Anti-inflammatory Effects Of Statins Research Articles

Statins Reduce Lipopolysaccharide-Induced Cytokine and Inflammatory Mediator Release in an In Vitro Model of Microglial-Like Cells.

The anti-inflammatory effects of statins (HMG-CoA reductase inhibitors) within the cardiovascular system are well-established; however, their neuroinflammatory potential is unclear. It is currently unknown whether statins' neurological effects are lipid-dependent or due to pleiotropic mechanisms. Therefore, the assumption that all statin compounds will have the same effect within the central nervous system is potentially inappropriate, with no studies to date having compared all statins in a single model. Thus, the aim of this study was to compare the effects of the six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) within a single in vitro model of neuroinflammation. To achieve this, PMA-differentiated THP-1 cells were used as surrogate microglial cells, and LPS was used to induce inflammatory conditions. Here, we show that pretreatment with all statins was able to significantly reduce LPS-induced interleukin (IL)-1β and tumour necrosis factor (TNF)-α release, as well as decrease LPS-induced prostaglandin E2 (PGE2). Similarly, global reactive oxygen species (ROS) and nitric oxide (NO) production were decreased following pretreatment with all statins. Based on these findings, it is suggested that more complex cellular models should be considered to further compare individual statin compounds, including translation into in vivo models of acute and/or chronic neuroinflammation.

Association of serum lipid indices and statin consumption with periodontal status.

Periodontal and cardiovascular diseases share some common underlying mechanisms. Hyperlipidemia is a major risk factor for cardiovascular diseases. This study sought to assess the association of hyperlipidemia and statin consumption with periodontal status. This cross-sectional study was conducted on 150 participants including 50 individuals with normal lipid profile (group C), 50 hyperlipidemic patients without drug therapy (group N), and 50 hyperlipidemic patients on drug therapy for a minimum of 3months (group S). Periodontal parameters including plaque index (PI), clinical attachment level (CAL), bleeding on probing (BOP), and pocket depth (PD) were measured for all teeth except for the third molars. Serum levels of total cholesterol (TC), HDL, LDL, and triglycerides (TGs) were measured. The mean values of CAL and PD were significantly higher in the two hyperlipidemic groups compared with the C group (P<0.005). Also, CAL and PD had significant associations with serum levels of TGs, LDL, and TC (P<0.0001); PI in the group S was significantly lower than that in the other groups (P<0.005). Hyperlipidemic patients showed higher values of periodontal parameters compared with the statin-treated and control groups. Lower PI in the group S may indicate the anti-inflammatory effect of statin.

Statins attenuate hyperalgesia and inflammation in experimentally induced acute and neuropathic pain in rats

Background Available medications for the treatment of neuropathic pain, such as steroidal anti-inflammatory drugs and NSAIDs, were shown to be of limited therapeutic benefit. Objectives This study aimed to evaluate the analgesic and anti-inflammatory effects of atorvastatin and pravastatin in acute and neuropathic pain in rats. Materials and methods Acute and neuropathic pains were induced in rat models by means of subplantar carrageenan injection and partial sciatic nerve ligation (PSNL), respectively. The anti-inflammatory effect of statins was assessed by the reduction in plantar edema (at 0, 1, 2, and 3 h) and prolongation of paw withdrawal reaction time in response to thermal stimulation (at 0, 0.5, 1, 2, 3, and 4 h) after carrageenan injection. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered intraperitoneally 30 min before carrageenan injection. The effect of statins on neuropathic pain was assessed by prolongation of paw withdrawal reaction time in response to thermal stimulation evaluated at 0, 3, 6, 9, 12, 15, and 18 days after PSNL. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered orally for 18 consecutive days after PSNL. In addition, the effect of atorvastatin and pravastatin on total cholesterol and tumor necrosis factor-α levels was also assessed. Results Both atorvastatin and pravastatin ameliorated carrageenan-induced rat paw edema and prolonged withdrawal time in response to thermal-induced pain. Both statins were also effective in ameliorating neuropathic pain induced by PSNL. These effects were independent of statin-induced hypolipidemic action but were concomitant with reduction of serum tumor necrosis factor-α levels. Conclusion Atorvastatin and pravastatin demonstrated effective therapeutic potentials to reduce acute and chronic pain together with the associated inflammation and hyperalgesia independent of their hypolipidemic effect.

