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

Abstract

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.

• Authors: Matthias Hecker, Aniella Behnk, Rory Edward Morty, Natascha Sommer, István Vadász, Susanne Herold, Werner Seeger, Konstantin Mayer
• Journal: Experimental lung research (Exp Lung Res) Vol. 41 Issue 7 Pg. 393-403 ( 2015) ISSN: 1521-0499 [Electronic] England
• PMID: 26151160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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