Dexmedetomidine modulates macrophage polarization by inhibiting ferroptosis to exert protective effects on intestinal barrier function in sepsis

The intestine is believed to play a pivotal role in the onset and progression of sepsis, serving as the driving force behind multiple organ dysfunction syndrome. The polarization state of macrophages is pivotal in the intestinal barrier dysfunction associated with sepsis. M1 macrophages initiate the degradation of barrier-sealing molecules, increasing intestinal barrier permeability. Studies have demonstrated that dexmedetomidine offers protection for organ function in sepsis; however, the mechanism behind its protective effect on the intestinal barrier remains unclear. We utilized cecal ligation and perforation surgery to establish sepsis models, along with lipopolysaccharide (LPS)-treated intestinal epithelial and RAW264.7 cell models, to explore the protective effects and mechanisms of dexmedetomidine on intestinal barrier function in rats with sepsis. Our study demonstrated that dexmedetomidine protects intestinal barrier function in septic rats by suppressing inflammatory responses, enhancing the expression of tight junction proteins between intestinal epithelial cells, and significantly reducing intestinal permeability. Additionally, dexmedetomidine markedly decreases the number of inflammatory M1 macrophages in the intestines of septic rats, facilitates the polarization of macrophages toward the anti-inflammatory M2 phenotype, and suppresses the secretion of inflammatory cytokines. Research has indicated that dexmedetomidine is closely linked to ferroptosis, influencing the transport protein xCT to increase the GSH content and GPX4 expression within macrophages. This, in turn, reduces intracellular ROS and lipid ROS levels, mitigates macrophage ferroptosis, and curtails the polarization of macrophages toward the proinflammatory M1 phenotype.