Anti-inflammatory effects of statins

Anti-inflammatory effects of statins

The reduction of post-cardiac surgery infections by statins: solid evidence?

The reduction of post-cardiac surgery infections by statins: solid evidence?

Simvastatin reduces leucocyte– and platelet–endothelial cell interaction in murine antigen-induced arthritis in vivo

Objectives: The use of statins in the prevention and treatment of cardiovascular diseases is well established. Their use as anti-inflammatory and immunomodulatory agents in the treatment of rheumatoid arthritis (RA) has also been investigated, with several clinical and experimental studies indicating an anti-inflammatory effect of statins for RA, but other studies showing no effect or even the opposite. The current study was designed to examine the effect of simvastatin in an in vivo murine model of arthritis using intravital microscopy.Method: We assigned four groups (n = 7, female C57Bl6 mice), two with and two without antigen-induced arthritis (AiA), from which one of the non-AiA groups and one of the AiA groups were treated with simvastatin 40 mg/kg i.p. daily for 14 consecutive days after induction of arthritis. Platelet– and leucocyte–endothelial cell interaction was assessed by measurement of rolling and adherent fluorescence-labelled platelets and leucocytes, functional capillary density (FCD) was evaluated, and knee joint diameter was determined as a clinical parameter.Results: In arthritic mice treated with simvastatin, a significant reduction in platelet– and leucocyte–endothelial cell interaction was observed in comparison to arthritic mice treated with vehicle. In addition, a significant reduction in FCD was seen in arthritic mice treated with simvastatin, along with a reduction in knee joint swelling of the AiA mice.Conclusions: Treatment of AiA mice with simvastatin showed significant reductions in platelet– and leucocyte–endothelial cell interactions, in FCD, and in the swelling of the knee joint. These results support the hypothesis of the anti-inflammatory effects of statins in the treatment of RA.

A meta-analysis of randomized controlled trials on the use of statins in septic patients

Beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on vascular diseases have been demonstrated in several clinical trials. Recently discovered anti-inflammatory effects of statins seem to have an important role in counteracting the harmful effects of sepsis on the coagulation system. Many epidemiologic studies evidence that statin treatment may be associated with a better prognosis in severe bacterial infections, and a recent randomized trial found a reduced mortality in the statin group. We decided to perform a meta-analysis of all randomized controlled trials ever performed on statin therapy in septic patients to evaluate their effect on survival.

Atrial fibrillation after coronary artery bypass grafting

Atrial fibrillation after coronary artery bypass grafting

Anti inflammatory effects of statin in COPD

IntroductionStatins are now becoming recognized as powerful antiinflammatory agents that exert beneficial effects beyond low-density lipoprotein cholesterol reduction [1].COPD patients receiving statins obtain a benefit from these therapeutic agents. Clearly, the best medical evidence for the association of statins with improved outcomes for COPD patients [2].We aimed in this study to assess anti inflammatory effects of statin in COPD patients. Patients and methodsWe studied 28 patients with chronic obstructive lung disease. Fourteen patients (11 male and 3 female) receiving statin due to hyperlipidemia (9 patients received simvastatin and 5 patients atorvastatin), and other 14 patients (11 male and 3 female) not hyperlipidemic. All patients were subjected to Pulmonary function (spirometery) pre and at end of study. Sputum induction before and at end of 10months from statin starting, and determination of leptin, total and differential cell count pre and at end of study. ResultsAfter 10months from statin intake we found significant decrease of TCC in statin groupand also high significant decrease of sputum leptin, neutrophils, and COPD exacerbation in the same group when compared to control group. And significant decrease of TCC in statin group pre and at end of study with high significant decreases of sputum leptin, neutrophils, and COPD exacerbation of statin group pre and 10months of statin intake. Titropium bromide has positive significant effects on sputum leptin in statin group. ConclusionWe conclude that statin may lower the exacerbation in patients with chronic obstructive lung diseases and may lower the total cell count of inflammatory cells, sputum leptin and neutrophils.

Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion

AimsActivation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo.Methods and resultsPhysiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr−/− mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect.ConclusionsThese findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.

Commentary: simvastatin as the key to improving H. pylori eradication rates? Authors’ reply

We thank de Hollander and Kuipers for their comments on our article, in which we demonstrated in a randomised clinical trial (RCT), that simvastatin as adjuvant therapy to the standard triple therapy improves the eradication rate of Helicobacter pylori infection. We agree with de Hollander and Kuipers in noting that the treatment groups were small and we did not provide clinical information, especially on gastrointestinal pathology. On the subject of whether H. pylori eradication treatment is more effective in patients with peptic ulcer disease (PUD) than in those with non-ulcer dyspepsia (NUD) or other non-ulcer gastric diseases this remains controversial. 4 Huang et al. in a systematic review including 22 studies showed that there is no convincing evidence to suggest that NUD patients respond to H. pylori eradication treatments differently from those with PUD. However, there was a trend for patients with PUD who received the classical triad of proton pump inhibitor, clarithromycin and amoxicillin for 7 days. Regarding the underlying mechanisms involved in H. pylori eradication, we proposed a number of speculative mechanisms. One of these speculative mechanisms is the anti-inflammatory effect of statins. We agree with de Hollander and Kuipers that statins, by exerting anti-inflammatory effects, may play a significant role in H. pylori eradication. In contrast, statins have not been proven to reduce the progression of gastritis to gastric cancer. More RCTs are needed to assess the efficacy of statins in H. pylori eradication focusing on the impact of 10–14 days treatment, and the role of long-term statin use in preventing or reducing the risk of progression to neoplasia in Barrett's oesophagus and gastric cancer.

Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells

Statins are 3-hydroxy-3-methylglutaryl-co-enzyme A reductase inhibitors of cholesterol biosynthesis, and have been reported to exert pleiotropic effects on cellular signalling and cellular functions involved in inflammation. Recent reports have demonstrated that previous statin therapy reduced the risk of pneumonia or increased survival in patients with community-acquired pneumonia. However, the precise mechanisms responsible for these effects are unclear. In the present study, we examined the effects of statins on cytokine production from lipopolysaccharide (LPS)-stimulated human bronchial epithelial cells (BEAS-2B). Interleukin (IL)-6 and IL-8 mRNA expression and protein secretion in LPS-stimulated cells were inhibited significantly by the lipophilic statin pitavastatin and the hydrophilic statin pravastatin. As these inhibitory effects of statin were negated by adding mevalonate, the anti-inflammatory effects of statins appear to be exerted via the mevalonic cascade. In addition, the activation levels of Ras homologue gene family A (RhoA) in BEAS-2B cells cultured with pitavastatin were significantly lower than those without the statin. These results suggest that statins have anti-inflammatory effects by reducing cytokine production through inhibition of the mevalonic cascade followed by RhoA activation in the lung.

