大气细颗粒物心血管毒性的机制研究
|
摘要
大气污染是危害人类健康的主要环境因素之一,其中大气颗粒物因其粒径大小不同,含有多种有害化学组分,对人体健康有复杂的影响。大气颗粒物中空气动力学直径≤2.5μm的细颗粒物,由于其粒径小、表面积大,肺沉积率高,易于穿过内皮到达间质,对人体具有更大的危害性。其所含的炭核、氮、硫、有机物(多环芳烃)、生物化合物(内毒素,细胞片段)和过渡金属(铁,镍,锌,钒)等多种有害的化学成分对人体产生的负面影响,也逐渐成为研究者关注的热点。细颗粒物进入呼吸道,不仅可引起肺损伤,还可引起肺外其它器官如心血管系统、免疫系统及DNA的损伤。
细颗粒物与心血管系统疾病的关联性已在流行病学的研究中得到了一定的论证,但在毒理学的研究中尚未得到相关的系统论证,细颗粒物对心血管系统影响的作用机制也尚未阐明。本次研究通过动物实验和体外细胞实验从自主神经功能、炎症反应、纤溶/凝血、内皮功能和心肌缺血及细胞凋亡等方面对细颗粒物致心血管系统的损伤进行了较系统的毒理学研究,探索其可能作用机制,并通过他汀类药物的干预验证氧化损伤、炎症反应、内皮功能损伤和细胞凋亡等通路在细颗粒物致心血管系统损伤中的作用,为探寻其作用机制提供科学依据。
本研究在上海市市区采集大气细颗粒物,对不同生理病理状态大鼠(高血压大鼠(SHR)作为疾病模型组,Wistar大鼠(WKY)作为健康模型组)进行气管滴注染毒,对照组气管滴注生理盐水,试验组滴注剂量分别为1.6 mg/kg b.w、8.0 mg/kgb.w和40.0 mg/kg b.w的细颗粒物悬液,每天染毒1次,连续染毒3天。观察暴露于细颗粒物后大鼠自主神经功能的改变,包括血压、心率和心电图,以及对大鼠血液及心肌组织中反应炎症、纤溶/凝血、内皮功能及心肌细胞损伤或凋亡等因子的检测,结果发现,细颗粒物染毒组大鼠血压和心率明显升高,心电图ST-段抬高,T波低平。大鼠血液中高敏C-反应蛋白(hs-CRP)、D-二聚体、内皮素-1(ET-1)在染毒组明显高于对照组,并随染毒剂量增加而增加。血液中心肌酶学指标乳酸脱氢酶(LDH)和肌酸激酶同工酶(CK-MB)也随染毒剂量增加而增加,而血管舒张因子一氧化氮(NO)却明显减少。心肌组织内各炎症相关基因IL-1β、IL-6、TNF-α和MIP-2,内皮功能相关基因ET-1,内皮细胞粘附分子ICAM-1及介导细胞凋亡的促凋亡基因bax的mRNA表达均呈现升高趋势,而抗凋亡基因bcl-2的mRNA表达呈下降趋势。同时,利用免疫组织化学方法对暴露于大气细颗粒物后,心肌组织中bax和bcl-2的蛋白表达进行检测。结果发现,与对照组相比,染毒组的bax蛋白表达明显增加,而bcl-2蛋白表达明显降低,表明心肌组织中抗凋亡基因和促凋亡基因的调节出现紊乱,提示心肌细胞凋亡在细颗粒物所致心血管系统损伤中有着非常重要的作用。同样的方法对细颗粒物暴露的大鼠心肌组织中转化生长因子β_1(TGF-β_1)蛋白的表达强度进行了检测,发现暴露于细颗粒物后,心肌组织中TGF-β_1蛋白的表达明显高于对照组。这提示大鼠心肌组织中除内皮屏障功能受到破坏及血管通透性增加外,细胞外基质合成和分泌增加及降解减少、心血管纤维化病变也可能是细颗粒物致心血管系统损伤的作用机制。实验研究也发现,大气细颗粒物染毒剂量相同时,SHR大鼠血液及心肌组织中介导损伤的炎性细胞因子、内皮功能因子、细胞凋亡等因子的表达均明显高于WKY大鼠,表明大气细颗粒物对SHR大鼠心血管系统的毒性作用高于WKY大鼠,这一基于动物模型的实验结果与人群流行病学的研究具有一致性,后者的结论为患有心肺疾病的人群暴露于高浓度细颗粒物后,因心血管疾病发作而增加的死亡率高于健康人群,属于细颗粒物暴露损伤的易感人群。
为了更进一步了解大气细颗粒物对心血管系统的作用机制并探索细颗粒物不同化学成分在心血管系统损伤中的作用,本研究比较了细颗粒物不同成分的毒性大小,分别测定SO_4~(2-)、NO_3~-和Cl~-三种阴离子和五种金属阳离子对人脐静脉血管内皮细胞(EC-304)的毒性作用,结果发现在染毒浓度分别为0.01 mmol/L、0.05 mmol/L、0.1 mmol/L、0.5 mmol/L、1.0 mmol/L、5.0 mmol/L和10.0mmol/L的离子浓度时,阴离子中NO_3~-离子对细胞活性有抑制作用;五种金属阳离子对细胞活性均有抑制作用,其作用大小依次为Ni~(2+)＞Cu~(2+)＞Zn~(2+)＞Fe~(3+)＞Mg~(2+)。本次研究还提取了大气细颗粒物有机物、水溶成分和非水溶成分,每种成分分别按浓度100μg/ml、200μg/ml和400μg/ml,设为低、中、高三个浓度组对血管内皮细胞进行24h染毒,观察细颗粒物不同成分的毒性作用,进一步了解氧化应激、炎症反应、内皮功能紊乱和细胞凋亡在心血管系统损伤中的作用。结果发现细颗粒物有机提取物、水溶成分和非水溶成分使细胞存活率显著降低。细胞内活性氧族(ROS)、丙二醛(MDA)和上清液LDH/总LDH的比值均随着染毒浓度的增加而增加,而超氧化物歧化酶(SOD)及血管舒张因子NO含量却明显降低。细胞内与炎症相关基因IL-6、IL-4和TNF-α,内皮功能相关基因ET-1和TGF-β_1,凝血功能相关基因P-selectin,凋亡相关基因fas的mRNA表达随着染毒浓度的增加均明显升高,而内皮型一氧化氮合酶(eNOS)明显降低。同时发现,大气细颗粒物不同成分对血管内皮细胞的氧化损伤、炎症反应和内皮功能的作用大小依次为:水溶成分＞有机提取物＞非水溶成分,但对细胞凋亡和细胞ROS含量的影响却是有机提取物＞水溶成分＞非水溶成分。
他汀类药物能改善内皮功能,增加NO的生物活性,抑制炎性反应和调节免疫功能,并有很强的抗氧化功能,本次研究使用阿托伐他汀对细颗粒物有机提取物、水溶成分和非水溶成分致EC-304细胞的毒性进行干预,使用浓度为400μg/ml的细颗粒物有机提取物、水溶成分和非水溶成分分别对EC-304细胞进行染毒,同时加入阿托伐他汀药物进行干预,药物浓度为0μmol/L、0.1μmol/L、1μmol/L、10μmol/L,观察药物对细颗粒物不同成分氧化应激、内皮功能损伤和凋亡等毒性的干预作用。结果显示,加入阿托伐他汀后,细颗粒物不同成分染毒组的细胞内ROS、MDA和LDH较未加药组明显降低,而SOD和NO明显增加。同时,加入药物使细胞IL-6、IL-4、TNF-α、ET-1、P-selectin、fas和TGF-β_1 mRAN表达水平明显下调,使eNOS mRNA表达上调,并呈剂量-反应关系。由于他汀类药物在抗氧化损伤、减少炎症和改善内皮功能方面具有良好的药理作用,本次实验表明他汀类药物能明显减少细颗粒物暴露所致的氧化应激、炎症反应、内皮功能损伤和细胞凋亡,结果提示,细颗粒物对心血管系统的损伤是由氧化应激、炎症反应、内皮功能损伤和细胞凋亡等通路介导的。
由于大气细颗粒物对心血管系统的作用机制尚不清楚,本次研究通过动物实验和体外细胞实验研究了大气细颗粒物对心血管系统的毒性作用,并探索其可能作用机制。结果表明,自主神经功能失调、炎症反应、纤溶/凝血功能障碍、内皮功能损伤及心肌缺血和细胞凋亡是大气细颗粒物致心血管系统损伤的可能作用机制,通过他汀类药物的干预实验更进一步验证了这些损伤通路的存在。
总之,本实验从分子、细胞和动物体等不同的生物学层次进行了较为系统的细颗粒物致心血管损伤的毒理学机制的研究,取得了与人群流行病学研究相一致的结论,为今后大气细颗粒物污染的防治及有效地保护人类健康等方面提供理论依据。
Air pollution is one major pollution in perspective of public health.Air particulate matter(PM),varying in different aerodynamic diameters and generally composed of a complex of carbon,nitrogen,sulfur,biological chemicals and heavy metals,is one of the most important air pollutants.Among others,fine particles (aerodynamic diameter≤2.5μm),in comparison with coarse particles,have been considered as a more serious pollutant,due to its high deposition efficiency into human respiratory system as well as cardiovascular system.It is of major concern because of their high propensity to penetrate the epithelium and reach interstitial sites, even transportation to other organs by air exchange in human lungs,resulting in respiratory system diseases,and extrapulmonary injuries,such as in cardiovascular and immunonological system.
Epidemiological studies have shown that increases in airborne fine particle concentrations are adversely associated with cardiovascular health,but there is a lack of comprehensive studies on the effects of fine particles on cardiovascular system in toxicological perspectives,as well as the potential toxicity mechanisms.The purpose of this study is to explore the toxicological mechanisms of fine particles on cardiovascular system in respect to autonomic nervous system,inflammation, coagulation,endothelial function and cell apoptosis through animal experiment and cell culture studies.In addition,drug intervention studies by statin were performed to verify the possible toxicological mechanisms of fine particles on vein endothelial cells in vitro.
In this study,spontaneously hypertensive(SH) rats were used as a model of human cardiovascular disease and Wistar Kyoto(WKY) rats as a model of healthy human.Ambient fine particles were collected by air sampling in the urban area in Shanghai and prepared into particle solutions in different concentrations.Acute exposure to fine particle solution preparations were performed by intratracheally instillation.The SH model was exposed to a gradient of fine particle concentration in 1.6 mg/kg b.w,8.0 mg/kg b.w and 40.0 mg/kg b.w,respectively,while the control model was exposed to physiological saline.The exposure was performed once a day for three days.In 24h after the last exposure,blood pressure,heart rate and cardiogram were monitored in both types of rats,as well as the biomarkers of inflammation,coagulation,endothelial function and myocardial cells lesion in blood and cardiac muscle tissue.The results showed that blood pressure and heart rate significantly increased both in SH rats and WKY rats after exposure to fine particles with an elevation of ST segment in cardiograms.In blood samples,the levels of blood high sensitive C-response protein(hs-CRP),D-dimer and endothelin-1(ET-1) increased significantly in SHR and WKY rats in a dose-dependent manner,whereas the level of blood nitrous oxide(NO) was decreased.The serum level of myocardial enzyme MB isoenzyme of creatine kinase(CK-MB) and lactate dehydrogenase(LDH) increased both in SHR and WKY rats in a dose-dependent manner.In the cardiac muscle tissue,the mRNA expression of inflammation-related genes IL-1β,IL-6, TNF-α,MIP-2 significantly increased in rats,as well as the endothelial function-related gene ET-1 and coagulation function-related gene ICAM-1.Moreover, expression of apoptosis bax gene increased significantly in rats while the anti-apoptosis gene bcl-2 mRNA expression decreased.The latter result was consistent with the protein expression levels determined by immunohistochemical staining measurement.It was found that in rats,the protein expression of apoptosis bax gene was up-regulated while the anti-apoptosis bcl-2 gene was down-regulated. These results indicated that exposure to fine particle may cause inflammation, coagulation,endothelial dysfunction and apoptosis in rats.Finally,protein expression of transforming growth factor-beta_1(TGF-β_1) measured by the same staining method showed that the TGF-β_1 protein expression obviously increased in SH rats in comparison with WYK rats,which suggested that in the fine particle toxicity mechanisms,in addition to the endothelial dysfunction and the increase of vascular permeability,the extracellular matrix synthesis and secretion and myocardial fibrosis were potentially the additional ways of cardiovascular toxicity effects.Interestingly, when the same exposure level was performed in both SHR and WKY rats,the levels of hs-CRP,D-dimer,ET-1,LDH and CK-MB were significantly higher in SH rats than in WKY rats,which indicated that model rats with the presence of hypertension diseases could be more susceptible to fine particle exposure than normal ones.This is in agreement with the results from epidemiological studies on human population, which prove that after exposure to fine particles,higher rate of cardiopulmonary morbidity is more likely in people with cardiovascular disorders than in healthy people.
