title: Sub-anesthesia Dose of Isoflurane in 60% Oxygen Reduces Inflammatory Responses in Experimental Sepsis Models.
abstract: BACKGROUND
  Sepsis is a major cause of mortality in Intensive Care Units. Anesthetic dose isoflurane and 100% oxygen were proved to be beneficial in sepsis; however, their application in septic patients is limited because long-term hyperoxia may induce oxygen toxicity and anesthetic dose isoflurane has potential adverse consequences. This study was scheduled to find the optimal combination of isoflurane and oxygen in protecting experimental sepsis and its mechanisms.
  
  
  METHODS
  The effects of combined therapy with isoflurane and oxygen on lung injury and sepsis were determined in animal models of sepsis induced by cecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysaccharide (LPS) or zymosan. Mouse RAW264.7 cells or human peripheral blood mononuclear cells (PBMCs) were treated by LPS to probe mechanisms. The nuclear factor kappa B (NF-κB) signaling molecules were examined by Western blot and cellular immunohistochemistry.
  
  
  RESULTS
  The 0.5 minimum alveolar concentration (MAC) isoflurane in 60% oxygen was the best combination of oxygen and isoflurane for reducing mortality in experimental sepsis induced by CLP, intraperitoneal injection of LPS, or zymosan. The 0.5 MAC isoflurane in 60% oxygen inhibited proinflammatory cytokines in peritoneal lavage fluids (tumor necrosis factor-alpha [TNF-β]: 149.3 vs. 229.7 pg/ml, interleukin [IL]-1β: 12.5 vs. 20.6 pg/ml, IL-6: 86.1 vs. 116.1 pg/ml, and high-mobility group protein 1 [HMGB1]: 323.7 vs. 449.3 ng/ml; all P< 0.05) and serum (TNF-β: 302.7 vs. 450.7 pg/ml, IL-1β: 51.7 vs. 96.7 pg/ml, IL-6: 390.4 vs. 722.5 pg/ml, and HMGB1: 592.2 vs. 985.4 ng/ml; all P< 0.05) in septic animals. In vitro experiments showed that the 0.5 MAC isoflurane in 60% oxygen reduced inflammatory responses in mouse RAW264.7 cells, after LPS stimulation (all P< 0.05). Suppressed activation of NF-κB pathway was also observed in mouse RAW264.7 macrophages and human PBMCs after LPS stimulation or plasma from septic patients. The 0.5 MAC isoflurane in 60% oxygen also prevented the increases of phospho-IKKβ/β, phospho-IκBβ, and phospho-p65 expressions in RAW264.7 macrophages after LPS stimulation (all P< 0.05).
  
  
  CONCLUSIONS
  Combined administration of a sedative dose of isoflurane with 60% oxygen improves survival of septic animals through reducing inflammatory responses.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Ze-Xin
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Shao
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Han
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Er-Fei
authors.initials: EF
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Zhong-Shu
authors.initials: ZS
authors.lastname: Pu
authors.affiliation: Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Zuo-Xu
authors.initials: ZX
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Hai-Long
authors.initials: HL
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Li-Ze
authors.initials: LZ
authors.lastname: Xiong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Li-Chao
authors.initials: LC
authors.lastname: Hou
mesh_terms: D000328:Adult; D000758:Anesthesia / Q000379:methods*; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007530:Isoflurane / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007530:Isoflurane; D009195:Peroxidase; D010100:Oxygen