ObjectiveTo systematically review the efficacy and safety of simvastatin and its different doses in the adjunct therapy of chronic obstructive pulmonary disease (COPD).MethodsPubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data, CBM and VIP databases were electronically searched to collect randomized controlled trials (RCTs) on adjunct therapy of simvastatin in patients with COPD from inception to May 15th, 2020. Two reviewers independently screened literature, extracted data and assessed risk bias of included studies; then, meta-analysis was performed by using Stata 14.0 software.ResultsA total of 22 RCTs involving 2 377 patients were included. The results of meta-analysis showed that treatment with 20 mg simvastatin could improve FEV1%pred, FEV1/FVC, and reduce inflammatory indexes such as CRP, hs-CRP, IL-8 and TNF-α, while 40 mg failed to improve. Simvastatin could reduce COPD score (CAT), but failed to increase the 6-minute walking distance or alleviate acute exacerbation.ConclusionsCurrent evidence shows that treatment with 20 mg simvastatin can improve pulmonary function, reduce inflammatory index and optimize CAT score in COPD patients, but it cannot increase the 6-minute walking distance and reduce the number of acute exacerbations of COPD. Due to the limited quantity and quality of included studies, the above conclusions are needed to be verified by more high-quality studies.
Objective To investigate the effects of simvastatin on lung tissue in septic rats by observing the protein expression of nuclear factor kappa B ( NF-κB) and pathologic changes in lung tissue at different time points. Methods 90 healthy male Sprague-Dawley rats were randomly divided into three groups ( n =30 in each group) . All the rats received administration by caudal vein and capacity volume is 2 mL. The rats in the control group were treated with saline ( 2 mL) . The rats in the LPS group were treated with LPS ( 5 mg/kg ) . The rats in the simvastatin group were treated with LPS ( 5 mg/kg) and simvastatin ( 20 mg/kg) . Six rats in each group were killed randomly at 2, 4, 6, and 12 hours after the injection, and the right middle lobe of lung was taken out. Pathological changes of lung tissue wee investigated under light microscope. The expression of NF-κB in lung tissue was determined by immunohistochemistry ( IHC) method. Results Microscopic studies showed that there were not pathological changes in the lung tissue of rats in the control group. While in the LPS group, the alveolar spaces were narrowed and the alveolar wall were thickened. Furthermore, severe interstitial edema of lung and proliferation of epithelial cells were observed. In the simvastatin group, the degree of the infiltration of leukocytes and the lung interstitial edema were less severe than those in the simvastatin group. In the control group, the expression of NF-κB protein in most of lung tissue was negative. In the LPS group, the expression of NF-κB protein was detected at 2h, andreached the peak at 6h, then decreased at 12h. In the Simvastatin group, the NF-κB expression was significantly lower than that in the LPS group at all time points ( P lt; 0. 01) . Conclusion Simvastatin can ameliorate pathological lesions and decrease expression of NF-κB in lung tissue of septic rats.
【Abstract】 Objective To approach the possibil ity of combination of simvastatin and BMSCs transplantation forsteroid-associated osteonecrosis of femoral head. Methods The BMSCs harvested from 24 rabbits were prepared for cell suspension at a concentration of 1 × 107/mL, and combined with gelatin sponge. Seventy New Zealand white rabbits received one intravenous injection of l ipopolysaccharide (10 μg/ kg). After 24 hours, three injections of 20 mg/kg of methylprednisolone were given intramuscularly at a time interval of 24 hours. Forty-eight rabbits diagnosed as having femoral head necrosis by MRI were divided into 4 groups randomly, group A: no treatment; group B: only decompression; group C: decompression and BMSCs transplantation; and group D: simvastatin drench (10 mg/kg.d) decompression and BMSCs transplantation. The general information of animals were recorded; after 4 and 8 weeks of operation, 6 rabbits of each group were chosen randomly to do MRI scan, and femoral heads were harvested to do histopathology and scanning electron microscope examination. Results After 8 weeks, rabbits became more active than before treatment, and walking way became normal gradually in groups C and D. Fourweeks after operation, the MRI low signal region of all groups had no obvious changes, but 8 weeks later, the necrosis signal region of group A magnified while it reduced obviously in group D. Histopathological observation: 4 weeks after operation, diffuse presence of empty lacunae and pyknotic nuclei of osteocytes were found in the trabeculae, and few newborn micrangium could been seen in group A; lots of empty lacunae and a small quantity of newborn micrangium could been found in group B; and large amounts of osteoblats and newborn micrangium