The cardiovacular effects of fine particle ion components were analyzed on human umbilical vein endothelial cells(EC-304).Particle samples were extracted for specific anion samples including SO_4~(2-),NO_3~-,Cl~-,and five metal ion samples in doses of 0.01mmol/L,0.05mmol/L,0.1mmol/L,0.5mmol/L,1.0mmol/L,5.0mmol/L and 10.0mmol/L,respectively.After exposure experiment,it was found that only NO_3~-anions could inhibit cell activity in all the above concentration levels,and all metal ions could inhibit cell activity in different inhibition rates:Ni~(2+)＞Cu~(2+)＞Zn~(2+)＞Fe~(3+)＞Mg~(2+).Furthermore,the cardiovascular effects of chemical components,such as organic extracts,soluble and insoluble components of fine particles(exposure doses: 100μg/mL,200μg/mL and 400μg/mL,respectively for 3 kinds of components) were analyzed on EC-304 cells.Malondialdehyde(MDA),LDH,reactive oxygen species (ROS) increased and NO and Superoxide dismutase(SOD) decreased in EC-304 cells for all 3 component extraction exposure.The mRNA expression of IL-4,IL-6,TNF-α, ET-1,P-selectin and fas gene increased in EC-304 exposure cells while mRNA expression of eNOS decreased.Within the 3 different components,the inhibition effects of cell activity,oxidative stress,inflammatory response were more significant in soluble extracts than in organic extracts than in insoluble extracts.However,effects of cell apoptosis and ROS level were higher in organic extracts than in soluble extracts than insoluble extracts.In summary,different components of fine particles could lead to different levels of toxicity to cells.
Statin can improve endothelial function,elevate NO biological activity,inhibit inflammation,modulate immune function and reduce oxidation in clinical studies.In this study,atorvastatin was used for intervention studies on the possible toxicological mechanisms of fine particle components on EC-304.EC-304 were exposed to the 400μg/mL organic,soluble and insoluble extracts of fine particles,respectively,followed by an intervention of astorvastatin in concentrations of 0.1μmol/L,1μmol/L and 10μmol/L.The results showed that in comparison with the group of cells with no atorvastatin addition,the levels of ROS,MDA and LDH in EC-304 cells induced by either organic extract,soluble or insoluble components of fine particles,were obviously inhibited after the addition of atorvastatin,while cell activities,SOD and NO levels in EC-304 cells increased significantly.Furthermore,the mRNA expression of IL-4,IL-6,TNF-α,ET-1,P-selectin,TGF-β_1 and fas in cells decreased greatly after treatment with atorvastatin as well,and eNOS increased significantly in a dose-dependent manner.Since atorvastatin is a clinical drug for cure of cardiovascular disorders with the known effects of reducing inflammation and improving endothelial functions,this intervention study consistently suggested that oxidative stress, inflammation,endothelial dysfunction and apoptosis were the potential mechanisms of cardiovascular injuries caused by fine particles.
In summary,this study examined the potential biological pathways triggering toxicological effects of fine particles on cardiovascular system.By methods based on animal experiment and cell culture,the results indicated that fine particles increased the risk of cardiovascular disease by increasing autonomic nervous dysfunction, oxidative stress,inflammation,coagulation,endothelial dysfunction and apoptosis. Drug intervention studies further supported the presence of the above mechanisms. These results were in consistence with the main conclusions from epidemiological studies on human population exposed to fine particles.It will contribute in further exploration of the real mechanisms by fine particle on cardiovascular diseases,and will be of importance in understanding the effects of air particulate matter on human health.
细颗粒物与心血管系统疾病的关联性已在流行病学的研究中得到了一定的论证,但在毒理学的研究中尚未得到相关的系统论证,细颗粒物对心血管系统影响的作用机制也尚未阐明。本次研究通过动物实验和体外细胞实验从自主神经功能、炎症反应、纤溶/凝血、内皮功能和心肌缺血及细胞凋亡等方面对细颗粒物致心血管系统的损伤进行了较系统的毒理学研究,探索其可能作用机制,并通过他汀类药物的干预验证氧化损伤、炎症反应、内皮功能损伤和细胞凋亡等通路在细颗粒物致心血管系统损伤中的作用,为探寻其作用机制提供科学依据。
本研究在上海市市区采集大气细颗粒物,对不同生理病理状态大鼠(高血压大鼠(SHR)作为疾病模型组,Wistar大鼠(WKY)作为健康模型组)进行气管滴注染毒,对照组气管滴注生理盐水,试验组滴注剂量分别为1.6 mg/kg b.w、8.0 mg/kgb.w和40.0 mg/kg b.w的细颗粒物悬液,每天染毒1次,连续染毒3天。观察暴露于细颗粒物后大鼠自主神经功能的改变,包括血压、心率和心电图,以及对大鼠血液及心肌组织中反应炎症、纤溶/凝血、内皮功能及心肌细胞损伤或凋亡等因子的检测,结果发现,细颗粒物染毒组大鼠血压和心率明显升高,心电图ST-段抬高,T波低平。大鼠血液中高敏C-反应蛋白(hs-CRP)、D-二聚体、内皮素-1(ET-1)在染毒组明显高于对照组,并随染毒剂量增加而增加。血液中心肌酶学指标乳酸脱氢酶(LDH)和肌酸激酶同工酶(CK-MB)也随染毒剂量增加而增加,而血管舒张因子一氧化氮(NO)却明显减少。心肌组织内各炎症相关基因IL-1β、IL-6、TNF-α和MIP-2,内皮功能相关基因ET-1,内皮细胞粘附分子ICAM-1及介导细胞凋亡的促凋亡基因bax的mRNA表达均呈现升高趋势,而抗凋亡基因bcl-2的mRNA表达呈下降趋势。同时,利用免疫组织化学方法对暴露于大气细颗粒物后,心肌组织中bax和bcl-2的蛋白表达进行检测。结果发现,与对照组相比,染毒组的bax蛋白表达明显增加,而bcl-2蛋白表达明显降低,表明心肌组织中抗凋亡基因和促凋亡基因的调节出现紊乱,提示心肌细胞凋亡在细颗粒物所致心血管系统损伤中有着非常重要的作用。同样的方法对细颗粒物暴露的大鼠心肌组织中转化生长因子β_1(TGF-β_1)蛋白的表达强度进行了检测,发现暴露于细颗粒物后,心肌组织中TGF-β_1蛋白的表达明显高于对照组。这提示大鼠心肌组织中除内皮屏障功能受到破坏及血管通透性增加外,细胞外基质合成和分泌增加及降解减少、心血管纤维化病变也可能是细颗粒物致心血管系统损伤的作用机制。实验研究也发现,大气细颗粒物染毒剂量相同时,SHR大鼠血液及心肌组织中介导损伤的炎性细胞因子、内皮功能因子、细胞凋亡等因子的表达均明显高于WKY大鼠,表明大气细颗粒物对SHR大鼠心血管系统的毒性作用高于WKY大鼠,这一基于动物模型的实验结果与人群流行病学的研究具有一致性,后者的结论为患有心肺疾病的人群暴露于高浓度细颗粒物后,因心血管疾病发作而增加的死亡率高于健康人群,属于细颗粒物暴露损伤的易感人群。
为了更进一步了解大气细颗粒物对心血管系统的作用机制并探索细颗粒物不同化学成分在心血管系统损伤中的作用,本研究比较了细颗粒物不同成分的毒性大小,分别测定SO_4~(2-)、NO_3~-和Cl~-三种阴离子和五种金属阳离子对人脐静脉血管内皮细胞(EC-304)的毒性作用,结果发现在染毒浓度分别为0.01 mmol/L、0.05 mmol/L、0.1 mmol/L、0.5 mmol/L、1.0 mmol/L、5.0 mmol/L和10.0mmol/L的离子浓度时,阴离子中NO_3~-离子对细胞活性有抑制作用;五种金属阳离子对细胞活性均有抑制作用,其作用大小依次为Ni~(2+)＞Cu~(2+)＞Zn~(2+)＞Fe~(3+)＞Mg~(2+)。本次研究还提取了大气细颗粒物有机物、水溶成分和非水溶成分,每种成分分别按浓度100μg/ml、200μg/ml和400μg/ml,设为低、中、高三个浓度组对血管内皮细胞进行24h染毒,观察细颗粒物不同成分的毒性作用,进一步了解氧化应激、炎症反应、内皮功能紊乱和细胞凋亡在心血管系统损伤中的作用。结果发现细颗粒物有机提取物、水溶成分和非水溶成分使细胞存活率显著降低。细胞内活性氧族(ROS)、丙二醛(MDA)和上清液LDH/总LDH的比值均随着染毒浓度的增加而增加,而超氧化物歧化酶(SOD)及血管舒张因子NO含量却明显降低。细胞内与炎症相关基因IL-6、IL-4和TNF-α,内皮功能相关基因ET-1和TGF-β_1,凝血功能相关基因P-selectin,凋亡相关基因fas的mRNA表达随着染毒浓度的增加均明显升高,而内皮型一氧化氮合酶(eNOS)明显降低。同时发现,大气细颗粒物不同成分对血管内皮细胞的氧化损伤、炎症反应和内皮功能的作用大小依次为:水溶成分＞有机提取物＞非水溶成分,但对细胞凋亡和细胞ROS含量的影响却是有机提取物＞水溶成分＞非水溶成分。
他汀类药物能改善内皮功能,增加NO的生物活性,抑制炎性反应和调节免疫功能,并有很强的抗氧化功能,本次研究使用阿托伐他汀对细颗粒物有机提取物、水溶成分和非水溶成分致EC-304细胞的毒性进行干预,使用浓度为400μg/ml的细颗粒物有机提取物、水溶成分和非水溶成分分别对EC-304细胞进行染毒,同时加入阿托伐他汀药物进行干预,药物浓度为0μmol/L、0.1μmol/L、1μmol/L、10μmol/L,观察药物对细颗粒物不同成分氧化应激、内皮功能损伤和凋亡等毒性的干预作用。结果显示,加入阿托伐他汀后,细颗粒物不同成分染毒组的细胞内ROS、MDA和LDH较未加药组明显降低,而SOD和NO明显增加。同时,加入药物使细胞IL-6、IL-4、TNF-α、ET-1、P-selectin、fas和TGF-β_1 mRAN表达水平明显下调,使eNOS mRNA表达上调,并呈剂量-反应关系。由于他汀类药物在抗氧化损伤、减少炎症和改善内皮功能方面具有良好的药理作用,本次实验表明他汀类药物能明显减少细颗粒物暴露所致的氧化应激、炎症反应、内皮功能损伤和细胞凋亡,结果提示,细颗粒物对心血管系统的损伤是由氧化应激、炎症反应、内皮功能损伤和细胞凋亡等通路介导的。
由于大气细颗粒物对心血管系统的作用机制尚不清楚,本次研究通过动物实验和体外细胞实验研究了大气细颗粒物对心血管系统的毒性作用,并探索其可能作用机制。结果表明,自主神经功能失调、炎症反应、纤溶/凝血功能障碍、内皮功能损伤及心肌缺血和细胞凋亡是大气细颗粒物致心血管系统损伤的可能作用机制,通过他汀类药物的干预实验更进一步验证了这些损伤通路的存在。
总之,本实验从分子、细胞和动物体等不同的生物学层次进行了较为系统的细颗粒物致心血管损伤的毒理学机制的研究,取得了与人群流行病学研究相一致的结论,为今后大气细颗粒物污染的防治及有效地保护人类健康等方面提供理论依据。
Air pollution is one major pollution in perspective of public health.Air particulate matter(PM),varying in different aerodynamic diameters and generally composed of a complex of carbon,nitrogen,sulfur,biological chemicals and heavy metals,is one of the most important air pollutants.Among others,fine particles (aerodynamic diameter≤2.5μm),in comparison with coarse particles,have been considered as a more serious pollutant,due to its high deposition efficiency into human respiratory system as well as cardiovascular system.It is of major concern because of their high propensity to penetrate the epithelium and reach interstitial sites, even transportation to other organs by air exchange in human lungs,resulting in respiratory system diseases,and extrapulmonary injuries,such as in cardiovascular and immunonological system.
Epidemiological studies have shown that increases in airborne fine particle concentrations are adversely associated with cardiovascular health,but there is a lack of comprehensive studies on the effects of fine particles on cardiovascular system in toxicological perspectives,as well as the potential toxicity mechanisms.The purpose of this study is to explore the toxicological mechanisms of fine particles on cardiovascular system in respect to autonomic nervous system,inflammation, coagulation,endothelial function and cell apoptosis through animal experiment and cell culture studies.In addition,drug intervention studies by statin were performed to verify the possible toxicological mechanisms of fine particles on vein endothelial cells in vitro.
