PPARα mediates the anti-inflammatory effect of simvastatin in an experimental model of zymosan-induced multiple organ failure.

BACKGROUND AND PURPOSE Zymosan-induced non-septic shock is a multi-factorial pathology that involves several organs including the kidneys, liver and lungs. Its complexity and diversity presents a continuing therapeutic challenge. Given their pleiotropic effect, statins could be beneficial in non-septic shock. One of the molecular mechanisms underlying the anti-inflammatory effect of statins involves the peroxisome proliferator-activated receptor (PPAR) alpha. We used a zymosan-induced non-septic shock experimental model to investigate the role of PPAR alpha in the anti-inflammatory effects of simvastatin. EXPERIMENTAL APPROACH Effects of simvastatin (5 or 10 mg center dot kg-1 i.p.) were analysed in PPAR alpha knock-out (KO) and PPAR alpha wild type (WT) mice after zymosan or vehicle administration. Organ injury in lung, liver, kidney and intestine was evaluated by immunohistology. PPAR alpha mRNA expression and nuclear factor-kappa B activation were evaluated in all experimental groups, 18 h after study onset. Cytokine levels were measured in plasma, and nitrite/nitrate in plasma and peritoneal exudate. Nitric oxide synthase, nitrotyrosine and poly ADP-ribose were localized by immunohistochemical methods. KEY RESULTS Simvastatin significantly and dose-dependently increased the zymosan-induced expression of PPAR alpha levels in all tissues analysed. It also dose-dependently reduced systemic inflammation and the organ injury induced by zymosan in lung, liver, intestine and kidney. These effects were observed in PPAR alpha WT mice and in PPAR alpha KO mice. CONCLUSIONS AND IMPLICATIONS Simvastatin protected against the molecular and cellular damage caused by systemic inflammation in our experimental model. Our results also provide new information regarding the role of PPAR alpha in the anti-inflammatory effects of statins.