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

Abstract

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 Resuscitation was performed by reinfusing the withdrawn blood and infusing 0.9% NaCl, and SFN was administered intraperitoneally.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.