The volatile anesthetic sevoflurane reduces neutrophil apoptosisviaFas death domain–Fas‐associated death domain interaction

Abstract

Sepsis remains a significant health care burden, with high morbidities and mortalities. Patients with sepsis often require general anesthesia for procedures and imaging studies. Knowing that anesthetic drugs can pose immunomodulatory effects, it would be critical to understand the impact of anesthetics on sepsis pathophysiology. The volatile anesthetic sevoflurane is a common general anesthetic derived from ether as a prototype. Using a murine sepsis model induced by cecal ligation and puncture surgery, we examined the impact of sevoflurane on sepsis outcome. Different from volatile anesthetic isoflurane, sevoflurane exposure significantly improved the outcome of septic mice. This was associated with less apoptosis in the spleen. Because splenic apoptosis was largely attributed to the apoptosis of neutrophils, we examined the effect of sevoflurane on FasL‐induced neutrophil apoptosis. Sevoflurane exposure significantly attenuated apoptosis. Sevoflurane did not affect the binding of FasL to the extracellular domain of Fas receptor. Instead, in silico analysis suggested that sevoflurane would bind to the interphase between Fas death domain (DD) and Fas‐associated DD (FADD). The effect of sevoflurane on Fas DD‐FADD interaction was examined using fluorescence resonance energy transfer (FRET). Sevoflurane attenuated FRET efficiency, indicating that sevoflurane hindered the interaction between Fas DD and FADD. The predicted sevoflurane binding site is known to play a significant role in Fas DD‐FADD interaction, supporting our in vitro and in vivo apoptosis results.—Koutsogiannaki, S., Hou, L., Babazada, H., Okuno, T., Blazon‐Brown, N., Soriano, S. G., Yokomizo, T., Yuki, K. The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain‐Fas‐associated death domain interaction. FASEB J. 33, 12668–12679 (2019). http://www.fasebj.org

The effect of anesthetics on toll like receptor 9

“…We and others have described the immunomodulatory role of anesthetics 5,6 . Leukocyte function‐associated antigen‐1 (LFA‐1), macrophage‐1 antigen (Mac‐1), TLR2, TLR4, Ras‐related protein 1 (Rap1), and Fas pathway have been described 7,11,22,25,26,36‐40 . This study adds TLR9 to the list of anesthetic target molecules.…”

Sevoflurane, a sigh of relief in COVID-19?

“…17 In a lipopolysaccharide-induced sepsis model in rats, concentrations of MCP-1, interleukin-6, and cytokine-induced neutrophil chemoattractant protein-1 measured 3, 6, and 12 h after lipopolysaccharide infusion were lower in sevoflurane-treated rats compared with propofol-treated rats. 18 Koutsogiannaki and colleagues 19 showed that improved survival in sevoflurane-treated mice subjected to sepsis was associated with less apoptosis in the spleen. Sevoflurane reduced neutrophil apoptosis by a Fas death domain-Fas-associated death domain interaction.…”

Electrostatic Charge‐Mediated Apoptotic Vesicle Biodistribution Attenuates Sepsis by Switching Neutrophil NETosis to Apoptosis

“…[ 8,15 ] Fas, a member of the tumor necrosis factor (TNF) receptor superfamily, can trigger the apoptotic signaling cascade of neutrophils after stimulation by specific ligands, Fas ligand (FasL). [ 16 ] However, the relationship between the Fas/FasL pathway and NETosis remains unclear.…”