Protective Effects of Dexmedetomidine on Sepsis-Induced Vascular Leakage by Alleviating Ferroptosis via Regulating Metabolic Reprogramming

作者：Han She, Yi Hu, Yuanqun Zhou, Lei Tan, Yu Zhu, Chunhua Ma, Yue Wu, Wei Chen, Li Wang, Zi-sen Zhang, Liangming Liu, Tao Li · 发表于：Journal of Inflammation Research · 年份：2021 · DOI：10.2147/jir.s340420 · 被引用次数：49 · 研究领域：Medicine

Introduction Vascular leakage plays a vital role in sepsis-induced multi-organ dysfunction. Currently, no specific measures are available for vascular leakage. Ferroptosis, as a recently recognized form of cell death, plays a crucial role in cell dysfunction. It is still unknown whether ferroptosis participates in the occurrence of organ dysfunction following sepsis. Our previous study showed that dexmedetomidine (Dex) could alleviate sepsis-induced organ dysfunction. However, whether the mechanism is related to ferroptosis is not clear. Methods The publicly available datasets of septic patients were reanalyzed, and septic models in vivo and vitro by cecal ligation and puncture and lipopolysaccharide-stimulated vascular endothelial cells (VECs) were applied. The occurrence of ferroptosis in septic patients and rats was observed, and the protective effects of Dex on ferroptosis, and related mechanisms on regulating metabolic reprogramming and mitochondrial fission were further studied. Results The transcriptomics data of patients from the GEO database showed that ferroptosis was closely related to sepsis. Sepsis induced significant ferroptosis in VECs by metabolomics analysis. The level of lipid peroxidation was increased in VECs, and the mitochondrial cristae was decreased after sepsis. Metabolomics analysis showed that Dex activated the pentose phosphate pathway and increased glutathione in VECs via up-regulation of G6PD expression. Dex could antagonize sepsis-induced the de...