PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells

Exp Lung Res. 2015;41(7):393-403. doi: 10.3109/01902148.2015.1046200.


Purpose of the study: 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.

Materials and 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.

Conclusion: 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.

Keywords: acute lung injury; alveolar epithelial cells; fibrate; inflammation; peroxisome proliferator-activated receptor-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / microbiology
  • Animals
  • Chemokine CXCL2 / metabolism
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Inflammation / chemically induced*
  • Inflammation / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Lung Injury / metabolism
  • Mice
  • PPAR alpha / metabolism*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Lipopolysaccharides
  • PPAR alpha
  • Tumor Necrosis Factor-alpha
  • Dinoprostone