Beneficial Effects of Statins on the Microcirculation During Sepsis: The Role of Nitric Oxide
C.C. McGown, and Z.L.S. Brookes
(Br J Anaesth, 98:163-175, 2007)
Academic Unit of Anaesthesia and Microcirculation Research Group, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
During sepsis, pathophysiologic processes occur in the microcirculation that contribute to tissue damage, multiorgan failure, and death. Microvascular mechanisms responsible for these changes are the altered balance between inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS), both of which catalyze nitric oxide (NO) production. This review assesses the laboratory evidence for the effects of statins on the microvascular adaptations that occur during sepsis.
Statins, which are widely used to lower cholesterol levels, also have anti-inflammatory actions during sepsis, independent of their lipid-lowering effects. In the septic state, vascular inflammation and endothelial dysfunction are associated with a loss of eNOS-produced NO because of the vital role of this cascade in maintaining a nonthrombogenic endothelial cell surface. Mediators stimulate the overproduction of iNOS, which is inactive under normal physiologic conditions. Inducible nitric oxide synthase then acts to produce large amounts of NO, which is a major mediator of inflammation. In vivo studies showed that the beneficial effects of statins on inflammation were lacking in eNOS-deficient mice. An increase in eNOS by statins, accompanied by a simultaneous reduction in iNOS activity, could give endothelial-protective effects. Inducible nitric oxide synthase expression can be reduced through combinations of various cytokines owing to the inactivation of transcription factors. Statins may, thus, cause simultaneous up-regulation of eNOS and down-regulation of iNOS, thereby restoring vascular responsiveness during sepsis by reestablishing a favorable balance between eNOS and iNOS. Statins are also more effective during sepsis when given as a pretreatment measure.
Cardiovascular alterations in sepsis include a change in arteriolar tone that is responsible for maintaining blood pressure and blood flow to organs. As arteriolar tone deteriorates, severe hypotension and inadequate organ perfusion ensue, and increased endothelial-dependent production of NO by iNOS contributes to the hypotensive response and regulates adjacent vascular smooth muscle contractility. Statins may affect vascular reactivity secondary to alterations in eNOS and iNOS. Damage to the endothelial layer also occurs during inflammation, leading to macromolecular leak. This phenomenon is caused by release of proinflammatory mediators and alterations in the pathways and molecules that maintain tight and gap junctions.
Endotoxins in the blood up-regulate leukocyte-endothelial interactions during which leukocytes move along the vascular endothelium and then adhere and migrate into tissue. At that point, tissue damage occurs because of release of superoxide and transendothelial leukocyte proteases. The release of proinflammatory cytokines further increases expression of adhesion molecules. Statins can prevent these leukocyte-endothelial interactions during sepsis, including inhibition of Rho, which has been implicated in the expression of leukocyte-endothelial adhesion molecules. Inhibition of Rho decreases lipopolysaccharide-induced expression of intracellular adhesion molecule 1. This leads to down-regulation and interference with adhesive cell surface molecules and modulation of NO.
In summary, the main mechanism by which statins seem to be effective in treating sepsis is increased expression of eNOS, along with down-regulation of iNOS. This results in an increase in physiologic concentrations of NO, which restores endothelial function. Enhancement of eNOS activity during sepsis may restore microvascular tone, maintain microvascular integrity, and inhibit cell adhesion molecules. Other beneficial effects of statins include their antioxidant activity and their ability to alter the development of atherosclerosis. Additional studies are necessary to confirm the potential value of statins in treating sepsis.