title: Sevoflurane inhibits nuclear factor-κB activation in lipopolysaccharide-induced acute inflammatory lung injury via toll-like receptor 4 signaling.
abstract: BACKGROUND
  Infection is a common cause of acute lung injury (ALI). This study was aimed to explore whether Toll-like receptors 4 (TLR4) of airway smooth muscle cells (ASMCs) play a role in lipopolysaccharide (LPS)-induced airway hyperresponsiveness and potential mechanisms.
  
  
  METHODS
  In vivo: A sensitizing dose of LPS (50 µg) was administered i.p. to female mice before anesthesia with either 3% sevoflurane or phenobarbital i.p. After stabilization, the mice were challenged with 5 µg of intratracheal LPS to mimic inflammatory attack. The effects of sevoflurane were assessed by measurement of airway responsiveness to methacholine, histological examination, and IL-1, IL-6, TNF-α levels in bronchoalveolar lavage fluid (BALF). Protein and gene expression of TLR4 and NF-κB were also assessed. In vitro: After pre-sensitization of ASMCs and ASM segments for 24h, levels of TLR4 and NF-κB proteins in cultured ASMCs were measured after continuous LPS exposure for 1, 3, 5, 12 and 24h in presence or absence of sevoflurane. Constrictor and relaxant responsiveness of ASM was measured 24 h afterwards.
  
  
  RESULTS
  The mRNA and protein levels of NF-κB and TLR4 in ASM were increased and maintained at high level after LPS challenge throughout 24h observation period, both in vivo and in vitro. Sevoflurane reduced LPS-induced airway hyperresponsiveness, lung inflammatory cell infiltration and proinflammatory cytokines release in BALF as well as maximal isometric contractile force of ASM segments to acetylcholine, but it increased maximal relaxation response to isoproterenol. Treatment with specific NF-κB inhibitor produced similar protections as sevoflurane, including decreased expressions of TLR4 and NF-κB in cultured ASMCs and improved pharmacodynamic responsiveness of ASM to ACh and isoproterenol.
  
  
  CONCLUSIONS
  This study demonstrates the crucial role of TLR4 activation in ASMCs during ALI in response to LPS. Sevoflurane exerts direct relaxant and anti-inflammatory effects in vivo and in vitro via inhibition of TLR4/NF-κB pathway.
authors: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China.
authors: Xi Jia
authors: XJ
authors: Sun
authors: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China.
authors: Xiao Qian
authors: XQ
authors: Li
authors: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China.
authors: Xiao Long
authors: XL
authors: Wang
authors: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China.
authors: Wen Fei
authors: WF
authors: Tan
authors: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China.
authors: Jun Ke
authors: JK
authors: Wang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001993:Bronchodilator Agents / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D061251:Primary Cell Culture; D000077149:Sevoflurane; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008738:Methyl Ethers; D009125:Muscle Relaxants, Central; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C577686:interleukin-6, mouse; D000077149:Sevoflurane; D007545:Isoproterenol; D000109:Acetylcholine