An epidemiological study of the effects of statin use on airflow limitation in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is considered to be a systemic inflammatory disease, and systemic inflammation has been noted as a factor contributing to cardiovascular disease, which is one of the comorbidities associated with COPD. On the other hand, pleiotropic effects, such as the anti-inflammatory effects of statins, have attracted attention in recent years, and there have been a variety of reports regarding the usefulness of statins for patients with COPD. We investigated whether the use or non-use of statins influenced the prevalence of airflow limitation. All outpatients who were over the age of 40 years and who regularly visited a primary health care facility were invited to participate. Each participant underwent spirometry and completed a questionnaire regarding their clinical status, which was used to screen for COPD. A variety of factors that are potentially related to airflow limitation were assessed. Of the 853 patients included in the study, 81 (9.5%) had airflow limitation. The prevalence of airflow limitation was 2.3% among the 89 patients with a history of statin use, which was five times lower than the prevalence of airflow limitation among patients who had not used statins (10.5%). Among the 347 patients with a history of past or current smoking, airflow limitation was not observed in the 30 patients who had used statins. However, by multivariate analysis, statin use was not significantly associated with a lower prevalence of airflow limitation. This is the first cross-sectional study from Japan that has demonstrated that statin use has a potential impact on airflow limitation in patients with COPD.

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

Anti Inflammatory Effects of Statins in Cardiac Surgery Patients

Objectives: Cardiac surgery with cardiopulmonary bypass provokes systemic inflammatory response, which may cause organ dysfunction. Studies have suggested that pre-operative statin therapy can reduce morbidity and mortality associated with cardiac surgery; the mechanism for this remains unclear. We hypothesise that underlying mechanism of action for these effects of statins is through inhibition of neutrophil transendothelial migration. Methods: We recruited 151 patients undergoing cardiac surgery. Of these 41 patients were on no-statin; 48 patients on low-dose (10 - 30 mg) and 62 patients were on high-dose statin (40 - 80 mg). Ex vivo neutrophil migration was performed on pre-operative blood samples of 90 patients. Of these 90 patients we used 36 patients to assess the levels of TNF-α and sICAM-1. Clinical parameters of total 151 patients were assessed to analyse outcome. Results: Ex vivo neutrophil migration was decreased in high-dose statin group when compared to neutrophils isolated from no-statin or low-dose statin groups (p < 0.001). Serum TNF-α levels were lower in the high-dose statin group (p = 0.002) and sICAM-1 levels were decreased in both low (p = 0.02) and high-dose statin (p = 0.01) groups. Conclusion: Our study demonstrates that high-dose statins reduce ex-vivo transendothelial neutrophil migration, TNF-α and sICAM-1 serum levels suggesting that statins may help in decreasing the post-cardiac surgery morbidity.

Statins as Potentially Neuroprotective Agents: A Review

The aim of this literature review is to assess the experimental and clinical evidence regarding potential neuroprotective effects of statins and their possible perioperative benefit. Statins are drugs used to control cholesterol disorders and prevent cardiovascular diseases by four mechanisms: improvement of endothelial function, modulation of inflammatory responses, maintenance of plaque stability, and prevention of thrombus formation. It is possible that these various effects may also be neuroprotective. The anti-inflammatory effects of statins on endothelial cell mechanisms are better understood than their role in neuroprotection or tumoral apoptosis and evidence is only just emerging that statins may be beneficial. Data regarding perioperative use of statins in neurosurgery is scarce, controversial and inconclusive since there is a lack of convincing randomized, prospective clinical trials. More trials in humans are needed to determine whether statins could contribute to the current management of neurosurgical diseases. Not much is known about utilizing statins as a prophylactic treatment and some would probably advocate that we should be treating ‘at risk’ patients with statins perioperatively or at least it is important to try to put this into a clinical perspective.