In this study,spontaneously hypertensive(SH) rats were used as a model of human cardiovascular disease and Wistar Kyoto(WKY) rats as a model of healthy human.Ambient fine particles were collected by air sampling in the urban area in Shanghai and prepared into particle solutions in different concentrations.Acute exposure to fine particle solution preparations were performed by intratracheally instillation.The SH model was exposed to a gradient of fine particle concentration in 1.6 mg/kg b.w,8.0 mg/kg b.w and 40.0 mg/kg b.w,respectively,while the control model was exposed to physiological saline.The exposure was performed once a day for three days.In 24h after the last exposure,blood pressure,heart rate and cardiogram were monitored in both types of rats,as well as the biomarkers of inflammation,coagulation,endothelial function and myocardial cells lesion in blood and cardiac muscle tissue.The results showed that blood pressure and heart rate significantly increased both in SH rats and WKY rats after exposure to fine particles with an elevation of ST segment in cardiograms.In blood samples,the levels of blood high sensitive C-response protein(hs-CRP),D-dimer and endothelin-1(ET-1) increased significantly in SHR and WKY rats in a dose-dependent manner,whereas the level of blood nitrous oxide(NO) was decreased.The serum level of myocardial enzyme MB isoenzyme of creatine kinase(CK-MB) and lactate dehydrogenase(LDH) increased both in SHR and WKY rats in a dose-dependent manner.In the cardiac muscle tissue,the mRNA expression of inflammation-related genes IL-1β,IL-6, TNF-α,MIP-2 significantly increased in rats,as well as the endothelial function-related gene ET-1 and coagulation function-related gene ICAM-1.Moreover, expression of apoptosis bax gene increased significantly in rats while the anti-apoptosis gene bcl-2 mRNA expression decreased.The latter result was consistent with the protein expression levels determined by immunohistochemical staining measurement.It was found that in rats,the protein expression of apoptosis bax gene was up-regulated while the anti-apoptosis bcl-2 gene was down-regulated. These results indicated that exposure to fine particle may cause inflammation, coagulation,endothelial dysfunction and apoptosis in rats.Finally,protein expression of transforming growth factor-beta_1(TGF-β_1) measured by the same staining method showed that the TGF-β_1 protein expression obviously increased in SH rats in comparison with WYK rats,which suggested that in the fine particle toxicity mechanisms,in addition to the endothelial dysfunction and the increase of vascular permeability,the extracellular matrix synthesis and secretion and myocardial fibrosis were potentially the additional ways of cardiovascular toxicity effects.Interestingly, when the same exposure level was performed in both SHR and WKY rats,the levels of hs-CRP,D-dimer,ET-1,LDH and CK-MB were significantly higher in SH rats than in WKY rats,which indicated that model rats with the presence of hypertension diseases could be more susceptible to fine particle exposure than normal ones.This is in agreement with the results from epidemiological studies on human population, which prove that after exposure to fine particles,higher rate of cardiopulmonary morbidity is more likely in people with cardiovascular disorders than in healthy people.
The cardiovacular effects of fine particle ion components were analyzed on human umbilical vein endothelial cells(EC-304).Particle samples were extracted for specific anion samples including SO_4~(2-),NO_3~-,Cl~-,and five metal ion samples in doses of 0.01mmol/L,0.05mmol/L,0.1mmol/L,0.5mmol/L,1.0mmol/L,5.0mmol/L and 10.0mmol/L,respectively.After exposure experiment,it was found that only NO_3~-anions could inhibit cell activity in all the above concentration levels,and all metal ions could inhibit cell activity in different inhibition rates:Ni~(2+)＞Cu~(2+)＞Zn~(2+)＞Fe~(3+)＞Mg~(2+).Furthermore,the cardiovascular effects of chemical components,such as organic extracts,soluble and insoluble components of fine particles(exposure doses: 100μg/mL,200μg/mL and 400μg/mL,respectively for 3 kinds of components) were analyzed on EC-304 cells.Malondialdehyde(MDA),LDH,reactive oxygen species (ROS) increased and NO and Superoxide dismutase(SOD) decreased in EC-304 cells for all 3 component extraction exposure.The mRNA expression of IL-4,IL-6,TNF-α, ET-1,P-selectin and fas gene increased in EC-304 exposure cells while mRNA expression of eNOS decreased.Within the 3 different components,the inhibition effects of cell activity,oxidative stress,inflammatory response were more significant in soluble extracts than in organic extracts than in insoluble extracts.However,effects of cell apoptosis and ROS level were higher in organic extracts than in soluble extracts than insoluble extracts.In summary,different components of fine particles could lead to different levels of toxicity to cells.
Statin can improve endothelial function,elevate NO biological activity,inhibit inflammation,modulate immune function and reduce oxidation in clinical studies.In this study,atorvastatin was used for intervention studies on the possible toxicological mechanisms of fine particle components on EC-304.EC-304 were exposed to the 400μg/mL organic,soluble and insoluble extracts of fine particles,respectively,followed by an intervention of astorvastatin in concentrations of 0.1μmol/L,1μmol/L and 10μmol/L.The results showed that in comparison with the group of cells with no atorvastatin addition,the levels of ROS,MDA and LDH in EC-304 cells induced by either organic extract,soluble or insoluble components of fine particles,were obviously inhibited after the addition of atorvastatin,while cell activities,SOD and NO levels in EC-304 cells increased significantly.Furthermore,the mRNA expression of IL-4,IL-6,TNF-α,ET-1,P-selectin,TGF-β_1 and fas in cells decreased greatly after treatment with atorvastatin as well,and eNOS increased significantly in a dose-dependent manner.Since atorvastatin is a clinical drug for cure of cardiovascular disorders with the known effects of reducing inflammation and improving endothelial functions,this intervention study consistently suggested that oxidative stress, inflammation,endothelial dysfunction and apoptosis were the potential mechanisms of cardiovascular injuries caused by fine particles.
In summary,this study examined the potential biological pathways triggering toxicological effects of fine particles on cardiovascular system.By methods based on animal experiment and cell culture,the results indicated that fine particles increased the risk of cardiovascular disease by increasing autonomic nervous dysfunction, oxidative stress,inflammation,coagulation,endothelial dysfunction and apoptosis. Drug intervention studies further supported the presence of the above mechanisms. These results were in consistence with the main conclusions from epidemiological studies on human population exposed to fine particles.It will contribute in further exploration of the real mechanisms by fine particle on cardiovascular diseases,and will be of importance in understanding the effects of air particulate matter on human health.
引文
1.秦纲,吕吉元.大气细颗粒物与心血管疾病研究进展.中华心血管病杂志.2008,36(2):187-189.
2.WHO air quality guidelines global update 2005,Report on a working group meeting[R].Bonn,Germany,2005,18-20.
3.UN Environment Program and WHO Report.Air pollution in the world's megacities.A Report from the U.N.Environment Programme and WHO.Environment,1994,36,5-37.
4.戴海夏,宋伟民,高翔等.上海市A城区大气PM_(10)、PM_(2.5)、污染与居民死亡数的相关分析[J].卫生研究,2004,33(3):293-297.
5.Claxton LD,Matthews PP,Warren SH.The genotoxicity of ambient outdoor air,a review:Salamonella mutagenicity[J].Mutat Res,2004,567(2-3):347-399.
6.Schwarze PE,φvrevik J,Hetland RB,et al.Importance of size and composition of particles for effects on cells in vitro[J].Inhal Toxicol.2007,19(Suppl 1):17-22.
7.KatoT,YashiroT,Murata Y,et al.Evidence that exogenous substances can be phagocytized by alveolar epithelial cells and transported into blood capillaries[J].Cell Tissue Res,2003,311(1):47-51.
8.Nemmar A,Hoet,PH,Vanquickenbome B,et al.Passage of inhaled particles into the blood circulation in humans[J].Circulation,2002,105(4),411-414.
9.Nemmar A,Vanbilloen H.,Hoylaerts MF,et al.Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster[J].Am J Respir Crit Care Med,2001,164(9),1665-1668.
10.Oberd"orster G,Sharp Z,Atudorei V,et al.Extrapulmonary translocation of ultrafine carbon particle following whole-body inhalation exposure of rats[J].J Toxicol.Environ Health A.2002,65(20),1531-1543.
11.Dockery DW,Pope CA,Xu X,et al.,An association between air pollution and mortality in six U.S.cities[J].N Engl J Med,1993,329(24):1753-1759.
12.Pope CA,Burnett RT,Thun M J,et al.Lung cancer,cardiopulmonary mortality,and long-term exposure to fine particulate air pollution[J].Jama,2002,287(9):1132-1141.
13.Katsouyanni K,Touloumi G and Samoli E.Confounding and effect modification in the short-term effects of ambient particles on total mortality:results from 29 European cities within the APHEA2 project[J].Epidemiology,2001,12(5):521-531.
14.Pope Ⅲ CA.,Bates DV,Raizerme,ME.Health effects of particulate air pollution: time for reassessment? [J]. Environ Health Perspect, 1995, 103(5), 472- 480.
15. Sarnat SE, Suh HH, Coull BA, et al. Ambient particulate air pollution and cardiac arrhythmia in a panel of older adults in Steubenville, Ohio [J].Occup Environ Med, 2006,63(10):700-706.
16. Ostro B, Feng WY, Broadwin R, et al. The effects of components of fine particulate air pollution on mortality in California: results from CALFINE [J]. Environ Health Perspect, 2007, 115(1):13-9.
17. Wellenius GA, PHN. Saldiva JRF. Batalha, et al. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction[J]. Toxicol Sci. 2002, 66:327-335.
18. Suwa T, Hogg JC, Quinlan KB, et al. Particulate air pollution induces progression of atherosclerosis[J].J Am Coll Cardiol, 2002, 39(6), 935-942.
19. Nurkiewicz TR, Porter DW, Barger M, et al. Particulate Matter Exposure Impairs Systemic Microvascular Endothelium-Dependent Dilation. Environ Health Perspect, 2004,112 (13) : 1299-1306.
20. Dominici F, McDermott A, Daniels M, et al. Revised analyses of the National Morbidity, Mortality, and Air Pollution Study: mortality among residents of 90 cities [J]. J Toxicol Environ Health A, 2005, 68(13-14):1071-92.
21. Zeller M, Giroud M, Royer C, et al. Air pollution and cardiovascular and cerebrovascular disease: Epidemiologic Data [J]. Presse Med, 2006, 35(10Pt 2): 1517-22.
22. Kodavanti UP, Schladweiler MC, Ledbetter AD, et al.The Spontaneously Hypertensive Rat as a Model of Human Cardiovascular Disease: Evidence of Exacerbate Cardiopulmonary Injury and Oxidatives Stress from Inhaled Emission Particulate Matter [J]. Toxicology and Applied Pharmacology, 2000, 164(3): 250-263.
23. Cao Q, Zhang S, Dong C, Song WM. Pulmonary responses to fine particles: differences between the spontaneously hypertensive rats and wistar kyoto rats [J].Toxicol Lett, 2007, 171 (3): 126-37.
24. Dreher KL, Jaskot H, Lehmann JR, et al. Soluble transition metals mediate residual oil fly ash induced acute lung injury [J]. J Toxicol Environ Health, 1997, 50(3):285-305.
25. Ghio AJ, Stonehuerner J, Pritchard RJ, et al. Humic-like substances in air pollution particulates correlate with concentrations of transition metals and oxidant generation [J]. Inhal Toxicol, 1996, 8:479-494.
26. Harrison RM, Yin J. Paniculate matter in the atmosphere: which particle properties are important for its effect on health? [J]. Sci Total Environ, 2000, 249(1-3):85 -101.
27. Costa DL, Dreher KL. Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models [J]. Environ Health Perspect, 1997, 105(5): 1053-1060.
28. Frampton MW, Ghio AJ, Samet JM, et al. Effects of aqueous extracts of PM_(10) filters from the Utah valley on human airway epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol, 1999,277(5 Pt 1):L960-L967.
29. Endres M. Statins and stroke [J]. J Cereb Blood Flow Metab, 2005,25(9): 1093-1110.
30. Varughese GI, Patel JV, Lip GY, et al. Novel concepts of statin therapy for cardiovascular risk reduction in hypertension [J]. Curr Pharm Des, 2006, 12(13): 1593-1609.
31. Lahera V, Goicoechea M, de Vinuesa SG, et al. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins [J]. Curr Med Chem, 2007, 14(2):243-8.
32. Zmirou D, Schwartz J, Saez M, et al. Time-series analysis of air pollution and cause-specific mortality [J]. Epidemiology, 1998, 9(5):495-503.
33. Rivero DH, Soares SR, Lofenzi-Filho G, et al. Acute cardiopulmonary alterations induced by fine particulate matter of Sao Paulo, Brazil [J]. Toxicol Sci, 2005, 85(2):898-905.
34. Campbell A, Oldham M, Becaria A, et al.Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain [J]. Neurotoxicology, 2005, 26(1):133-140.
35. Risom L, M(?)ller P, Loft S. Oxidative stress-induced DNA damage by particulate air pollution [J]. Mutat Res, 2005, 592(1-2): 119-37
36. Dockery DW, Schwartz J, Spengler JD. Air pollution and daily mortality: association with particulates and acid aerosols [J]. Environ Res, 1992, 59(2):362-373.
37. Schwartz J, Dockery DW, Neas LM. Is daily mortality associated specifically with fine particles? [J]. J Air Waste Manag Assoc, 1996, 46(10):927-939.
38. World Heart Federation web site [On-line]. Available: www.worldheart.Org /introduction.
39. Becker S, Dailey LA, Soukup JM, et al. Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress [J]. Environ Health Perspect, 2005, 113(8): 1032-8.
40.Dick CA.Singh P,Daniels M,et al.Murine pulmonary inflammatory responses following instillation of size-fractionated ambient particulate matter[J].J Toxicol Environ Health A,2003,66(23):2193-2207.
41.lbald-Mulli A,Timonen KL,Peters A,et al.Effects of particulate air pollution on blood pressure and heart rate in subjects with cardiovascular disease:a multicenter approach[J].Environ Health Perspect,2004,112(3):369-77.
42.Ulrich,M.M.,Alink,G.M.,Kumarathasan,P.,et al.Health effects and time course of particulate matter on the cardiopulmonary system in rats with lung inflammation[J].J.Toxicol Environ Health A,2002,65(20):1571-1595.
43.Julius S.Autonomic nervous system dysregulation in human hypertension[J].Am J Cardiol,1991,67(10):3B-7B.
44.Peters A,Perz S,Doring A,et al.Increases in heart rate during an air pollution episode[J].Am J Epidemiolm,1999,150(10):1094-1098.
45.Ibald-Mulli A,Stieber J,Wichmann HE,et al.Effects of air pollution on blood pressure:a population based approach[J].Am J Public Health,2001,91(4):571-577.
46.Watkinson WP,Campen M J,Casta DL.Cardiac arrhythmia induction after exposure to residual oil fly ash particles in a rodent model of pulmonary hypertension[J].Toxicol Sci,1998,41(2):209-216.
47.Gordon T,Nadziejko C,Schlesinger R,et al.Pulmonary and cardiovascular effects of acute exposure to concentrated ambient particulate matter in rats[J].Toxicol Lett,1998,96-97:285-288.
48.Watkinson WP,Campen M J,Nolan JP,et al.Cardiovascular and systemic responses to inhaled pollutants in rodents:effects of ozone and particulate matter[J].Environ Health Perspect,2001,109(suppl 4):539-546.
49.陈秉衡,周国栋,毛惠琴,等.室内空气污染及其对健康影响的研究[M].上海,上海医科大学环境卫生教研室.1987:6-22.
50.Abou Chakra OR,Joyeux M,Nerriere E,et al.Genotoxicity of organic extracts of urban airborne particulate matter:an assessment within a personal exposure study[J].Chemosphere,2007,66(7):1375-1381.
51.Gurgueira SA,Lawrence J,Coull B,et al.Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation[J].Environ Health Perspect,2002,110(8):749-755.
52.Chuen-Chau C,Jing-Shiang H,Chang-Chuan C,et al.Effects of Concentrated Ambient Particles on Heart Rate,Blood Pressure,and Cardiac Contractility in Spontaneously Hypertensive Rats[J].Inhalation Toxicology,2004,16(6-7):421-429.
53.Wichers LB,Nolan JP,Winsett DW,et al.Effects of Instilled Combustion-Derived Particles in Spontaneously Hypertensive Rats[J].Part 1:Cardiovascular Responses.Inhalation Toxicology,2004,16(6-7):391-405.
54.Bagate K,Meiring JJ,Gerlofs-Nijland ME,et al.Signal transduction pathways involved in particulate matter induced relaxation in rat aorta-spontaneous hypertensive versus Wistar Kyoto rats[J].Toxicol In Vitro,2006,20(1):52-62.
55.Bagate K,Meiring JJ,Gerlofs-Nijland ME,et al.Vascular effects of ambient particulate matter instillation in spontaneous hypertensive rats[J].Toxicol Appl Pharmacol,2004,197(1):29-39.
56.樊曙先,樊建凌,郑有飞.南京市区与郊区大气PM_(2.5)中元素的对比分析.中国环境科学,2005,25(2):146-150.
57.鲁兴,吴贤涛.北京市采暖期大气种PM_(10)和PM_(2.5)质量浓度变化分析.焦作工学院学报,2004,23(6):487-490.
58.Reyes DR,Rosario O,Rodriguez JF,et al.Toxic evaluation of organic extracts from airborne particulate matter in Puerto Rico[J].Environ Health Perspect,2000,108(7):635-40.
59.曹强.大气细颗粒物致肺损伤的易感性研究.[D]上海:复旦大学,2007.
60.Godleski JJ,Verrier RL,Koutrakis P,et al.Mechanisms of morbidity and mortality from exposure to ambient air particles[J].Res.Rep.Health Eff.Inst.2000,91:5-88.
61.Chang CC,Hwang JS,Chan CC,et al.Effects of concentrated ambient particles on heart rate,blood pressure,and cardiac contractility in spontaneously hypertensive rats [J].Inhal Toxicol,2004,16(6-7):421-429.
62.Gold DR,Litonjua AA,Zanobetti A,et al.Air pollution and ST-segment depression in elderly subjects[J].Environ Health Perspect,2005,113(7):883-7.
63.Pekkanen,J.,A.Peters,G.Hoek,et al.Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease:the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air(ULTRA) study[J].Circulation,2002,106(8):933-938.
64.Holguin F,Tellez-Rojo MM,Hernandez M,et al.Air pollution and heart rate variability among the elderly in Mexico City[J].Epidemiology.2003,14(5):521-527.
65.Magari S R,Schwartz J,Williams P L,et al.The association between personal measurements of environmental exposure to particulates and heart rate variability[J]. Epidemiology, 2002, 13(3): 305-310.
66. Liao D. Creason J, Shy C, et al. Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly[J]. Environ Health Perspect, 1999, 107(7): 521-525.
67. Gold D R, Litonjua A, Schwartz J, et al. Ambient pollution and heart rate variability[J]. Circulation, 2000, 101(11): 1267-1273.
38. Gilmour PS, Schladweiler MC, Nyska A, et al. Systemic imbalance of essential metals and cardiac gene expression in rats following acute pulmonary zinc exposure [J]. J Toxicol Environ Health A, 2006, 69(22): 2011-2032.
69. Chvapil M. Effect of zinc on cells and biomembranes [J]. Med Clin N Am, 1976, 60: 799-812.
70. Pritchard RJ, Ghio AJ, Lehmann JR, et al. Oxidant generation and lung injury after particulate air pollution exposure increase with the concentrations of associated metals [J]. Inhal Toxicol, 1996, 8: 457-477.
71. Ghil AJ. Biological effects of Utah valley ambient air partcles in humans: a review [J]. Journal of Aerosol Medicine, 2004,17(2): 157-164.
72. Fanning AS, Jameson JA, Jesaitis LA, et al. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton [J]. J Biol Chem. 1998,273(45):29745-29753.
73. Haley KJ, Lilly CM, Yang JH, et al. Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation [J]. Circulation, 2000, 102(18): 2185-2189.
74. Utell MJ, Frampton MW,Zareba W, et al. Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing [J]. Inhal Toxicol, 2002, 14(12):1231-1247.
75. Donaldson KV, Stone A, Seaton, et al. Ambient particle inhalation and the cardiovascular system: potential mechanisms. Environ [J]. Health Perspec, 2001, 109(Suppl 4):523-527.
76. Donaldson K, Tran CL. Inflammation caused by particles and fibers [J]. Inhal. Toxicol. 2002, 14(1):5-27.
77. Donaldson KV, Stone PJ, Borm, et al. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM_(10)) [J]. Free Radic Biol Med, 2003, 34(11):1369-1382.
78. Seaton A, Soutar A, Crawford V, et al. Particulate air pollution and the blood. Thorax.1999,54(11),1027-1032.
79.Mukae H,Vincent R,Quinlan K,et al.The effect of repeated exposure to particulate air pollution(PM_(10)) on the bone marrow[J].Am J Respir Crit Care Med.2001,163(1):201-209.
80.Danesh JP,Whincup M,Walker et al.Low grade inflammation and coronary heart disease:prospective study and updated meta-analyses[J].BMJ,2000,321(7255):199-204.
81.Mukae H,Hogg JC,English D,et al.Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow[J].Am J Physiol Lung Cell MolPhysiol,2000,279(5),L924-L931.
82.Blake G J,Ridker PM.Inflammatory bio-markers and cardiovascular risk prediction [J].J.Intern Med,2002,252(2),283-294.
83.Li J J,Fang CH.C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular disease[J].Med Hypotheses,2004,62(4):499-506.
84.Backes JM,HowardPA,et al.Role of C-reactive protein in cardiovascular disease[J].Ann Pharmacother,2004,38(1):110-118.
85.杨胜利,何秉贤.C反应蛋白和冠心病.中华心血管病杂志,200l,29(3):187-188.
86.Koenig WM,Sund M,Frohlich,et al.C-Reactive protein,a sensitive marker of inflammation,predicts future risk of coronary heart disease in initially healthy middle-aged men:results from the MONICA(Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study.1984 to 1992[J].Circulation.1999.99:237-242.
87.Peters A,Wichmann HE,Koenig W.Air pollution exposure influences cardiovascular risk factors:a link to mortality?.In Proc Int Inhal Symp Hanover,Germany.1999.
88.Pope CA,Hansen ML,Long RW,et al.Ambient particulate air pollution,heart rate variability,and blood markers of inflammation in a panel of elderly subjects.Environ.Health Perspect.2004,112(3):339-345.
89.Committee on Care and Use of Spontaneously Hypertensive(SHR) Rats(1976).Spontaneously hypertensive(SHR) rats:Guidelines for breeding,care,and use.ILAR News ⅩⅨ(3),G1-G20.
90.Derhaschnig U,Shehata M,Herkner H,et al.Increased levels of transforming growth factor-betal in essential hypertension[J].Am J Hypertens,2002,15(3):207-11.
91. Wang Y, Thorlacius H. Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice [J]. Br J Pharmacol, 2005, 145(8): 1062-1068.
92. Nageswara R, Madamanchi, Aleksandr Vendrov, et al. Oxidative Stress and Vascular Disease [J]. Arterioscler Thromb Vasc Biol, 2005, 25:29-38.
93. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management [J]. J. Am. Med. Assoc, 2002, 287(19):2570-2581.
94. Tao F, Gonzalez-Flecha B, Kobzik L. Reactive oxygen species in pulmonary inflammation by ambient particulates [J]. Free Radical Biol Med, 2003, 35,327-340.
95. Knaapen AM, Shi T, Borm PJA, et al. Soluble metals as well as the insoluble particle fraction are involved in cellular DNA damage induced by particulate matter [J]. Mol Cell Biochem, 2002, 234/235(1-2):317-326.
96. Sorensen M, Schins RPF, Hertel O, et al. Transition metals in personal samples of PM_(2.5) and oxidative stress in human volunteers [J]. Cancer Epidemiol Biomarkers Prev,2005, 14(5):1340-1343.
97. Prahalad AK, Soukup JM, Inmon J, et al. Ambient air particles: effects on cellular oxidant radical generation in relation to particulate elemental chemistry [J]. Toxicol. Appl. Pharmacol, 1999, 158(2), 81-91
98. Clarke RW, Coull B, Reinisch U, et al. Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines [J]. Environ. Health Perspect, 2000, 108(12): 1179-1187.
99. Gutierrez-Castillo ME, Roubicek DA, Cebrian-Garcia ME, et al. Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter [J].Environ Mol Mutagen, 2006,47(3): 199-211.
100. Gurgueira SA, Lawrence J, Coull B, et al. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation [J]. Environ Health Perspect, 2002, 110(8), 749- 755.
101. Wilson MR, Lightbody JH, Donaldson K, et al. Interactions between ultrafine particles and transition metals in vivo and in vitro [J]. Toxicol Appl Pharmacol, 2002, 184(3): 172-179.
102. Molinelli AR, Madden MC, McGee JK, et al. Effect of metal removal on the toxicity of airborne particulate matter from the Utah Valley [J]. Inhal Toxicol, 2002, 14(10): 1069-86.
103. Claxton LD, Matthews PP, Warren SH. The genotoxicity of ambient outdoor air, a review: Salamonella mutagenicity [J]. Mutat Res, 2004, 567(2-3):347-399.
104. Healey K, Lingard JJ, Tomlin AS, et al. Genotoxicity of size-fractionated samples of urban particulate matter [J]. Environ Mol Mutagen, 2005,45(4):380-387.
105. Matsuki T, Duling BR. TNF-alpha modulates arteriolar reactivity secondary to a change in intimal permeability [J]. Microcirculation, 2000, 7(6 Pt 1):411-418.
106. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s [J]. Nature, 1993,362(6423):801-9.
107. Farmer JA, Torre-Amione G. Atherosclerosis and inflammation [J]. Curr Atheroscler Rep, 2002,4:92-98.
108. Guzik TJ., Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation [J]. J Physiol Pharmacol, 2003, 54(4):469-487.
109. Packer R, Bergler-Klein J, Globits S, et al. Plasma big endothelin-1 concentrations in or congestive heart failure patients with or without systemic hypertension. Am J Cardiol, 1993,71(15), 1293-1299.
110. Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis [J]. N Engl J Med, 1991, 325(14):997-1001.
111. Bouthillier L, Vincent R, Goegan P, et al. Acute effects of inhaled urban particles and ozone: lung morphology, macrophage activity, and plasma endothelin-1 [J]. Am. J. Pathol, 1998, 153(6): 1873-1884.
112. Vincent R, Kumarathasan P, Goegan P, et al. Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats. Res Rep Health Eff Inst. 2001, 104:5-54.
113. O'Neill MS, Veves A, Zanobetti A, et al. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function [J]. Circulation, 2005, 111(22):2913-2920.
114. Lei YC, Hwang JS, Chan CC, et al. Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles [J]. Environ Res, 2005, 99(3):335-43.
115. Koenig WM. Sund B. Filipiak, et al. Plasma viscosity and the risk of coronary heart disease: Results from the MONICA-Augsburg cohort study, 1984 to 1992 [J]. Arterioscler Thromb Vasc Biol, 1998,18(5): 768-772.
116. Seaton A, MacNee W, Donaldon K, et al. Particulate air pollution and acute health effects [J]. Lancet, 1995, 345(8943), 176-178.
117. Brauner EV, Forchhammer L, M(?)ller P, et al. Indoor particles affect vascular function in the aged: an air filtration-based intervention study. Am J Respir Crit Care Med. 2008 ,177(4):419-25.
118. Peters A, A Doring HE, Wichmann, et al. Increased plasma viscosity during the 1985 air pollution episode: a link to mortality? [J], Lancet, 1997, 349(9065): 1582-1587.
119. Pekkanen J, Brunner EJ, Anderson HR, et al. Daily concentrations of air pollution and plasma fibrinogen in London [J]. Occup Environ Med, 2000, 57(12):818-822.
120. Huang YC, Ghio AJ, Stonehuerner J, et al. The role of soluble components in ambient fine particles- induced changes in human lungs and blood [J]. Inhal Toxicol, 2003, 15(4):327-342.
121. Salvi S., A. Blomberg B. Rudell, et al. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers [J]. Am J Respir Crit Care Med, 1999, 159(3):702-709.
122. Andrej Khandoga MD,Andreas Stampfl MSc, Shinji Takenaka DVM,et al.Ultrafme particles exert prothrombotic but not inflammatory effects on the hepatic microcirculation in healthy mice In vivo [J]. Circulation, 2004, J 09:1320-1325.
123. Alfaro-Moreno E, Lopez-Marure R. Montiel-Davalos A, et al. E-Selectin expression in human endothelial cells exposed to PM10: the role of endotoxin and insoluble fraction [J].Environ Res, 2007,103(2):221-8.
124. Gilmour PS, Ziesenis A, Morrison ER, et al.Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles. Toxicol Appl Pharmacol, 2004,195(1):35-44.
125. Goldsmith IR, Blann AD, Patel RL, et al. Plasma fibrinogen, soluble P-selectin, and von Willebrand factor in aortic valve disease: evidence for abnormal haemorheology, platelet activation, and endothelial dysfunction [J]. Heart, 2000 , 83(5):577-8.
126. Massberg S, Enders G, Leiderer R, et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin [J]. Blood, 1998 , 92(2):507-15.
127. Behzadian MA, Wang XL, Al-Shabrawey M, et al. Effects of hypoxia on glial cell expression of angiogenesis-regulating factors VEGF and TGF-beta [J]. Glia, 1998 , 24(2):216-25.
128. Behzadian MA, Wang XL, Windsor LJ, et al. TGF-beta increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function [J]. Invest Ophthalmol Vis Sci, 2001, 42(3):853-9.
129. Zhu Y, Culmsee C, Klumpp S, et al. Neuroprotection by transforming growth factor-betal involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways [J].Neuroscience, 2004, 123(4):897-906.
130. Ikedo H, Tamaki K, Ueda S, et al. Smad protein and TGF-beta signaling in vascular smooth muscle cells [J]. Int J Mol Med, 2003, 11(5):645-50.
131. Harbord M, Novelli M, Canas B, et al. Yml is a neutrophil granule protein that crystallizes in p47phox-deficient mice [J]. J Biol Chem, 2002, 277: 5468-5475.
132. Cruzado MC, Risler NR, Miatello RM, et al. Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: Effect of angiotensin II and role of insulinlike growth factor-1 receptor transactivation [J]. Am J Hypertens, 2005, 18(1):81-7.
133. Fukuda N, Hu WY, Kubo A, et al. Abnormal regulation of transforming Growth factor-preceptor on vascular smooth muscle cell from Spontaneously hypertension rats by AngII [J]. Hypertension, 1998, 31:672- 677.
134. von Klot S, Peters A, Aalto P, et al. Health Effects of Particles on Susceptible Subpopulations (HEAPSS) Study Group.Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities [J]. Circulation, 2005, 112(20):3073-9.
135. Zanobetti A, Schwartz J. The effect of particulate air pollution on emergency admissions for myocardial infarction: a multicity case-crossover analysis [J]. Environ Health Perspect, 2005, 113(8):978-982.
136. Sullivan J, Sheppard L, Schreuder A, et al. Relation between short-term fine-particulate matter exposure and onset of myocardial infarction [J]. Epidemiology, 2005, 16(1):41-48.
137. Karacalioglu O, Arslan Z, Kilic S, et al. Baseline serum levels of cardiac biomarkers in patients with stable coronary artery disease [J]. Biomarkers, 2007, 12(5):533-40.
138. Reed JC.Double identity for proteins of the bcl-2 family [J], Nature, 1997, 387(6635):773-776.
139. Strasser A, Connor LO, Dixit VM. Apoptosis signaling [J]. Annu Rev Biochem, 2000, 69,217-245.
140. Reed JC. bcl-2 and the regulation of programmed cell death. J. Cell Biol, 1994, 124(1-2), 1-6.
141.Hockenbery D,Nunez G,Miiliman C,et al.bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death[J].Nature,1990,348(6299):334-336.
142.Sato T,Hanada M,Bodrug S,et al.Interactions among members of the bcl-2 protein family analyzed with a yeast two-hybrid system[J].Proc Natl Acad Sci,1994,91(20):9238-9242.
143.Yin XM,Oltvai ZN,Korsmeyer SJ.bhl and bh2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax[J].Nature,1994,369(3478):321-333.
144.Bai J,Meng Z.Expression of apoptosis-related genes in livers from rats exposed to sulfur dioxide[J].Toxicology,2005,216(2-3):253-60.
145.Diez J,Panizo A,Hemandez M,et al.Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats?[J].Hypertension,1997,29(3):776-780.
146.钱华,伏晴艳,马伯文.上海市环境空气中多坏芳烃与苯并[a]芘的监测分析[J].上海环境科学,2003,22(11):779-784.
147.Gutierrez-Castillo ME,Roubicek DA,Cebrian-Garcia ME,et al.Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter [J].Environ Mol Mutagen,2006,47(3):199-211.
148.Steinert SA.Contribution ofapoptosis to observed DNA damage in muscle cells[J].Mar.Environ.Res.1996,42:253-259.
149.Dorszewska,J.,Adamczewska-Goncerzewicz,Z.Oxidative damage to DNA,p53gene expression and p53 protein level in the process of aging in rat brain[J].Res.Physiol Neurobiol,2004,139(3):227-236.
150.Chandra J.,Samali A.,Orrenius S.Triggering and modulation of apoptosis by oxidative stress[J].Free Radical Biol.Med,2000,29(3-4),323-333.
151.Freeman BA,Grapo JD.Biology of disease:free radical and tissue injury[J].Lab.Invest.1982,47(5),412-426.
152.Varughese GI,Patel JV,Lip GY,et al.Novel concepts of statin therapy for cardiovascular risk reduction in hypertension[J].Curr Pharm Des,2006,12(13):1593-609.
153.Elrod JW,Lefer DJ.The effects of statins on endothelium,inflammation and cardioprotection.Timely Top Med Cardiovasc Dis.2005 Aug 1;9:E20.
154.Piconi L.Corgnali M,Da Ros R,et al.The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose[J].J Diabetes Complications,2008,22(1):38-45.
155.Schupp N,Schmid U,Heidland A,et al.Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis.Atherosclerosis.2007.
156.朱鸣雷.他汀类药物在炎性刺激下对脐静脉血管内皮细胞炎性相关分析表达的影响.[D].北京:中国协和医科大学.2002.
157.Omi H,Okayama N,Shimizu M,et al.Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide [J].Microvasc Res,2003,65(2):118-24
158.Okouchi M,Okayama N,Omi H,et al.Cerivastatin ameliorates high insulin-enhanced neutrophil-endothelial cell adhesion and endothelial intercellular adhesion molecule-1expression by inhibiting mitogen-activated protein kinase activation[J].J Diabetes Complications,2003,17(6):380.
159.Bellosta S,Ferri N,Arnaboldi L,et al.Pleiotropic effects of statins in atherosclerosis and diabetes.Diabetes Care.2000,23(Suppl 2):B72-8.
160.Yamakawa T,Tanaka S,Kamei J,et al.Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2[J].J Atheroscler Thromb,2003,10(1):37-42.
161.Endres M.Statins:potential new indications in inflammatory conditions[J].Atheroscler Suppl,2006,7(1):31-5.
162.Kishi T,Hirooka Y,Shimokawa H,et al.Clin Exp Hypertens.Atorvastatin reduces oxidative stress in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats[J].Clinical and Experimental Hypertension,2008,30(1):3-11.
163.Chang LT,Sun CK,Chiang CH,et al.Impact of simvastatin and losartan on antiinflammatory effect:in vitro study[J].J Cardiovasc Pharmacol,2007,49(1):20-6.
164.Martinez-Sales V,Vila V,Ferrando M,et al.Atorvastatin neutralizes the up-regulation of thrombospondin-I induced by thrombin in human umbilical vein endothelial cells[J].Endothelium,2007,14(4-5):233-8.
165.Soehnlein O,Eskafi S,Schmeisser A,Kloos H,Daniel WG,Garlichs CD.Atorvastatin induces tissue transglutaminase in human endothelial cells[J].Biochem Biophys Res Commun,2004,322(1):105-9.
166.Ungureanu D,Filip C,Artenie A,Artenie R.Evaluation of simvastatin antioxidant effects[J].Rev Med Chir Soc Med Nat lasi,2003,107(1):66-71.
167.Christ M,Bauersachs J,Liebetrau C,et al.Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation:attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin[J].Diabetes,2002,51(8):2648-52.
168.Wang HR,Li J J,Huang CX,et al.Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein[J].Clin Chim Acta,2005,353(1-2):53-60.
169.Li J-J,Fang C-H,Chen M-Z,et al.Rapid effects on lipid profile and C-reactive protein by simvastatin in patients with hypercholesterolemia[J].Clin Cardiol,2003,26(10):472-476.
170.Li J-J,Fang C-H.Effect of a single high-dose of simvastatin on C-reactive protein in patients with unstable angina.Heart Drug,2004,5:140-145.
171.Wolfrum S,Jensen K,Liao J.Endothelial-dependent effects of statins[J].Arterioscler Thromb Vasc Biol,2003,23(5):729-736.
172.Cooke JP.Therapeutic intervention in endothelial dysfunction:endothelium as a target organ.Clin Cardiol.1997,20:1145-1151.
173.Bonetti PO,Lerman LO,Lerman A.Endothelial dysfunction:A marker of atherosclerotic risk[J].Arterioscler Thromb Vasc Biol,2003,23(2):168-175.
