title: Isoflurane Ameliorates Acute Lung Injury by Preserving Epithelial Tight Junction Integrity.
abstract: BACKGROUND
  Isoflurane may be protective in preclinical models of lung injury, but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. The authors hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome.
  
  
  METHODS
  Wild-type mice were treated with isoflurane 1 h after exposure to nebulized endotoxin (n = 8) or saline control (n = 9) and then allowed to recover for 24 h before mechanical ventilation (MV; tidal volume, 15 ml/kg, 2 h) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane 1 h after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo.
  
  
  RESULTS
  Mice treated with isoflurane following exposure to inhaled endotoxin and before MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice after treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e., zona occludens 1) that was rescued by isoflurane treatment.
  
  
  CONCLUSIONS
  Isoflurane rescued lung injury induced by a two-hit model of endotoxin exposure followed by MV by maintaining the integrity of the alveolar-capillary barrier possibly by modulating the expression of a key tight junction protein.
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (J.A.E., D.A.-M., M.P.V., C.I., J.G., B.M., M.S.V., A.C., A.L., L.E.F., R.M.B.) and Department of Anesthesiology, Perioperative, and Pain Medicine (A.A.M., D.J.C., G.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Englert
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Macias
authors.forename: Diana
authors.initials: D
authors.lastname: Amador-Munoz
authors.forename: Miguel
authors.initials: M
authors.lastname: Pinilla Vera
authors.forename: Colleen
authors.initials: C
authors.lastname: Isabelle
authors.forename: Jiazhen
authors.initials: J
authors.lastname: Guan
authors.forename: Brady
authors.initials: B
authors.lastname: Magaoay
authors.forename: Margarita
authors.initials: M
authors.lastname: Suarez Velandia
authors.forename: Anna
authors.initials: A
authors.lastname: Coronata
authors.forename: Awapuhi
authors.initials: A
authors.lastname: Lee
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Culley
authors.forename: Gregory
authors.initials: G
authors.lastname: Crosby
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D002461:Cell Line, Transformed; D007530:Isoflurane / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane