Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide

This review describes the laboratory evidence and microvascular mechanisms responsible for the beneficial effects of statins in sepsis. During sepsis, changes occur within the microcirculation including alterations in arteriolar tone influencing blood pressure, adaptations to endothelial cell integrity causing leakage of proteins and macromolecules, and adhesion and migration of leucocytes through the vascular endothelium. Statins are widely used as cholesterol-lowering agents, but appear to have anti-inflammatory actions during sepsis. We have discussed the effects of statins on specific pathological processed within the microcirculation and focused on the role of nitric oxide (NO). The main mechanism by which statins appear to be an effective treatment for sepsis is increased expression of endothelial nitric oxide synthase (eNOS), in conjunction with down-regulation of inducible nitric oxide synthase. Combined, this results in an increase in physiological concentrations of NO, thus restoring endothelial function. Laboratory studies have therefore suggested that enhancement of eNOS activity during sepsis may lead to restoration of microvascular tone, maintenance of microvascular integrity, and inhibition of cell adhesion molecules. However, other mechanisms independent of lipid-lowering effects, including antioxidant activity and alterations in the development of vascular atherosclerosis, may also contribute to the beneficial effects of statins. We have also addressed the influence on the effects of statins of lipid solubility and pre- and pro-phylactic administration.