174.Behzadian MA,Wang XL,Windsor L J,et al.TGF-beta increases retinal endothelial cell permeability by increasing MMP-9:possible role of glial cells in endothelial barrier function[J].Invest Ophthalmol Vis Sci,2001,42(3):853-9.
175.张静静,刘廷,王易强,董晓光.转化生长因子β_1对内皮细胞屏障功能的影响.齐鲁医学杂志,2007,22(4):297-300.
176.Thurberg BL,Collins T.The nuclear factor-kappa B/inhibitor of kappa B autoregulatory system and atherosclerosis[J].Curr Opin Lipidol,1998,9(5):387-96.
177.Tokoro,T.,Wang,J.,Kitajima,I.The novel HMG-CoA reductase inhibitor,pitavastatin,induces a protective action in vascular endothelial cells through the production of nitric oxide(NO)[J].Yakugaku Zasshi,2004,124:121-126.
178.Lefer AM,Campbell B,Shin YK,et al.Simvastatin preserves the ischemicreperfused myocardium in normocholesterolemic rat hearts[J].Circulation,1999,100(2):178-184.
179.Mooradian AD,Haas M J,Batejko O,et al.Statins ameliorate endothelial barrier permeability changes in the cerebral tissue of streptozotocin-induced diabetic rats[J].Diabetes,2005,54(10):2977-2982.
180.Takemoto M,Liao JK.Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors[J].Arterioscler Thromb Vasc Biol.2001,21(11):1712-1719.
181.Hasegawa H,Yamamoto R,Takano H,et al.3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats[J].J Mol Cell Cardiol,2003,35(8):953-60.
1.Ostro B,Feng WY,Broadwin R,et al.The effects of components of fine particulate air pollution on mortality in califomia:results from CALFINE[J].Environ Health Perspect,2007,115(1):13-9.
2.Kan H,London S J,Chen G,Zhang Y,et al.Differentiating the effects of fine and coarse particles on daily mortality in Shanghai,China[J].Environ Int.2007,33(3):376-84.
3.Pope Ⅲ CA,Bumett RT.,Thun MJ,et al.Lung cancer,cardiopulmonary mortality,and long-term exposure to fine particulate air pollution[J].JAMA,2002,287:1132-1141.
4.Goldberg MS,Bumett RT,Bailar JC Ⅲ,et al.Identification of persons with cardiorespiratory conditions who are at risk of dying from the acute effects of ambient air particles[J].Environ Health Perspect,2001,109(suppl 4):487-494.
5.Samet JM,Dominici F,Curriero FC,et al.Fine particulate air pollution and mortality in 20 U.S.cities,1987-1994[J].N Engl J Med,2000,343(16):1742-1749.
6.Dominici F,McDermott A,Daniels M,et al.Revised analyses of the National Morbidity,Mortality,and Air Pollution Study:mortality among residents of 90 cities [J].J Toxicol Environ Health A,2005,68(13-14):1071-92.
7.Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies:part Ⅰ[J].Circulation,2003,108(15):1664-1672.
8.Schwartz J,Dockery D W,Neas L M.Is daily mortality associated specifically with fine particles? J Air Waste Manag Assoc[J].1996,46(10):927-939.
9.Barnett AG,Williams GM,Schwartz J,et al.The effects of air pollution on hospitalizations for cardiovascular disease in elderly people in Australian and New Zealand cities[J].Environ Health Perspect,2006,114(7):1018-23.
10.Braga AL,Zanobetti A,Schwartz J.The lag structure between particulate air pollution and respiratory and cardiovascular deaths in 10 US cities [J]. Occup. Environ. Med, 2001, 43(11): 927-933.
11. Harrison RM, Yin J. Particulate matter in the atmosphere:which particle properties are important for its effect on health? [J]. Sci Total Environ, 2000, 249(1-3):85 -101.
12. de Hartog JJ, Hoek G, Peters A, et al. Effects of fine and ultrafine particles on cardiorespiratory symptoms in elderly subjects with coronary heart disease [J]. American Journal of Epidemiology, 2003, 157(7):613-623.
13. Gilmour PS, Ziesenis A, Morrison ER, et al. Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles [J]. Toxicol Appl Pharmacol, 2004,195(1):35-44.
14. Singh S, Shi T, Duffin R, et al. Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles [J]. Toxicol Appl Pharmacol, 2007,222(2): 141-51..
15. Karoly ED, Li Z, Dailey LA, et al.Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure [J]. Environ Health Perspect,2007, 115(4):535-40.
16. Kodavanti UP., Moyer CF., Ledbetter AD., er al. Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat [J]. Toxicol Sci, 2003,71(2):237-245.
17. Zhang Q.W., Kusaka Y., Zhu X.Q., et al. Comparative toxicity of standard nickel and ultrafine nickel in lung after intratracheal instillation [J]. Occ Health, 2003, 45(1): 23-30.
18. Nemmar A, Hoet PHM, Vanquickenborne B, et al. Passage of inhaled particles into the blood circulation in humans [J]. Circulation, 2002,105(4): 411-414.
19. Nemmar A, Vanbilloen H, Hoylaerts MF, et al. Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster [J]. Am J Respir Crit Care Med, 2001,164(9): 1665-1668.
20. Oberdorster G, Sharp Z, Atudorei V, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats [J]. J Toxicol Environ Health A, 2002, 65(20): 1531-1543.
21. Suwa T, Hogg JC, Quinlan, K.B, et al. Particulate air pollution induces progression of atherosclerosis [J]. Am. Coll. Cardiol, 2002, 39(6):935-942.
22. Nurkiewicz TR, Porter DW, Barger M, et al. Particulate Matter Exposure Impairs Systemic Microvascular Endothelium-Dependent Dilation.2004,112(13): 1299-1306.
23. Kreyling W., Semmler M., Erbe F, et al. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low [J]. Toxicol Environ. Health A, 2002, 65(20): 1513-1530.
24. Donaldson K, Stone V, Seaton A, et al. Ambient particle inhalation and the cardiovascular system: potential mechanisms [J]. Environ Health Perspect, 2001, 109(suppl 4):523-527.
25. Elder AC, Gelein R, Azadniv M, et al.Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains [J]. Inhal Toxicol, 2004, 16(6-7):461-71.
26. Gerlofs-Nijland ME, Boere AJ, Leseman DL, et al. Effects of particulate matter on the pulmonary and vascular system: time course in spontaneously hypertensive rats [J]. Part Fibre Toxicol, 2005,2(1):2.
27. Rivero DH, Soares SR, Lorenzi-Filho G, et al. Acute cardiopulmonary alterations induced by fine particulate matter of Sao Paulo, Brazil [J]. Toxicol Sci. 2005, 85(2):898-905.
28. Haley K.J., Lilly C.M., Yang J.H., et al. Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation [J]. Circulation, 2000, 102(18):2185- 2189.
29. van Eeden SF, Hogg JC. Systemic inflammatory response induced by particulate matter air pollution: the importance of bone-marrow stimulation [J]. J Toxicol Environ Health A, 2002,65(20): 1597-613.
30. Riediker M, Devlin RB, Griggs TR, et al. Cardiovascular effects in patrol officers are associated with fine particulate matter from brake wear and engine emissions [J].Part Fibre Toxicol, 2004, 1(1):2.
31. Pope CA, Hansen ML, Long RW, et al. Ambient particulate air pollution, heart rate variability, and blood markers of inflammation in a panel of elderly subjects.Environ Health Perspect [J]. 2004, 112(3):339-45.
32. Driscoll KE, Simpson L, Carter J, et al. Ozone inhalation stimulates expression of a neutrophil chemotactic protein, macrophage inflammatory protein 2[J]. Toxicol Appl Pharmacol. 1993, 119(2): 306-309.
33. Kodavanti UP, Schladweiler MC, Richards JR,et al. Acute lung injury from intratracheal exposure to fugitive residual oil fly ash and its constituent metals in normo- and spontaneously hypertensive rats. Inhal Toxicol. 2001, 13(1):37-54.
34. Kodavanti UP, Jaskot RH, Costa DL, et al: Pulmonary proinflammatory gene induction following acute exposure to residual oil fly ash: roles of particle associated metals [J]. Inhal Toxicol .1997, 9:679-701.
35. Kodavanti UP,Schladweiler MC,Ledbetter AD, et al. The spontaneously hypertensive rat as a model of human cardiovascular disease:evidence of exacerbated cardiopulmonary injury and oxidative stress from inhaled emission particulate matter [J]. Toxicol Appl Pharmacol, 2000, 164(3):250-63.
36. Nadadur SS, Kodavanti UP. Altered gene expression profiles of rat lung in response to an emission particulate and its metal constituents [J].J Toxicol Environ Health A. 2002, 65(18): 1333-50.
37. Adamson IY, Prieditis H, Vincent R. Soluble and insoluble air particle fractions induce differential production of tumor necrosis factor alpha in rat lung [J].Exp Lung Res, 2004,30(5):355-68.
38. Shaw CA,Taylor EL,Megson IL,et al. Nitric oxide and the resolution of inflammation: implications for atherosclerosis[J]. Mem Inst Oswaldo Cruz, 2005,100:67
39. Hirano S, Furuyama A, Koike E, et al. Oxidative-stress potency of organic extracts of diesel exhaust and urban fine particles in rat heart microvessel endothelial cells [J]. Toxicology, 2003,187(2-3): 161-70.
40. Brauner EV, Forchhammer L, M(?)ller P, et al. Indoor particles affect vascular function in the aged: an air filtration-based intervention study [J]. Am J Respir Crit Care Med, 2008, 177(4):419-25.
41. Heart rate variability standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [J].Circulation, 1996, 93(5): 1043 -1065.
42. Devlin RB, Ghio AL Kelhd H, et al. Elderly humans exposed to Concentrated air polution particles have decreased heart rate variability [J]. Eur respair j,2003,21: 69,76-80
43. Chen LC, Hwang JS. Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice IV, Characterization of acute and chronic effects of ambient air fine particulate matter exposures on heart-rate variability [J]. Inhal Toxicol 2005, 17(4-5):209-216.
44. Wichers LB, Nolan JP, Winsett DW, et al. Effects of instilled combustion-derived particles in spontaneously hypertensive rats [J] . Part I: Cardiovascular responses. Inhal Toxicol, 2004, 16(6-7):391-405.
45. Bagate K, Meiring JJ, Gerlofs-Nijland ME, et al.Vascular effects of ambient particulate matter instillation in spontaneous hypertensive rats [J]. Toxicol Appl Pharmacol, 2004, 197(1):29-39.
46. Mills NL, Tornqvist H, Gonzalez MC, et al. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease [J].N Engl J Med. 2007 ,357(11): 1075-82.
47. Peters A, Liu E, Verrier RL, et al. Air pollution and incidence of cardiac arrhythmia [J]. Epidemiology, 2000, 11(1): 11-17.
48. Schulz H. Fine particulate matter-a health hazard for lungs and other organs? [J] Pneumologie, 2006, 60(10):611-5.
49. Wellenius GA, Saldiva PH, Batalha JR, et al. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction [J]. Toxicol Sci, 2002, 66(2): 327- 335.
50. Wang B, Feng WY, Wang M, et al.Transport of intranasally instilled fine Fe_2O_3 particles into the brain: micro-distribution, chemical states, and histopathological observation [J]. Biol Trace Elem Res, 2007,118(3):233-43.
51. Campbell A, Oldham M, Becaria A, et al. Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain [J]. Neurotoxicology, 2005, 26(1):133-40.
52. UN Environment Program and WHO Report. Air pollution in the world's megacities. A Report from the U.N. Environment Programme and WHO. Environment, 1994, 36, 5-37.
53. Bell ML, Samet JM, Dominici F: Time-series studies of particulate matter [J]. Annu Rev Public Health, 2004,25:247-280.
54. Sorensen M, Daneshvar B, Hansen M, et al. Personal PM2.5 exposure and markers of oxidative stress in blood [J]. Environ Health Perspect, 2003, 111 (2): 161—166.
1.Stoll LL,McCormick ML,Denning GM,et al.Antioxidant effects of statins[J].Drugs Today(Barc) 2004,40(12):975-90.
2.Lauts V,La Fata V,PlutzkyJ,et al.Upregulation of endothelial nitric Oxide synthase by HMG CoS reductase inhibitors[J].Greulation.1998,97(5):1129-1135.
3.Bates K,Ruggeroli CE,Goldman S,Gaballa MA.Simvastatin restores endothelial NO-mediated vasorelaxation in large arteries after myocardial infarction[J].Am J Physiol Heart Circ Physiol,2002,283(2):H768-775.
4.Wei CM,Lerman A,Rodeheffer RJ,et al.Endothelin in human congestive heart failure[J].Circulation,1994,89(4):1580-6.
