title: Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury.
abstract: OBJECTIVE
  We previously reported the expression of the two-pore-domain K channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study, we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury.
  
  
  METHODS
  Laboratory animal experiments.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Wild-type and TREK-1-deficient mice.
  
  
  METHODS
  Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, and 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours.
  
  
  RESULTS
  Hyperoxia exposure accentuated lung injury in TREK-1-deficient mice but not controls, resulting in increase in lung injury scores, bronchoalveolar lavage fluid cell numbers, and cellular apoptosis and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage and increased lung injury scores and bronchoalveolar lavage fluid cell numbers in control but not TREK-1-deficient mice. At baseline and after hyperoxia exposure, bronchoalveolar lavage cytokine levels were unchanged in TREK-1-deficient mice compared with controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in bronchoalveolar lavage interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α levels in both mouse types, but the increase in interleukin-6 and monocyte chemotactic protein-1 levels was less prominent in TREK-1-deficient mice than in controls. Lung tissue macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin-1β gene expression was not altered by hyperoxia in TREK-1-deficient mice compared with controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired tumor necrosis factor-α secretion from TREK-1-deficient macrophages.
  
  
  CONCLUSIONS
  TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia, but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxia-induced lung injury.
authors.affiliation: 1Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN. 2Department of Physiology, University of Tennessee Health Science Center, Memphis, TN. 3Department of Medicine, University of Tennessee Health Science Center, Memphis, TN. 4Department of Pathology, University of Tennessee Health Science Center, Memphis, TN. 5Department of Anesthesiology, Baylor College of Medicine, Houston, TX.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwingshackl
authors.forename: Bin
authors.initials: B
authors.lastname: Teng
authors.forename: Patrudu
authors.initials: P
authors.lastname: Makena
authors.forename: Manik
authors.initials: M
authors.lastname: Ghosh
authors.forename: Scott E
authors.initials: SE
authors.lastname: Sinclair
authors.forename: Charlean
authors.initials: C
authors.lastname: Luellen
authors.forename: Louisa
authors.initials: L
authors.lastname: Balasz
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rovnaghi
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bryan
authors.forename: Eric E
authors.initials: EE
authors.lastname: Lloyd
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.forename: Jordy S
authors.initials: JS
authors.lastname: Saravia
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018496:Hyperoxia / Q000150:complications*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency* / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012121:Respiration, Artificial; D018570:Risk Assessment; D012720:Severity of Illness Index
chemical_list: D016207:Cytokines; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1