It is clear that atherosclerosis is a chronic disease of arterial wall in which immuno-inflammatory mechanisms are involved . It is well known the role of monocytes, as representatives of the innate immune system, in atherosclerosis development . Since a body of research carried out over the last decade has disclosed the complex behaviour of PMNs, unraveling a key role in the onset and progression of atheroma, we decided to focus our attention on these cells .
The main finding of this study is the observation that a prolonged treatment with statin, in patients with increased cardiovascular risk, is consistently associated with reduction in IL-8 cellular production by primed neutrophils. Pathogenic effects of PMNs in atherosclerosis are mediated through production of pro-inflammatory cytokines [IL-8, tumor necrosis factor alpha (TNFa)] and reactive oxygen species . Chemokines are a number of small, inducible, proinflammatory proteins that direct migration of circulating leukocytes to sites of inflammation. This superfamily is divided into α and β-chemokine subfamilies. IL-8 is one of the main proinflammatory cytokine produced by neutrophils and it is the prototypical member of α-chemokine subfamily [19–24]. Generation of IL-8 can be expected upon infection, ischemia, trauma and other disturbances of tissue homeostasis since the levels of IL-1 and TNFa, which are important IL-8 inducers, are elevated. IL-8 is likely to be the main cause of local accumulation of neutrophils . IL-8 might have atherogenic function through multiple actions: it facilitates recruitment of neutrophils and T-lymphocytes into sub-endothelial space, monocytes activation and adhesion to endothelium [21, 22], migration of vascular smooth muscle cells . Macrophage-derivated human foam cells contain high amounts of IL-8 [23, 24]. It has also been reported that apparently healthy subjects in the highest serum IL-8 level quartile had an increased risk of coronary events when compared with those in the lowest quartile .
In our study we observed a lack of significant correlation between basal levels of IL-8 and age, CRP, non HDL cholesterol and apoB/apoA ratio. Furthermore despite a similar reduction after simvastatin treatment (from baseline to 1 year) of IL-8, LDL cholesterol and CRP, we did not see any significant correlation. From our point of view these results are largely explained by the small sample size of the study.
Statins have pharmacological activities independently of their lipid-lowering action, that can be in part attributed to their ability to interfere with inflammatory mechanisms . Among the several ancillary actions of statins, these drugs are able to down-regulate expression of adhesion molecules, to inhibit expression of chemokine monocyte chemo-attractant protein-1 in activated leukocytes, to block expression of integrins and to reduce monocytes adhesiveness to endothelium [27–30]. As regards IL-8 production by human neutrophils, it has been demonstrated that simvastatin treatment could reduce peripheral blood monocyte mRNA expression of IL-8 and IL-6 and monocyte chemo-attractant protein-1 after 6 week of treatment  and we reported that cellular PMNs IL-8 release was reduced upon 1-month statin therapy . In this study, one year of simvastatin treatment reduced IL-8 production in comparison to pre-treatment values, thus excluding the occurrence of a potential tolerance phenomenon after long-term treatment. Moreover, IL-8 production after 1 year of treatment was reduced to levels which were lower than those observed in control subjects. Our results seem to suggest that simvastatin can contribute to modulate inflammation by IL-8 reduction.
In our study simvastatin treatment reduced LDL cholesterol in men and in women, but the degree of this lowering was more evident in females. This result may be in part due to a higher LDL cholesterol baseline value than in men and to the prevalent menopausal status in enrolled women. Nevertheless the small sample size (8 women) does not allow to draw definitive conclusions. From recent meta-analyses statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men .
The study has some limitations: 1) we have not collected informations about subclinical atherosclerosis (intima-media thickness, carotid plaque); 2) we have evaluated IL-8 production as marker of inflammatory response, but inflammation can also be evaluated by several different parameters, such as IL-6, IL-15, TNFα, not assessed in this study.