title: Isoflurane regulates atypical type-A γ-aminobutyric acid receptors in alveolar type II epithelial cells.
abstract: BACKGROUND
  Volatile anesthetics act primarily through upregulating the activity of γ-aminobutyric acid type A (GABAA) receptors. They also exhibit antiinflammatory actions in the lung. Rodent alveolar type II (ATII) epithelial cells express GABAA receptors and the inflammatory factor cyclooxygenase-2 (COX-2). The goal of this study was to determine whether human ATII cells also express GABAA receptors and whether volatile anesthetics upregulate GABAA receptor activity, thereby reducing the expression of COX-2 in ATII cells.
  
  
  METHODS
  The expression of GABAA receptor subunits and COX-2 in ATII cells of human lung tissue and in the human ATII cell line A549 was studied with immunostaining and immunoblot analyses. Patch clamp recordings were used to study the functional and pharmacological properties of GABAA receptors in cultured A549 cells.
  
  
  RESULTS
  ATII cells in human lungs and cultured A549 cells expressed GABAA receptor subunits and COX-2. GABA induced currents in A549 cells, with half-maximal effective concentration of 2.5 µM. Isoflurane (0.1-250 µM) enhanced the GABA currents, which were partially inhibited by bicuculline. Treating A549 cells with muscimol or with isoflurane (250 µM) reduced the expression of COX-2, an effect that was attenuated by cotreatment with bicuculline.
  
  
  CONCLUSIONS
  GABAA receptors expressed by human ATII cells differ pharmacologically from those in neurons, exhibiting a higher affinity for GABA and lower sensitivity to bicuculline. Clinically relevant concentrations of isoflurane increased the activity of GABAA receptors and reduced the expression of COX-2 in ATII cells. These findings reveal a novel mechanism that could contribute to the antiinflammatory effect of isoflurane in the human lung.
authors.affiliation: Department of Physiology and Pharmacology and Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
authors.forename: Yun-Yan
authors.initials: YY
authors.lastname: Xiang
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Chen
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Wang
authors.forename: Gil
authors.initials: G
authors.lastname: Faclier
authors.forename: John F
authors.initials: JF
authors.lastname: Macdonald
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
mesh_terms: D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D004396:Coloring Agents; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004847:Epithelial Cells / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D007530:Isoflurane / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018613:Microscopy, Confocal; D009118:Muscimol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects*; D012996:Solutions; D014343:Trypan Blue
chemical_list: D018685:Anesthetics, Inhalation; D004396:Coloring Agents; D018755:GABA Agonists; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D012996:Solutions; D009118:Muscimol; D007530:Isoflurane; D051546:Cyclooxygenase 2; D014343:Trypan Blue; D001640:Bicuculline