The CYP2E1 inhibitor Q11 ameliorates LPS-induced sepsis in mice by suppressing oxidative stress and NLRP3 activation

  • Impact factors: 5.8
  • Publication: BIOCHEMICAL PHARMACOLOGY
  • Author:Na Gao, Jingjing Chen, Yunchao Li, Ying Ding, Zixinying Han, Haiwei Xu, Hailing Qiao
  • DOI citation-doi:10.1016/j.bcp.2023.115638
  • Date:2023-06-07

Sepsis is an infection-induced, multi-organ system failure with a pathophysiology related to inflammation and oxidative stress. Increasing evidence indicates that cytochrome P450 2E1 (CYP2E1) is involved in the incidence and development of inflammatory diseases . However, a role for CYP2E1 in lipopolysaccharide (LPS)-induced sepsis has not been completely explored. Here we use Cyp2e1 knockout ( cyp2e1-/- ) mice to determine if CYP2E1 could be a therapeutic target for sepsis. We also evaluated the ability of Q11, a new specific CYP2E1 inhibitor , to prevent and ameliorate LPS-induced sepsis in mice and in LPS-treated J774A.1 and RAW264.7 cells. Cyp2e1 deletion significantly reduced hypothermia, multi-organ dysfunction and histological abnormalities in LPS-treated mice; consistent with this finding, the CYP2E1 inhibitor Q11 significantly prolonged the survival time of septic mice and ameliorated multi-organ injury induced by LPS . CYP2E1 activity in liver correlated with indicators of multi-organ injury, such as the level of lactate dehydrogenase (LDH) and blood urea nitrogen (BUN) ( P  < 0.05). Q11 significantly suppressed the expression of NLRP3 in tissues after LPS injection; in vitro studies revealed that activation of NLRP3 signaling and increase of ROS was attenuated by Q11 in LPS-stimulated macrophages, which was reflected by reduced expression of caspase-1 and formation of ASC specks. Overall, our results indicate that Q11 improves the survival of mice with LPS-induced sepsis and attenuates sepsis-induced multiple-organ injury, suggesting that CYP2E1 could be a therapeutic target for sepsis.

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