Volatile Anesthetic Isoflurane Attenuates Liver Injury in Experimental Polymicrobial Sepsis Model

Volatile anesthetics are often administered to patients with sepsis for procedural anesthesia or sedation in intensive care units. Sepsis still carries significant morbidities and mortalities, and organ injuries pose major complications. Early liver dysfunction is associated with poor outcome mainly as a result of overwhelming neutrophil recruitment. Leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) are major adhesion molecules on neutrophils and involved in neutrophil recruitment. We have previously showed that volatile anesthetic isoflurane inhibited LFA-1 and Mac-1. Here we studied the role of isoflurane, LFA-1 and Mac-1 on neutrophil recruitment to the liver and liver injury using experimental polymicrobial abdominal sepsis induced by cecal ligation and puncture (CLP) surgery. We used wild type (WT), LFA-1, Mac-1 and intercellular adhesion molecule-1 (ICAM-1) knockout (KO) mice. Following the induction of sepsis by CLP surgery, a group of mice were exposed to isoflurane for 2 hours. We found that Mac-1 and ICAM-1, but not LFA-1 were involved in neutrophil recruitment to liver. Isoflurane attenuated neutrophil recruitment and liver injury in WT and LFA-1 KO mice. Mac-1 KO mice had limited neutrophil recruitment and liver injury, both of which were not attenuated by isoflurane further, suggesting that isoflurane mitigated liver injury via Mac-1. Mac-1 colocalized with ICAM-1 and fibrinogen on liver tissues. In the presence of fibrinogen Mac-1 bound ICAM-1 significantly more, while LFA-1 bound less to ICAM-1, suggesting that Mac-1 used fibrinogen as a bridging molecule to bind ICAM-1. In conclusion, isoflurane exposure attenuated neutrophil recruitment and liver injury via Mac-1.