Statins alter neutrophil migration by modulating cellular Rho activity—a potential mechanism for statins-mediated pleotropic effects?

Abstract

The ability of neutrophils to sense and migrate toward damaged tissue is a vital component of the innate immune response. Paradoxically, this same migration serves as the hallmark of a number of inflammatory conditions, including ischemic reperfusion injury, atherosclerosis, arthritis, and Crohn's disease. More recent evidence suggests that neutrophil infiltration into the cardiac allograft following transplantation is a contributing factor in allograft rejection. We have demonstrated previously a positive correlation between the degree of neutrophil migration and subsequent rejection grades in a cohort of cardiac transplant recipients. Intracellular signaling pathways that are intimately involved in neutrophil migration thus offer potential targets of manipulation in the treatment of such conditions. 3-hydroxy-3-methylyglutaryl-coenzyme A reductase inhibitors or statins are emerging as potential anti-inflammatory agents and have a proven survival benefit in the transplant population. Yet, little is known about their ability to modulate neutrophil function and their subsequent mechanism of action. We demonstrate here that pravastatin, simvastatin, and atorvastatin significantly reduce neutrophil transendothelial migration toward the chemoattractant fMLP. This effect is independent of any change in neutrophil adhesion or adhesion molecule expression but is related to the ability of statins to reduce fMLP-induced Rho activity in neutrophils. This was confirmed by the ability of the Rho precursor geranylgeranyl pyrophosphate to rescue the statin-mediated reduction in neutrophil transendothelial migration. Understanding the mechanisms of action of statins in the neutrophil allows for their use in targeting excessive migration in inappropriate inflammatory conditions.

Pharmacological actions of statins: potential utility in COPD

“…Statins could conceivably affect these pathways through their inhibition of intracellular prenylation and inhibition of the GTP-binding proteins that underlie these inflammatory pathways [76,117,118]. Given these diverse actions on key components of the pathways underlying COPD, it is possible that such effects might explain the benefits observed in the observational studies.…”

“…Further support for the protective role of statins on lung inflammation comes from lung transplant studies that show concomitant use of statins reduces post-transplant bronchiolitis and improves lung function compared to patients not receiving statins [70,76,82,121]. This is an inflammatorybased complication of lung transplantation with over lapping pathology with COPD, including small airway inflammation dominated by airway fibrosis (bronchiolitis obliterans).…”

“…Studies have shown that statins reduce neutrophil influx in the lung which might have a strong effect on attenuating the downstream inflammatory events, such as macrophage influx, lymphocyte activation and inhibition of cytokine release, in particular IL-8 that appears central to the neutrophil inflammation of the lung [67][68][69][70][71][72][73][74][75][76][77][80][81][82][83][84][85][86][87][88]. The inhibition of IL-6, IL-8 and GM-CSF expression by statins has been shown in cell cultures of human BEC [65,70].…”

New Approaches in the Regulation of Blood Phagocytes and Reduction in the Formation of Oxygen Radicals in Patients with Heart Failure

“…Важная роль в повреждениях, сопровождающих воспале-ние, принадлежит супероксид-анион радикалам, которые в больших количествах генерируются НАДФН-оксидаз-ной системой фагоцитов крови [2,3,5]. Снижение интенсивности образования радикалов кислорода или подавление хемотаксиса и активности фагоцитов эф-фективно уменьшает повреждение окружающих клеток в легких, центральной нервной системе и миокарде [6][7][8]. Таким образом, нейтрализация радикалов кисло-рода, генерируемых фагоцитами крови, является одной из перспективных мишеней для фармакологического воздействия, направленного против неадекватного вос-палительного ответа.…”

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

“…This enzyme is also involved in the production of isoprenoids, which are precursors of lipids that are required for the association of several proteins, including small GTPases, with membranes. By preventing or reducing the isoprenylation of RhoA, statins inhibit its activity, resulting in actin depolymerization (77). Since actin polymerization is important for endocytosis in various systems, we hypothesized that statins could induce AQP2 membrane accumulation by inhibiting the endocytotic arm of its recycling pathway, as described above (Fig.…”