Pretreatment with peroxysome proliferator-activated receptor alpha agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxin-induced shock.
OBJECTIVE
To investigate the effects of fenofibrate, an activator of peroxysome proliferator activated receptor (PPAR) alpha, on vascular endothelium and on hemostasis in a rabbit endotoxic shock model.


METHODS
Prospective laboratory study in a university laboratory.


METHODS
36 male New Zealand rabbits weighing 2.5-3 kg.


METHODS
We determined in vitro vascular reactivity, endothelium CD31-platelet/endothelial cell adhesion molecule (PECAM) 1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor expression 5 days after onset of endotoxic shock (0.5 mg/kg intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by fenofibrate (mixed in the chow at a concentration of 0.5%) for 15 days before lipopolysaccharide injection and 5 days afterward.


RESULTS
Metabolic acidosis and coagulation activation confirmed presence of shock. Fenofibrate decreased monocyte tissue factor expression. It improved endothelial-dependent relaxation at 5 days (Emax=68.2+/-3.3%, vs. 44.2+/-2.5% in the non-treated group). Endotoxin-induced deendothelialization was significantly decreased by fenofibrate at 5 days (8.5+/-1.3% vs. 19.2+/-3.1% in the nontreated group) .


CONCLUSIONS
These data indicate for the first time that fenofibrate, an activator of PPAR-alpha, inhibits monocyte tissue factor expression and protects against endothelial dysfunction and histological injury in endotoxin-induced shock.
Wiel
Eric
E
EA 1046, Laboratory of Pharmacology, University Hospital of Lille, 59037 Lille Cedex, France. e-wiel@chru-lille.fr
Lebuffe
Gilles
G
Robin
Emmanuel
E
Gasan
Gaëlle
G
Corseaux
Delphine
D
Tavernier
Benoît
B
Jude
Brigitte
B
Bordet
Régis
R
Vallet
Benoît
B
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000097:blood / Q000517:prevention & control*; D011345:Fenofibrate / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008297:Male; D047493:PPAR alpha / Q000627:therapeutic use*; D011817:Rabbits; D012772:Shock, Septic / Q000097:blood / Q000517:prevention & control*
D000960:Hypolipidemic Agents; D047493:PPAR alpha; D011345:Fenofibrate