via the Nrf2/HO-1 pathway in a hemorrhagic shock/resuscitation (HS/R) model in mice.

METHODS

Male c57/BL6 mice were subjected to hemorrhagic shock (HS) for 90 min under blood pressure control. Resuscitation was performed by reinfusing the withdrawn blood and infusing 0.9% NaCl, and SFN was administered intraperitoneally. All animals were euthanized 24 h after resuscitation, and liver tissue samples were collected for TUNEL staining, western blot analysis, immunohistochemical staining, immunofluorescence staining, and observation using transmission electron microscopy (TEM). Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was performed to verify the SFN distribution in the liver.

RESULTS

SFN reached the liver within the first hour after it was injected. SFN was found to promote the hepatic Nrf2/HO-1 pathway and the polarization of Kupffer cells to the M2 phenotype rather than the M1 phenotype after HS/R. Furthermore, SFN inhibited hepatic apoptosis after HS/R, as demonstrated by a decrease in the Bax/Bcl-2 ratio, fewer TUNEL-positive cells, and changes in cleaved caspase 3 expression. Enhanced hepatic autophagy was observed after HS/R, as shown by an increase in the number of autophagosomes, a higher LC3-II/LC3-I ratio, and decreased expression of p62 and beclin-1.

CONCLUSIONS

In this study, SFN administration inhibited hepatic apoptosis and promoted hepatic autophagy by inducing Kupffer cells to polarize to the M2 phenotype rather than the M1 phenotype via the Nrf2/HO-1 pathway.