Koutsogiannaki Sophia, Zha Hui, Yuki Koichi
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.
Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.
Transl Perioper Pain Med. 2018;5(3):63-74. doi: 10.31480/2330-4871/071. Epub 2018 May 22.
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.
在重症监护病房中，挥发性麻醉剂常用于为脓毒症患者进行手术麻醉或镇静。脓毒症仍然具有较高的发病率和死亡率，器官损伤是主要并发症。早期肝功能障碍与不良预后相关，主要原因是中性粒细胞大量募集。白细胞功能相关抗原-1（LFA-1）和巨噬细胞-1抗原（Mac-1）是中性粒细胞上的主要黏附分子，参与中性粒细胞募集。我们之前已表明挥发性麻醉剂异氟烷可抑制LFA-1和Mac-1。在此，我们利用盲肠结扎和穿刺（CLP）手术诱导的实验性多微生物腹部脓毒症，研究异氟烷、LFA-1和Mac-1在中性粒细胞向肝脏募集中的作用以及对肝损伤的影响。我们使用野生型（WT）、LFA-1、Mac-1和细胞间黏附分子-1（ICAM-1）基因敲除（KO）小鼠。通过CLP手术诱导脓毒症后，一组小鼠暴露于异氟烷2小时。我们发现Mac-1和ICAM-1而非LFA-1参与中性粒细胞向肝脏的募集。异氟烷减轻了WT和LFA-1 KO小鼠的中性粒细胞募集和肝损伤。Mac-1 KO小鼠的中性粒细胞募集和肝损伤有限，且两者均未被异氟烷进一步减轻，这表明异氟烷通过Mac-1减轻肝损伤。Mac-1与ICAM-1和纤维蛋白原在肝组织上共定位。在有纤维蛋白原存在的情况下，Mac-1与ICAM-1的结合显著增多，而LFA-1与ICAM-1的结合减少，这表明Mac-1利用纤维蛋白原作为桥接分子来结合ICAM-1。总之，暴露于异氟烷通过Mac-1减轻中性粒细胞募集和肝损伤。
