Statins in Animal Models of Infection
Marc W. Merx · International Journal of Infectious Diseases · 2008
Statins, are effective lipid lowering agents used extensively in medical practice. Recent statin studies have extended statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol independent therapeutic benefits, termed “pleiotropic” effects, which have added a wide scope of potential targets for statin therapy. Since the approval for clinical use in humans of lovastatin as the first statin several statins have become commercially available including pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin (withdrawn in 2001), pitavastatin and rosuvastatin. While all these statins share HMG-CoA reductase inhibition as common mechanism of action, they differ in absorption, affinity, binding, solubility and excretion. Apart from causing variations in efficacy of cholesterol lowering between the agents, differences in these pharmacologic properties might also be relevant with respect to so called “pleiotropic” effects of statins. These “pleiotropic” effects include anti-inflammatory and antioxidative properties, improvement of endothelial function and increased nitric oxide bioavailability and thus might contribute to the benefit observed with statin therapy. Notably, these important immunomodulatory effects of statins have been demonstrated to be independent of lipid lowering and appear to be mediated via interference with the synthesis of mevalonate metabolites (nonsteroidal isoprenoid products). In addition, mechanisms for anti-inflammatory actions of statins have been revealed that are not related to the isoprenoid metabolism. For instance, it has been identified that some statins act as direct antagonists of LFA-1 due to their capacity to bind to the regulatory site in the LFA-1 i-domain. Several animal models of infection ranging from bacterial, and fungal to viral causative agents have been studied toward potential beneficial application of statins. The present talk will give an overview of animal models of infection with respect to effects of statin treatment.