title: PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells.
abstract: OBJECTIVE
  Acute respiratory distress syndrome (ARDS) represents a major cause of mortality in intensive care patients. Activation of peroxisome proliferator-activated receptor-α (PPAR-α) by fibrates, such as WY-14643 (WY), has been described to beneficially influence inflammation and experimental lung injury. The impact of PPAR-α activation on alveolar epithelial cells (AEC) has not been studied yet.
  
  
  METHODS
  To investigate the effect of PPAR-α activator WY in wild-type (WT) and in PPAR-α knockout (PPAR-α(-/-)) animals, mice were treated in different regimes: mice received chow enriched with or without WY for 14 days prior AEC isolation (in-vivo treatment). Furthermore, isolated AEC from both groups were subsequently cultured with or without WY (in-vitro treatment). AEC were stimulated with lipopolysaccharide (LPS). Cell culture supernatant and cell lysate were used for analysis of pro-inflammatory mediators.
  
  
  RESULTS
  AEC challenged with LPS showed a significantly increased generation of pro-inflammatory mediators. After in-vivo WY-exposure, AEC displayed significantly reduced concentration of TNF-α, MIP-2, and TxB2 after LPS stimulation. This beneficial effect was abrogated in PPAR-α(-/-) animals. Interestingly, sole in-vitro application of WY-14643 failed to reduce levels of pro-inflammatory mediators whereas we found an additive effect of a combined in-vivo and in-vitro PPAR-α activation. PGE2 concentration remained high after LPS challenge and was unaffected by WY treatment.
  
  
  CONCLUSIONS
  PPAR-α activation by in-vivo exposure to fibrates reduced the inflammatory response in isolated AEC. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of ARDS.
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hecker
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Aniella
authors.initials: A
authors.lastname: Behnk
authors.affiliation: b 2 Department of Lung Development and Remodelling , Max Planck Institute for Heart and Lung Research , Bad Nauheim, Germany.
authors.forename: Rory Edward
authors.initials: RE
authors.lastname: Morty
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Sommer
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: a 1 University of Giessen and Marburg Lung Center (UGMLC) , Justus-Liebig-University of Giessen , Giessen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D055370:Lung Injury / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone
keywords: acute lung injury; alveolar epithelial cells; fibrate; inflammation; peroxisome proliferator-activated receptor-α