5.Seljeflot I,Tonstad S,Hjermann I,Amesen H.Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease[J].Atherosclerosis,2002,162(1):179-85.
6.Hemandez-Perera O,Perez-Sala D,Navarro-Antolin J,et al.Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors,atorvastatin and simvastatin,on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells[J].J Clin Invest 1998,101(12):2711-2719.
7.Aukrust P,Ueland T,Muller F,et al.Elevated circulating levels ofC-C chemokines in patients with congestive heart failure[J].Circulation,1998,97(12):1136-43.
8.Christ M,Bauersachs J,Liebetrau C,et al.Glucose increases endothelial- dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation:attenuation by the 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor atorvastatin[J].Diabetes,2002,51:2648-2652.
9.Wassmann S,Laufs U,Muller K,et al.Cellular antioxidant effects of atorvastatin in vitro and in vivo[J].Arterioscler Thromb Vasc Biol,2002,22(2):300-5.
10.Carneado J,Alvarez de Sotomayor M,Perez-Guerrero C,et al.Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect [J]. J Hypertens, 2002, 20(3):429-37.
11. Grosser N, Erdmann K, Hemmerle A, et al. Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1 [J]. Biochem Biophys Res Commun, 2004, 325(3):871-6.
12. Hsu M, Muchova L, Morioka I, et al. Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo [J]. Biochem Biophys Res Commun, 2006, 343(3):738-744.
13. Berton G, Cordiano R, Palmieri R, Pianca S, Pagliara V, Palatini P. C-reactive protein in acute myocardial infarction: association with heart failure [J]. Am Heart J, 2003, 145(6): 1094-1101.
14. Blanco-Colio LM, Tunon J, Martin-Ventura JL, et al. Antiinflammatory and immunomodulatory effects of statins [J]. Kidney Int, 2003, 63(1): 12-23.
15. Hasegawa H, Yamamoto R, Takano H, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats [J]. J Mol Cell Cardiol, 2003, 35(8):953-60.
16. Wang HR, Li JJ, Huang CX, Jiang H. Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein [J]. Clin Chim Acta, 2005, 353(1-2):53-60.
17. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future [J]. Circ Res, 2002,91(11):988-98.
18. Namazi MR. Decreasing the expression of LFA-1 and ICAM-1 as well as hindering their interaction as the major mechanism for statin-induced neutrophil dysfunction [J]. Ann Thorac Surg, 2007, 84(6):2137-8.
19. Kimura M, Kurose I, Russell J, et al. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats [J]. Arterioscler Thromb Vasc Biol, 1997, 17(8): 1521-6.
20. Niwa S, Totsuka T, Hayashi S. Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line [J]. Int J Immunopharmacol, 1996, 18(11):669-75.
21. Serebruany VL, Murugesan SR, Pothula A, et al. Increased soluble platelet/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy [J]. Eur J Heart Fail, 1999, 1(3):243-9.
22.Amoroso G,van Veldhuisen DJ Tio RA,et al.Pathophysiology of vascular endothelium and circulating platelets:implications for coronary revascularization and treatment[J].Int J Cardiol,2001,79(3).265-275.
23.Joukhadar C,Klein N,Prinz M,et al.Similar effects of atorvastatin,simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia[J].Thromb Haemost,2001,85(1):47-51
24.Schafer A,Fraccarollo D,Eigenthaler M,et al.Rosuvastatin reduces platelet activation in heart failure:role of NO bioavailability[J].Arterioscler Thromb Vasc Biol,2005,25(5):1071-7.
25.Tousoulis D,Antoniades C,Bosinakou E,et al.Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure[J].Heart,2005,91(1):27-31.
26.徐成斌.冠心病防治在调脂领域.的某些进展与动向.心血管病学进展,2002,23(1):1-5.
27.Node K,Fujita M,Kitakaze M,et al.Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy[J].Circulation,2003,108(7):839-43.
28.Bellosta S,Via D,Canavesi M,et al.HMG-CoA reductase inhibitors reduce MMP-9secretion by macrophages[J].Arterioscler Thromb Vasc Biol,1998,18(11):1671-1678.
29.Rossig L,Haendeler J,Mallat Z,et al.Congestive heart failure induces endothelial cell apoptosis:protective role of carvedilol[J].J Am Coil Cardiol,2000,36(7):2081-9.
2.WHO air quality guidelines global update 2005,Report on a working group meeting[R].Bonn,Germany,2005,18-20.
3.UN Environment Program and WHO Report.Air pollution in the world's megacities.A Report from the U.N.Environment Programme and WHO.Environment,1994,36,5-37.
4.戴海夏,宋伟民,高翔等.上海市A城区大气PM_(10)、PM_(2.5)、污染与居民死亡数的相关分析[J].卫生研究,2004,33(3):293-297.
5.Claxton LD,Matthews PP,Warren SH.The genotoxicity of ambient outdoor air,a review:Salamonella mutagenicity[J].Mutat Res,2004,567(2-3):347-399.
6.Schwarze PE,φvrevik J,Hetland RB,et al.Importance of size and composition of particles for effects on cells in vitro[J].Inhal Toxicol.2007,19(Suppl 1):17-22.
7.KatoT,YashiroT,Murata Y,et al.Evidence that exogenous substances can be phagocytized by alveolar epithelial cells and transported into blood capillaries[J].Cell Tissue Res,2003,311(1):47-51.
8.Nemmar A,Hoet,PH,Vanquickenbome B,et al.Passage of inhaled particles into the blood circulation in humans[J].Circulation,2002,105(4),411-414.
9.Nemmar A,Vanbilloen H.,Hoylaerts MF,et al.Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster[J].Am J Respir Crit Care Med,2001,164(9),1665-1668.
10.Oberd"orster G,Sharp Z,Atudorei V,et al.Extrapulmonary translocation of ultrafine carbon particle following whole-body inhalation exposure of rats[J].J Toxicol.Environ Health A.2002,65(20),1531-1543.
11.Dockery DW,Pope CA,Xu X,et al.,An association between air pollution and mortality in six U.S.cities[J].N Engl J Med,1993,329(24):1753-1759.
12.Pope CA,Burnett RT,Thun M J,et al.Lung cancer,cardiopulmonary mortality,and long-term exposure to fine particulate air pollution[J].Jama,2002,287(9):1132-1141.
13.Katsouyanni K,Touloumi G and Samoli E.Confounding and effect modification in the short-term effects of ambient particles on total mortality:results from 29 European cities within the APHEA2 project[J].Epidemiology,2001,12(5):521-531.
14.Pope Ⅲ CA.,Bates DV,Raizerme,ME.Health effects of particulate air pollution: time for reassessment? [J]. Environ Health Perspect, 1995, 103(5), 472- 480.
15. Sarnat SE, Suh HH, Coull BA, et al. Ambient particulate air pollution and cardiac arrhythmia in a panel of older adults in Steubenville, Ohio [J].Occup Environ Med, 2006,63(10):700-706.
16. Ostro B, Feng WY, Broadwin R, et al. The effects of components of fine particulate air pollution on mortality in California: results from CALFINE [J]. Environ Health Perspect, 2007, 115(1):13-9.
17. Wellenius GA, PHN. Saldiva JRF. Batalha, et al. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction[J]. Toxicol Sci. 2002, 66:327-335.
18. Suwa T, Hogg JC, Quinlan KB, et al. Particulate air pollution induces progression of atherosclerosis[J].J Am Coll Cardiol, 2002, 39(6), 935-942.
19. Nurkiewicz TR, Porter DW, Barger M, et al. Particulate Matter Exposure Impairs Systemic Microvascular Endothelium-Dependent Dilation. Environ Health Perspect, 2004,112 (13) : 1299-1306.
20. Dominici F, McDermott A, Daniels M, et al. Revised analyses of the National Morbidity, Mortality, and Air Pollution Study: mortality among residents of 90 cities [J]. J Toxicol Environ Health A, 2005, 68(13-14):1071-92.
21. Zeller M, Giroud M, Royer C, et al. Air pollution and cardiovascular and cerebrovascular disease: Epidemiologic Data [J]. Presse Med, 2006, 35(10Pt 2): 1517-22.
22. Kodavanti UP, Schladweiler MC, Ledbetter AD, et al.The Spontaneously Hypertensive Rat as a Model of Human Cardiovascular Disease: Evidence of Exacerbate Cardiopulmonary Injury and Oxidatives Stress from Inhaled Emission Particulate Matter [J]. Toxicology and Applied Pharmacology, 2000, 164(3): 250-263.
23. Cao Q, Zhang S, Dong C, Song WM. Pulmonary responses to fine particles: differences between the spontaneously hypertensive rats and wistar kyoto rats [J].Toxicol Lett, 2007, 171 (3): 126-37.
24. Dreher KL, Jaskot H, Lehmann JR, et al. Soluble transition metals mediate residual oil fly ash induced acute lung injury [J]. J Toxicol Environ Health, 1997, 50(3):285-305.
25. Ghio AJ, Stonehuerner J, Pritchard RJ, et al. Humic-like substances in air pollution particulates correlate with concentrations of transition metals and oxidant generation [J]. Inhal Toxicol, 1996, 8:479-494.
26. Harrison RM, Yin J. Paniculate matter in the atmosphere: which particle properties are important for its effect on health? [J]. Sci Total Environ, 2000, 249(1-3):85 -101.
27. Costa DL, Dreher KL. Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models [J]. Environ Health Perspect, 1997, 105(5): 1053-1060.
28. Frampton MW, Ghio AJ, Samet JM, et al. Effects of aqueous extracts of PM_(10) filters from the Utah valley on human airway epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol, 1999,277(5 Pt 1):L960-L967.
29. Endres M. Statins and stroke [J]. J Cereb Blood Flow Metab, 2005,25(9): 1093-1110.
30. Varughese GI, Patel JV, Lip GY, et al. Novel concepts of statin therapy for cardiovascular risk reduction in hypertension [J]. Curr Pharm Des, 2006, 12(13): 1593-1609.
31. Lahera V, Goicoechea M, de Vinuesa SG, et al. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins [J]. Curr Med Chem, 2007, 14(2):243-8.
32. Zmirou D, Schwartz J, Saez M, et al. Time-series analysis of air pollution and cause-specific mortality [J]. Epidemiology, 1998, 9(5):495-503.
33. Rivero DH, Soares SR, Lofenzi-Filho G, et al. Acute cardiopulmonary alterations induced by fine particulate matter of Sao Paulo, Brazil [J]. Toxicol Sci, 2005, 85(2):898-905.
34. Campbell A, Oldham M, Becaria A, et al.Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain [J]. Neurotoxicology, 2005, 26(1):133-140.
35. Risom L, M(?)ller P, Loft S. Oxidative stress-induced DNA damage by particulate air pollution [J]. Mutat Res, 2005, 592(1-2): 119-37
36. Dockery DW, Schwartz J, Spengler JD. Air pollution and daily mortality: association with particulates and acid aerosols [J]. Environ Res, 1992, 59(2):362-373.
37. Schwartz J, Dockery DW, Neas LM. Is daily mortality associated specifically with fine particles? [J]. J Air Waste Manag Assoc, 1996, 46(10):927-939.
38. World Heart Federation web site [On-line]. Available: www.worldheart.Org /introduction.
39. Becker S, Dailey LA, Soukup JM, et al. Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress [J]. Environ Health Perspect, 2005, 113(8): 1032-8.
40.Dick CA.Singh P,Daniels M,et al.Murine pulmonary inflammatory responses following instillation of size-fractionated ambient particulate matter[J].J Toxicol Environ Health A,2003,66(23):2193-2207.
41.lbald-Mulli A,Timonen KL,Peters A,et al.Effects of particulate air pollution on blood pressure and heart rate in subjects with cardiovascular disease:a multicenter approach[J].Environ Health Perspect,2004,112(3):369-77.
42.Ulrich,M.M.,Alink,G.M.,Kumarathasan,P.,et al.Health effects and time course of particulate matter on the cardiopulmonary system in rats with lung inflammation[J].J.Toxicol Environ Health A,2002,65(20):1571-1595.
43.Julius S.Autonomic nervous system dysregulation in human hypertension[J].Am J Cardiol,1991,67(10):3B-7B.
44.Peters A,Perz S,Doring A,et al.Increases in heart rate during an air pollution episode[J].Am J Epidemiolm,1999,150(10):1094-1098.
45.Ibald-Mulli A,Stieber J,Wichmann HE,et al.Effects of air pollution on blood pressure:a population based approach[J].Am J Public Health,2001,91(4):571-577.
46.Watkinson WP,Campen M J,Casta DL.Cardiac arrhythmia induction after exposure to residual oil fly ash particles in a rodent model of pulmonary hypertension[J].Toxicol Sci,1998,41(2):209-216.
