Biphasic effects of atorvastatin on inflammation.

Statins have been shown to exert 'pleiotropic effects' independent of their cholesterol lowering actions that include anti-inflammatory properties. We show in this study that atorvastatin dependent on the way of administration may exert anti- or pro- inflammation effects. Carrageenan-induced rat paw edema and mouse air-pouch as inflammatory models were used in this study. Animals were received statins orally prior to induction of inflammation by injection of carrageenan into rat paw or the pouch. The local effect of atorvastatin was determined by injection of the drug into the pouch. Oral administration of statins reduced both the maximal edema response and neutrophils infiltration in the inflammation zone. Lovastatin had the lowest and atorvastatin had the greatest effects. Also, in the mouse air-pouch model oral treatment by atorvastatin produced a very significant (p<0.0001) reduction in carrageenan-induced pouch leukocyte recruitment and exudates production. Concurrent administration of mevalonate reversed the anti-inflammatory effect of atorvastatin. However, local injection of atorvastatin into the pouch induced a dose depend and significant increase in leukocyte recruitment into the pouch that was not reversed by co-administration of mevalonate. This study shows that atorvastatin dependent on the way of administration has both pro- and anti-inflammatory properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of HMG CoA reductase inhibition and can be mediated directly by atorvastatin.