PMID- 16091136
OWN - NLM
STAT- MEDLINE
DCOM- 20060329
LR  - 20181113
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 6
IP  - 1
DP  - 2005 Aug 9
TI  - PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the 
      mouse.
PG  - 91
AB  - BACKGROUND: Inflammation is a hallmark of acute lung injury and chronic airway 
      diseases. In chronic airway diseases, it is associated with profound tissue 
      remodeling. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a 
      ligand-activated transcription factor, that belongs to the nuclear receptor 
      family. Agonists for PPARalpha have been recently shown to reduce 
      lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix 
      metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, 
      suggesting that PPARalpha may play a beneficial role in inflammation and tissue 
      remodeling. METHODS: We have investigated the role of PPARalpha in a mouse model 
      of LPS-induced airway inflammation characterized by neutrophil and macrophage 
      infiltration, by production of the chemoattractants, tumor necrosis factor-alpha 
      (TNF-alpha), keratinocyte derived-chemokine (KC), macrophage inflammatory 
      protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by 
      increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The 
      role of PPARalpha in this model was studied using both PPARalpha-deficient mice 
      and mice treated with the PPARalpha activator, fenofibrate. RESULTS: Upon 
      intranasal exposure to LPS, PPARalpha-/- mice exhibited greater neutrophil and 
      macrophage number in BALF, as well as increased levels of TNF-alpha, KC, MIP-2 
      and MCP-1, when compared to PPARalpha+/+ mice. PPARalpha-/- mice also displayed 
      enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) 
      dose-dependently reduced the increase in neutrophil and macrophage number induced 
      by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this 
      effect was associated with a reduction in TNF-alpha, KC, MIP-2 and MCP-1 levels, 
      as well as in MMP-2 and MMP-9 activity. PPARalpha-/- mice treated with 15 mg/day 
      fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, 
      demonstrating that PPARalpha mediates the anti-inflammatory effect of 
      fenofibrate. CONCLUSION: Using both genetic and pharmacological approaches, our 
      data clearly show that PPARalpha downregulates cell infiltration, chemoattractant 
      production and enhanced MMP activity triggered by LPS in mouse lung. This 
      suggests that PPARalpha activation may have a beneficial effect in acute or 
      chronic inflammatory airway disorders involving neutrophils and macrophages.
FAU - Delayre-Orthez, Carine
AU  - Delayre-Orthez C
AD  - EA 3771, Inflammation et Environnement dans l'Asthme, Faculte de Pharmacie, 
      Universite Louis Pasteur-Strasbourg I, Illkirch, France. 
      orthez@pharma.u-strasbg.fr
FAU - Becker, Julien
AU  - Becker J
FAU - Guenon, Isabelle
AU  - Guenon I
FAU - Lagente, Vincent
AU  - Lagente V
FAU - Auwerx, Johan
AU  - Auwerx J
FAU - Frossard, Nelly
AU  - Frossard N
FAU - Pons, Francoise
AU  - Pons F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050809
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Chemotactic Factors)
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (PPAR alpha)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Animals
MH  - Chemotactic Factors/*immunology
MH  - Cytokines/*immunology
MH  - Down-Regulation/immunology
MH  - Lipopolysaccharides
MH  - Male
MH  - Matrix Metalloproteinases/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - PPAR alpha/*deficiency/*immunology
MH  - Pneumonia/chemically induced/*immunology/*pathology
PMC - PMC1199625
EDAT- 2005/08/11 09:00
MHDA- 2006/03/30 09:00
PMCR- 2005/08/09
CRDT- 2005/08/11 09:00
PHST- 2005/01/26 00:00 [received]
PHST- 2005/08/09 00:00 [accepted]
PHST- 2005/08/11 09:00 [pubmed]
PHST- 2006/03/30 09:00 [medline]
PHST- 2005/08/11 09:00 [entrez]
PHST- 2005/08/09 00:00 [pmc-release]
AID - 1465-9921-6-91 [pii]
AID - 10.1186/1465-9921-6-91 [doi]
PST - epublish
SO  - Respir Res. 2005 Aug 9;6(1):91. doi: 10.1186/1465-9921-6-91.