Abstract
Our research explores the immunomodulatory effects of sulforaphane (SFN), a well-known nuclear factor erythroid 2-related factor 2 (Nrf2) pathway agonist, on the sterile inflammation of and ischemia-reperfusion injuries to the liver after hemorrhagic shock (HS) followed by resuscitation (R). Male C57/BL6 wild-type and transgenic ARE-luc mice were exposed to mean arterial pressure-controlled HS. Fluid resuscitation was performed after 90 min of HS, and SFN was administrated intraperitoneally after that. The animals were sacrificed at 6 h, 24 h, and 72 h after resuscitation, and their livers were extracted to perform H&E staining and myeloperoxidase (MPO) activity analysis. The Kupffer cells were isolated for cytokines profile measurements and Nrf2 immunofluorescence staining. Further, the ARE-luc mice were used to assess hepatic Nrf2 activity in vivo. We identified that SFN-activated Kupffer cells’ Nrf2 pathway and modulated its cytokines expression, including TNF-α, MCP-1, KC/CXCL1, IL-6, and IL-10. Furthermore, SFN mitigated liver ischemia-reperfusion injury, as evidenced by the downregulation of the Suzuki score and the enhanced hepatic Nrf2 activity. The in vivo SFN treatment decreased neutrophils infiltration, as shown by the decreased MPO levels. Our study shows that SFN can decrease HS/R-induced hepatic ischemia-reperfusion injury and modulate the activity of Kupffer cells via an Nrf2-dependent pathway.
Highlights
Hemorrhagic shock (HS) remains one of the leading causes of death in traumatized patients [1] and negatively affects multiple organs of survivors by causing hypoxia, cell damage, and organ failure
Kupffer cells serve as a major source of proinflammatory cytokines and reactive oxygen species (ROS), which are liberated during the early stages of HS [6]
We investigated the effects of SFN on HS/Rinduced liver damage because compared to other organs, the liver is well-protected from general ischemic injury due to its dual blood flow system
Summary
Hemorrhagic shock (HS) remains one of the leading causes of death in traumatized patients [1] and negatively affects multiple organs of survivors by causing hypoxia, cell damage, and organ failure. This process is accompanied by a sterile inflammatory response that includes an overwhelming oxidative stress reaction [2]. The nuclear factor erythroid 2-related factor 2 (Nrf2) has been proven to exert hepatoprotective effects in case of toxin induced hepatitis. It belongs to the family of basic region leucine zipper (bZIP) transcription factors. Due to the aforementioned aspects, Nrf has been considered as a target for new therapeutic approaches in the treatment of several liver diseases [9]
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