title: The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome.
abstract: OBJECTIVE
  Inflammation and oxygen toxicity increase free radical production and contribute to the development of acute respiratory distress syndrome (ARDS), which is a significant cause of morbidity and mortality in intensive care patients. We have previously reported increased glutathione (GSH) levels in lung epithelial cells in vitro and attenuated adult murine hyperoxic lung injury in vivo after pharmacological thioredoxin reductase-1 (TrxR1) inhibition. Using a murine ARDS model, we tested the hypothesis that aurothioglucose (ATG) treatment increases pulmonary GSH levels, attenuates lung injury, and decreases mortality in a GSH-dependent manner.
  
  
  RESULTS
  Adult mice received a single intratracheal dose of 0.375 μg/g lipopolysaccharide (LPS) 12 h before a single intraperitoneal injection of 25 mg/kg ATG. Control mice received intratracheal and/or intraperitoneal saline. Mice were then exposed to room air or hyperoxia (>95% O2). Lung injury was assessed by bronchoalveolar lavage protein concentrations. Expression of glutamate-cysteine ligase modifier subunit (GCLM), GSH, cytokines, and chemokines was determined. Exposure to LPS/hyperoxia induced inflammation and lung injury. ATG treatment significantly attenuated lung injury, increased lung GCLM expression and GSH levels, and decreased mortality. GSH depletion completely prevented the protective effects of ATG in LPS/hyperoxia-exposed mice.
  
  
  METHODS
  ATG treatment significantly attenuates lung injury and enhances survival in a clinically relevant murine model of ARDS. The protective effects of ATG are GSH dependent.
  
  
  CONCLUSIONS
  Augmentation of GSH systems by TrxR1 inhibition could represent a promising therapeutic approach to attenuate oxidant-mediated lung injury and improve patient outcomes.
authors.affiliation: 1 Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital , Columbus, Ohio.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Locy
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
mesh_terms: D000818:Animals; D006051:Aurothioglucose / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005609:Free Radicals / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000633:toxicity; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005609:Free Radicals; D006051:Aurothioglucose; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D005978:Glutathione; D010100:Oxygen