Effect of Statins on C-reactive Protein, Lipoprotein(a) and Fibrinogen in Hypercholesterolemic Patients

Objective: C-reactive protein (CRP), lipoprotein (a)[Lp(a)], and fibrinogen are associated with systemic inflammatory reactions. Statins have anti-inflammatory effects. However, the effect of statins on these parameters is inconsistent. We evaluated the effect of statins on inflammatory markers and variables related to changes in these markers. Methods: A total of 390 hypercholesterolemic patients were enrolled. Atorvastatin (n=112), lovastatin (n=25), pitavastatin (n=49), rosuvastatin (n=20), and simvastatin (n=184) were administered. Lipids, CRP, Lp(a), and fibrinogen levels were measured before and after 2 months of the therapy. Results: Statins reduced cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride levels by -28.9±9.1% (P=0.000), -41.4±12.4% (P=0.000), and -11.6±39.4% (P=0.000), respectively and increased high density lipoprotein (HDL) cholesterol level by 2.56±13.2% (P=0.014). CRP levels decreased from 1.23±1.30 to 1.14±1.29 mg/L (P=0.000). Lp(a) levels were not changed (P=0.91) and fibrinogen levels increased from 277.8±54.4 to 282.6±56.9 mg/dL (P=0.042). Changes in CRP levels were associated with baseline CRP levels (r=-0.56, P=0.000) and changes in HDL cholesterol levels (r=-0.14, P=0.005). Changes in Lp(a) levels were associated with changes in triglyceride (r=-0.24, P=0.000) and baseline aspartate aminotransferase level (r=0.12, P=0.015). Changes in fibrinogen levels were associated with baseline fibrinogen levels (r=-0.40, P=0.000), sex (r=0.18, P=0.001), and changes in HDL cholesterol levels (r=-0.15, P=0.003). Conclusion: Inflammatory markers showed different responses to statins and changes in these markers were associated with different parameters. This finding suggests that anti-inflammatory effect of statin is confined to a specific pathway of inflammation.

Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4(+) T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway--geranylgeranylation or farnesylation--is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.

Inflammation as a Marker for the Prediction of Internal Carotid Artery Restenosis Following Eversion Endarterectomy—Evidence From Clinical Studies

The role of inflammation is well established in the pathogenesis of atherosclerosis and an increased level of circulating inflammatory markers may predict the future risk of atherosclerosis progression and plaque rupture. C-reactive protein (CRP) identification by hypersensitive methods (high-sensitivity CRP [hsCRP]) has become a clinical and laboratory inflammation marker. Carotid endarterectomy (CEA) is a well-established procedure for carotid stenosis treatment which can reduce stroke rate. Internal carotid artery (ICA) restenosis reduction may be prevented by the anti-inflammatory effect of statins. This review considers the recent findings on the presence of hsCRP and C3 complement concentration and inflammatory plaque composition as well as their effects on ICA restenosis rate, following eversion CEA with emphasis on human studies.

Association of lower total bilirubin level with statin usage: The United States National Health and Nutrition Examination Survey 1999–2008

ObjectiveA low circulating level of bilirubin is associated with increased cardiovascular risk. As statins can stimulate heme oxygenase-1 (HO-1), which increases bilirubin production, we investigated whether statins in routine use increase total bilirubin levels in subjects at high cardiovascular risk. MethodsData from 3290 subjects with self-reported history of hypercholesterolemia, diabetes, or cardiovascular diseases in the United States National Health and Nutrition Examination Survey (NHANES) 1999–2008 were analyzed. ResultsSubjects taking statins (n=1156) had lower total bilirubin levels than those not taking any lipid-lowering medication (n=2134) after adjusting for age, sex, race/ethnicity, and survey period (adjusted mean=0.699 vs 0.729mg/dl respectively, P=0.001). The association remained significant after adjusting for more covariates (P=0.002), but was attenuated after further adjusting for glycosylated hemoglobin, insulin resistance index, and low-density lipoprotein (LDL) cholesterol (P=0.043). The use of lovastatin, rosuvastatin, and cerivastatin was associated with lower total bilirubin levels in the full adjustment model (P<0.05). ConclusionThe use of statins was associated unexpectedly with lower total bilirubin levels. This could be explained at least partly by the effect of statins on glycemia and LDL cholesterol. Our results do not suggest that the anti-oxidant and anti-inflammatory effects of statins are due to HO-1 induction and increased serum bilirubin levels.