were found around the necrosis regions in groups C and D. The positive ratio of empty lacunae and microvessel density in group D were 19.30 ± 1.52 and 7.08 ± 1.09, showing significant difference compared with other groups (P lt; 0.05). After 8 weeks of treatment, the bone trabecula collapsed in many regions in group A; there was fibra callus formation along the decompression channel in group B; few empty lacunae was in the bone trabecular, but the shape of marrow cavity was not normal in group C; and it showed almost normal appearance in group D. The positive ratio of empty lacunae and microvessel density in group D were 11.31 ± 1.28 and 12.37 ± 1.32, showing significant differences compared with other groups (P lt; 0.05), meanwhile, showing significant difference compared with that of 4 weeks after operation(P lt; 0.05). Scanning electron microscope: 8 weeks after operation, the bone trabecula collapsed in many regions, and few osteoblasts could be found on the surface, a great quantity of fat cells cumulated in the bone marrow in group A; cracked bone trabecula could be found occasionally in group B; the density of bone trabecula was lower than the normal in group C; and the shape of the marrow avity and thedensity of bone trabecula were similar to the normal in group D. Conclusion Simvastatin can promote the differentiation of osteocyte and vascular endothel ial cell from MSCs, the combination of simvastatin and marrow stem cells transplantation for the treatment of steroid-associated osteonecrosis of femoral head have good appl ication prospects.
ObjectiveTo explore the effects of simvastatin on the expression of matrix metalloproteinase (MMP) and inflammatory factors in rats with smoke-induced chronic obstructive pulmonary disease (COPD). Methods40 male Wistar rats were randomly divided into four groups, including a normal group (group A), a simvastatin group (group B), a COPD model group (group C) and a simvastatin intervention group (group D). The COPD model of the group C and D were induced through exposing to the cigarette smoke repeatedly. At the same time, the rats of group B and D were given by gavage 5 mg/(kg·d) with simvastatin, and the other two groups were given with the same volume saline for 16 weeks. Pulmonary function tests and pathological examination of the lung tissue were performed after the induction of COPD model. Enzyme-linked immunosorbent assay (ELISA) method was used to measure the content of MMP-2, MMP-9, IL-6, IL-8, TNF-α in lung tissue homogenate. ResultsThe airway resistance of group C and group D was significantly higher than the group A and group B (P<0.01), and the airway resistance of group D was significantly lower than group C (P<0.01). The degree of bronchial inflammation and emphysema of group C was more apparent than group D in the pathological section, and there were no bronchial inflammation and emphysema in group A and group B. The ELISA results showed that the contents of MMP-2, MMP-9, IL-6, IL-8, TNF-α in group C were all significantly higher than those in group D. ConclusionSimvastatin has inhibitory effect on pulmonary inflammation of COPD, and can reduce the expression of matrix metalloproteinase and inflammatory factors in the lung.
Objective To investigate the preventive effect of simvastatin，a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor，on hypoxic pulmonary hypertension and the relation between it and the angiotensin Ⅱ receptor-1（AT1R） expression in pulmonary arteriole.Methods Thirty male Sprague-Drawley rats were randomly allocated into three groups：a control group，a hypoxic group and a simvastatin preventive group.The animal model of hypoxic pulmonary hypertension was established by exposing the rats to normobaric hypoxic condition（8 h×6 d×3 w），and the preventive group were treated with simvastatin 10 mg/kg before hypoxic processing while the control and hypoxic groups were treated with sodium chloride.The mean pulmonary pressure（mPAP），serum cholesterol concentration，right ventricular hypertrophy index [RV/（LV+S）]，percentage of the wall thickness in the external diameter（WT%），percentage of the wall area in the total vascular area（WA%），and the AT1R expression in pulmonary arterioles were measured.Results When compared with the hypoxic group，in the preventive group，the mPAP and RV/（LV+S）obviously reduced [（22.6±3.86）mm Hg vs （29.3±2.27）mm Hg，（25.13±0.75）% vs （33.18±1.58）%，Plt;0.01 respectively]，the indices of wall thickness of rat pulmonary arteriole and area also decreased significantly [WT%：（15.98±1.96）% vs （25.14±1.85）%；WA%：（54.60±3.94）% vs 74.77±4.52）%；Plt;0.01 respectively]，and the positive degree of AT1R still lessened noticeably（1.23±0.09 vs 1.57±0.13，Plt;0.01）.All of the indices above in the hypoxic group increased markedly compared with the control group（Plt;0.01 respectively）.However，the differences of serum cholesterol among three groups were not significant（Pgt;0.05）.Conclusions Simvastatin can suppress the expression of AT1R in pulmonary vessel and prevent hypoxic pulmonary hypertension.
