title: Deletion of peroxiredoxin 6 potentiates lipopolysaccharide-induced acute lung injury in mice.
abstract: OBJECTIVE
  To investigate the role and signaling pathway of peroxiredoxin 6, a newly identified peroxidase, in lipopolysaccharide-induced acute lung injury.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Peroxiredoxin 6 (-/-) and wild-type C57BL/6 mice.
  
  
  METHODS
  Wild-type or peroxiredoxin 6 (-/-) mice were challenged by intratracheal instillation of lipopolysaccharide (5 mg/kg) for 4 hrs or 24 hrs for lung injury measurement. In other studies, peritoneal macrophages, isolated from wild-type and peroxiredoxin 6 (-/-) mice, were preincubated in presence or absence of mitogen-activated protein kinases inhibitors for 30 mins before being stimulated with lipopolysaccharide (1 μg/mL) for 4 hrs.
  
  
  RESULTS
  Bronchoalveolar lavage myeloperoxidase activity and the lung injury score were significantly increased in peroxiredoxin 6 (-/-) mice compared with wild-type mice after lipopolysaccharide instillation at both 4 hrs and 24 hrs. Hydrogen peroxide and malondialdehyde levels, as well as nuclear factor-κB activities, tumor necrosis factor-α, interleukin-1β, and matrix metalloproteinase-9 messenger RNA, protein concentration, and activities were significantly increased whereas total antioxidative capability was markedly decreased in lungs of peroxiredoxin 6 (-/-) mice compared with wild-type mice. In vitro studies showed intracellular reactive oxygen species levels and release of tumor necrosis factor-α, interleukin-1, and matrix metalloproteinase-9 were significantly increased in macrophages from peroxiredoxin 6 (-/-) mice compared with that from wild-type mice after lipopolysaccharide stimulation. Cytokines release was partially suppressed by extracellular signal-regulated kinase and c-Jun N-terminal kinase inhibitors, but not by the p38 mitogen-activated protein kinase inhibitor.
  
  
  CONCLUSIONS
  Deletion of peroxiredoxin 6 exaggerates lipopolysaccharide-induced acute lung injury and inflammation with increased oxidative stress, inflammatory responses, and matrix degradation, all of which were partially dependent on nuclear factor-κB, extracellular signal-regulated kinase, and c-Jun N-terminal kinase pathways.
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Sun
authors.forename: Yong
authors.initials: Y
authors.lastname: Ben
authors.forename: Xiaojing
authors.initials: X
authors.lastname: An
authors.forename: Lin
authors.initials: L
authors.lastname: Tong
authors.forename: Jing
authors.initials: J
authors.lastname: Bi
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D006861:Hydrogen Peroxide / Q000032:analysis; D053583:Interleukin-1beta / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000737:chemistry; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000032:analysis; D018384:Oxidative Stress; D054465:Peroxiredoxin VI / Q000172:deficiency / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse; D020780:Matrix Metalloproteinase 9