Objective To evaluate the effectiveness and safety of simvastatin 40 mg daily use in treatment of coronary heart disease. Methods The study was designed as before-after study in the same patients. One hundred and sixty seven patients with coronary heart disease were prescribed simvastatin 40 mg daily for 3 and 6 months. Total cholestero (TC), low-density lipoproteins cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerldes (TG), ALT and creatine kinase (CK) in serum before therapy and at the end of 3 months and 6 months treatment were dectected. Continuous data were analyzed by standard difference of blocked randomization and described by mean±SD. Dunnet-t test was used for multiple comparison of trial and control groups. Statistical difference was set up at P＜0.05. Success rate was assessed by chi square test at the end of 3 and 6 months treatment. Results Simvastatin 40 mg/d significantly decreased the level of TC (P＜0.000 5), LDL-C (P＜0.000 5), TG (P＜0.05), and could elevate HDL-C (P＜0.05). There were 39.5% of patients whose LDL-C reduced below 70 mg/dl. One patient whose CK raised 5.6 times of upper line of normal range and 4 patients whose ALT raised more than 2 times of upper line of normal range withdrew. The reliability of simvastatin 40 mg/d was relatively good. Conclusions Simvastatin 40 mg/d could significantly improve the lipid profile, and is relatively reliable in treatment of coronary heart disease.
OBJECTIVE: To study the effect of simvastatin on the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphates (ALP) activity in the primary cultured bone marrow stromal cells, and to elucidate the mechanism of the anabolic osteogenetic effect of simvastatin. METHODS: Bone marrow stromal cells in femur and tibia of adult mouse were cultured in vitro. after treated with different concentrations of simvastatin (0, 0.1, 0.2, 0.5 and 1.0 mumol/L) or recombinant human BMP-2 for 72 hours, ALP activity of bone marrow stromal cells was determined. BMP-2 expression of bone marrow stromal cells was analyzed by using immunocytochemistry and Western blotting. RESULTS: After treated with simvastatin for 72 hours, BMP-2 expression increased, while little BMP-2 expression could be observed in the control group. ALP activity also increased in a dose-dependent manner; t-test showed that ALP activity in the group which concentrations of simvastatin were 0.5 mumol/L (t = 2.35, P = 0.041), 1.0 mumol/L (t = 2.348, P = 0.041) had significant difference when compared with control group. CONCLUSION: Simvastatin lead to high expression of BMP-2 in bone marrow stromal cells, via the increased auto- or para-crine of BMP-2, and ALP activity increased. These may be parts of the mechanism on the anabolic osteogenetic effect of simvastatin.
Objective To confirm the stimulating effect of simvastatin on BMSCs of SD rats osteogenic differentiation, and to further study the role of Wnt signal ing pathway in this process. Methods BMSCs derived from the tibia and femur of 6-week-old female SD rats were cultured in vitro．Two groups were establ ished: control group and experimental group. After the 2nd passage, the cells of experimental group were treated with simvastatin (1 × 10-7mol/L) and the cells of control group with absolute ethyl alcohol and PBS. ALP staining was used at 7 days and von Kossa staining was appl ied at 28 days to assess osteoblastic differentiation and mineral ization. Real-time quantitative PCR was performed to evaluate theexpressions of Axin2, β-catenin, osteocalcin (OC), frizzled-2, Lef-1, and Wnt5a mRNA at 7 days and 14 days after simvastatin treatment. Results The observation of inverted phase contrast microscope showed that the majority of cells were polygonal and triangular in the experimental group, and were spindle-shaped in the control group at 7 days. The ALP staining showed blue cytoplasm, the positive cells for ALP staining in the experimental group were more than those in the control group at 7 days. The von Kossa staining showed that mineral ization of extracelluar matrix at 28 days in two groups, but the mineral ization in the experimental group was more obvious than that in the control group. The expression of Axin2 mRNA was significantly lower, and frizzled-2, Lef-1 mRNA were significantly higher in the experimental group than in the control group (P lt; 0.05) at 7 days, while the mRNA expressions of Axin2, OC, frizzled-2, Lef-1, and Wnt5a were significantly higher in the experimental group than in the control group at 14 days (P lt; 0.05). Conclusion Simvastatin can promote the osteogenic differentiation of BMSCs and change the expression of mRNA of some components of Wnt signal ing pathway.
Objective To observe the protective effects of simvastatin at different stages on monocrotaline (MCT) induced pulmonary arteral hypertension (PAH) in rats and evaluate the early preventive effect of simvastatin. Methods Twenty-four male SD rats were randomized into a control group, a PAH group, an early intervention group, and a late intervention group, with 6 rats in each group. The rats in the control group received intraperitoneal injection of normal saline (NS) on d0. The rats in the PAH group received one-off intraperitoneal injection of MCT (50 mg/kg) on d0. The rats in the early intervention group were pretreated with oral gavage of simvastatin (20 mg·kg–1·d–1)(d–7––1) before the intraperitoneal one-off injection of MCT (50 mg/kg, d0) and continued with oral gavage of simvastatin for 14 days (d1~14). The rats in the late intervention group received one-off intraperitoneal injection of MCT (50 mg/kg)(d0) and oral gavage of simvastatin (20 mg·kg–1·d–1) for the next 21 days (d15~35). Thirty-five days after the MCT injection (d36), mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured by right heart catheter. Then the rats were sacrificed for separating the heart and lung, the right ventricular hypertrophy index (RVHI) and percentage of small pulmonary arteries media thickness (WT%), the inflammation score around the small pulmonary arterial were recorded. Results Compared with those in the PAH group, RVSP, mPAP, RVHI and WT% in two simvastatin interventiongroups got much better (P＜0.01), and the inflammation score around the small pulmonary arterial declined (P＜0.05). Compared with those in the late intervention group, RVSP, mPAP in the early intervention group improved (P＜0.05) and WT% decreased more significantly (P＜0.01). However RVHI and the inflammation score around the small pulmonary arterial were not different between two simvastatin intervention groups. Conclusions Both early intervention and late intervention with simvastatin can reduce RVSP, mPAP and WT% in MCT induced PAH rats. Compared with later intervention, early intervention can prevent PAH more remarkably.
Objective To investigate the effects of simvastatin on monocrotaline-induced pulmonary hypertension in rats, and explore the potential mechanism of simvastatin by blocking heme oxygenase-1( HO-1) expression. Methods 52 male Sprague-Dawley rats were randomly divided into five groups, ie. a control group, a simvastatin control group, a pulmonary hypertension model group, a simvastatin treatment group, a ZnPP ( chemical inhibitor of HO) group. Mean pulmonary arterial pressure ( mPAP) and right ventricular systolic pressure ( RVSP) were detected by right heart catheter at 5th week. Right ventricular hypertrophy index ( RVHI) was calculated as the right ventricle to the left ventricle plus septum weight. Histopathology changes of small intrapulmonary arteries were evaluated via image analysis system.Immunohistochemical analysis was used to investigate the expression and location of HO-1. HO-1 protein level in lung tissue were determined by western blot. Results Compared with the model group, simvastatin treatment decreased mPAP and RVHI significantly [ ( 35. 63 ±5. 10) mm Hg vs. ( 65. 78 ±15. 51) mm Hg,0. 33 ±0. 05 vs. 0. 53 ±0. 06, both P lt; 0. 05 ] . Moreover, simvastatin treatment partially reversed the increase of arterial wall area and arterial wall diameter [ ( 50. 78 ±9. 03 ) % vs. ( 65. 92 ±7. 19) % ,( 43. 75 ±4. 23) % vs. ( 52. 00 ±5. 35) % , both P lt; 0. 01) . In the model group, HO-1 staining was primarily detected in alveolar macrophages. Simvastatin treatment increased HO-1 protein expression significantly, especially in the thickened smooth muscle layer and alveolar macrophages. Inhibiting HO-1 expression using ZnPP resulted in a loss of the effects of simvastatin. mPAP in the ZnPP group was ( 52. 88±17. 45) mm Hg, while arterial wall area and arterial wall diameter were ( 50. 78 ±9. 03) % and ( 52. 00 ±5. 35) % , respectively. Conclusions Simvastatin attenuates established pulmonary arterial hypertension andpulmonary artery remodeling in monocrotaline-induced pulmonary hypertension rats. The effect of simvastatin is associated with HO-1.