47.Gordon T,Nadziejko C,Schlesinger R,et al.Pulmonary and cardiovascular effects of acute exposure to concentrated ambient particulate matter in rats[J].Toxicol Lett,1998,96-97:285-288.
48.Watkinson WP,Campen M J,Nolan JP,et al.Cardiovascular and systemic responses to inhaled pollutants in rodents:effects of ozone and particulate matter[J].Environ Health Perspect,2001,109(suppl 4):539-546.
49.陈秉衡,周国栋,毛惠琴,等.室内空气污染及其对健康影响的研究[M].上海,上海医科大学环境卫生教研室.1987:6-22.
50.Abou Chakra OR,Joyeux M,Nerriere E,et al.Genotoxicity of organic extracts of urban airborne particulate matter:an assessment within a personal exposure study[J].Chemosphere,2007,66(7):1375-1381.
51.Gurgueira SA,Lawrence J,Coull B,et al.Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation[J].Environ Health Perspect,2002,110(8):749-755.
52.Chuen-Chau C,Jing-Shiang H,Chang-Chuan C,et al.Effects of Concentrated Ambient Particles on Heart Rate,Blood Pressure,and Cardiac Contractility in Spontaneously Hypertensive Rats[J].Inhalation Toxicology,2004,16(6-7):421-429.
53.Wichers LB,Nolan JP,Winsett DW,et al.Effects of Instilled Combustion-Derived Particles in Spontaneously Hypertensive Rats[J].Part 1:Cardiovascular Responses.Inhalation Toxicology,2004,16(6-7):391-405.
54.Bagate K,Meiring JJ,Gerlofs-Nijland ME,et al.Signal transduction pathways involved in particulate matter induced relaxation in rat aorta-spontaneous hypertensive versus Wistar Kyoto rats[J].Toxicol In Vitro,2006,20(1):52-62.
55.Bagate K,Meiring JJ,Gerlofs-Nijland ME,et al.Vascular effects of ambient particulate matter instillation in spontaneous hypertensive rats[J].Toxicol Appl Pharmacol,2004,197(1):29-39.
56.樊曙先,樊建凌,郑有飞.南京市区与郊区大气PM_(2.5)中元素的对比分析.中国环境科学,2005,25(2):146-150.
57.鲁兴,吴贤涛.北京市采暖期大气种PM_(10)和PM_(2.5)质量浓度变化分析.焦作工学院学报,2004,23(6):487-490.
58.Reyes DR,Rosario O,Rodriguez JF,et al.Toxic evaluation of organic extracts from airborne particulate matter in Puerto Rico[J].Environ Health Perspect,2000,108(7):635-40.
59.曹强.大气细颗粒物致肺损伤的易感性研究.[D]上海:复旦大学,2007.
60.Godleski JJ,Verrier RL,Koutrakis P,et al.Mechanisms of morbidity and mortality from exposure to ambient air particles[J].Res.Rep.Health Eff.Inst.2000,91:5-88.
61.Chang CC,Hwang JS,Chan CC,et al.Effects of concentrated ambient particles on heart rate,blood pressure,and cardiac contractility in spontaneously hypertensive rats [J].Inhal Toxicol,2004,16(6-7):421-429.
62.Gold DR,Litonjua AA,Zanobetti A,et al.Air pollution and ST-segment depression in elderly subjects[J].Environ Health Perspect,2005,113(7):883-7.
63.Pekkanen,J.,A.Peters,G.Hoek,et al.Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease:the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air(ULTRA) study[J].Circulation,2002,106(8):933-938.
64.Holguin F,Tellez-Rojo MM,Hernandez M,et al.Air pollution and heart rate variability among the elderly in Mexico City[J].Epidemiology.2003,14(5):521-527.
65.Magari S R,Schwartz J,Williams P L,et al.The association between personal measurements of environmental exposure to particulates and heart rate variability[J]. Epidemiology, 2002, 13(3): 305-310.
66. Liao D. Creason J, Shy C, et al. Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly[J]. Environ Health Perspect, 1999, 107(7): 521-525.
67. Gold D R, Litonjua A, Schwartz J, et al. Ambient pollution and heart rate variability[J]. Circulation, 2000, 101(11): 1267-1273.
38. Gilmour PS, Schladweiler MC, Nyska A, et al. Systemic imbalance of essential metals and cardiac gene expression in rats following acute pulmonary zinc exposure [J]. J Toxicol Environ Health A, 2006, 69(22): 2011-2032.
69. Chvapil M. Effect of zinc on cells and biomembranes [J]. Med Clin N Am, 1976, 60: 799-812.
70. Pritchard RJ, Ghio AJ, Lehmann JR, et al. Oxidant generation and lung injury after particulate air pollution exposure increase with the concentrations of associated metals [J]. Inhal Toxicol, 1996, 8: 457-477.
71. Ghil AJ. Biological effects of Utah valley ambient air partcles in humans: a review [J]. Journal of Aerosol Medicine, 2004,17(2): 157-164.
72. Fanning AS, Jameson JA, Jesaitis LA, et al. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton [J]. J Biol Chem. 1998,273(45):29745-29753.
73. Haley KJ, Lilly CM, Yang JH, et al. Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation [J]. Circulation, 2000, 102(18): 2185-2189.
74. Utell MJ, Frampton MW,Zareba W, et al. Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing [J]. Inhal Toxicol, 2002, 14(12):1231-1247.
75. Donaldson KV, Stone A, Seaton, et al. Ambient particle inhalation and the cardiovascular system: potential mechanisms. Environ [J]. Health Perspec, 2001, 109(Suppl 4):523-527.
76. Donaldson K, Tran CL. Inflammation caused by particles and fibers [J]. Inhal. Toxicol. 2002, 14(1):5-27.
77. Donaldson KV, Stone PJ, Borm, et al. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM_(10)) [J]. Free Radic Biol Med, 2003, 34(11):1369-1382.
78. Seaton A, Soutar A, Crawford V, et al. Particulate air pollution and the blood. Thorax.1999,54(11),1027-1032.
79.Mukae H,Vincent R,Quinlan K,et al.The effect of repeated exposure to particulate air pollution(PM_(10)) on the bone marrow[J].Am J Respir Crit Care Med.2001,163(1):201-209.
80.Danesh JP,Whincup M,Walker et al.Low grade inflammation and coronary heart disease:prospective study and updated meta-analyses[J].BMJ,2000,321(7255):199-204.
81.Mukae H,Hogg JC,English D,et al.Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow[J].Am J Physiol Lung Cell MolPhysiol,2000,279(5),L924-L931.
82.Blake G J,Ridker PM.Inflammatory bio-markers and cardiovascular risk prediction [J].J.Intern Med,2002,252(2),283-294.
83.Li J J,Fang CH.C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular disease[J].Med Hypotheses,2004,62(4):499-506.
84.Backes JM,HowardPA,et al.Role of C-reactive protein in cardiovascular disease[J].Ann Pharmacother,2004,38(1):110-118.
85.杨胜利,何秉贤.C反应蛋白和冠心病.中华心血管病杂志,200l,29(3):187-188.
86.Koenig WM,Sund M,Frohlich,et al.C-Reactive protein,a sensitive marker of inflammation,predicts future risk of coronary heart disease in initially healthy middle-aged men:results from the MONICA(Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study.1984 to 1992[J].Circulation.1999.99:237-242.
87.Peters A,Wichmann HE,Koenig W.Air pollution exposure influences cardiovascular risk factors:a link to mortality?.In Proc Int Inhal Symp Hanover,Germany.1999.
88.Pope CA,Hansen ML,Long RW,et al.Ambient particulate air pollution,heart rate variability,and blood markers of inflammation in a panel of elderly subjects.Environ.Health Perspect.2004,112(3):339-345.
89.Committee on Care and Use of Spontaneously Hypertensive(SHR) Rats(1976).Spontaneously hypertensive(SHR) rats:Guidelines for breeding,care,and use.ILAR News ⅩⅨ(3),G1-G20.
90.Derhaschnig U,Shehata M,Herkner H,et al.Increased levels of transforming growth factor-betal in essential hypertension[J].Am J Hypertens,2002,15(3):207-11.
91. Wang Y, Thorlacius H. Mast cell-derived tumour necrosis factor-alpha mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice [J]. Br J Pharmacol, 2005, 145(8): 1062-1068.
92. Nageswara R, Madamanchi, Aleksandr Vendrov, et al. Oxidative Stress and Vascular Disease [J]. Arterioscler Thromb Vasc Biol, 2005, 25:29-38.
93. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management [J]. J. Am. Med. Assoc, 2002, 287(19):2570-2581.
94. Tao F, Gonzalez-Flecha B, Kobzik L. Reactive oxygen species in pulmonary inflammation by ambient particulates [J]. Free Radical Biol Med, 2003, 35,327-340.
95. Knaapen AM, Shi T, Borm PJA, et al. Soluble metals as well as the insoluble particle fraction are involved in cellular DNA damage induced by particulate matter [J]. Mol Cell Biochem, 2002, 234/235(1-2):317-326.
96. Sorensen M, Schins RPF, Hertel O, et al. Transition metals in personal samples of PM_(2.5) and oxidative stress in human volunteers [J]. Cancer Epidemiol Biomarkers Prev,2005, 14(5):1340-1343.
97. Prahalad AK, Soukup JM, Inmon J, et al. Ambient air particles: effects on cellular oxidant radical generation in relation to particulate elemental chemistry [J]. Toxicol. Appl. Pharmacol, 1999, 158(2), 81-91
98. Clarke RW, Coull B, Reinisch U, et al. Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines [J]. Environ. Health Perspect, 2000, 108(12): 1179-1187.
99. Gutierrez-Castillo ME, Roubicek DA, Cebrian-Garcia ME, et al. Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter [J].Environ Mol Mutagen, 2006,47(3): 199-211.
100. Gurgueira SA, Lawrence J, Coull B, et al. Rapid increases in the steady-state concentration of reactive oxygen species in the lungs and heart after particulate air pollution inhalation [J]. Environ Health Perspect, 2002, 110(8), 749- 755.
101. Wilson MR, Lightbody JH, Donaldson K, et al. Interactions between ultrafine particles and transition metals in vivo and in vitro [J]. Toxicol Appl Pharmacol, 2002, 184(3): 172-179.
102. Molinelli AR, Madden MC, McGee JK, et al. Effect of metal removal on the toxicity of airborne particulate matter from the Utah Valley [J]. Inhal Toxicol, 2002, 14(10): 1069-86.
103. Claxton LD, Matthews PP, Warren SH. The genotoxicity of ambient outdoor air, a review: Salamonella mutagenicity [J]. Mutat Res, 2004, 567(2-3):347-399.
104. Healey K, Lingard JJ, Tomlin AS, et al. Genotoxicity of size-fractionated samples of urban particulate matter [J]. Environ Mol Mutagen, 2005,45(4):380-387.
105. Matsuki T, Duling BR. TNF-alpha modulates arteriolar reactivity secondary to a change in intimal permeability [J]. Microcirculation, 2000, 7(6 Pt 1):411-418.
106. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s [J]. Nature, 1993,362(6423):801-9.
107. Farmer JA, Torre-Amione G. Atherosclerosis and inflammation [J]. Curr Atheroscler Rep, 2002,4:92-98.
108. Guzik TJ., Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation [J]. J Physiol Pharmacol, 2003, 54(4):469-487.
109. Packer R, Bergler-Klein J, Globits S, et al. Plasma big endothelin-1 concentrations in or congestive heart failure patients with or without systemic hypertension. Am J Cardiol, 1993,71(15), 1293-1299.
110. Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis [J]. N Engl J Med, 1991, 325(14):997-1001.
111. Bouthillier L, Vincent R, Goegan P, et al. Acute effects of inhaled urban particles and ozone: lung morphology, macrophage activity, and plasma endothelin-1 [J]. Am. J. Pathol, 1998, 153(6): 1873-1884.
112. Vincent R, Kumarathasan P, Goegan P, et al. Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats. Res Rep Health Eff Inst. 2001, 104:5-54.
113. O'Neill MS, Veves A, Zanobetti A, et al. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function [J]. Circulation, 2005, 111(22):2913-2920.
114. Lei YC, Hwang JS, Chan CC, et al. Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles [J]. Environ Res, 2005, 99(3):335-43.
115. Koenig WM. Sund B. Filipiak, et al. Plasma viscosity and the risk of coronary heart disease: Results from the MONICA-Augsburg cohort study, 1984 to 1992 [J]. Arterioscler Thromb Vasc Biol, 1998,18(5): 768-772.
116. Seaton A, MacNee W, Donaldon K, et al. Particulate air pollution and acute health effects [J]. Lancet, 1995, 345(8943), 176-178.
117. Brauner EV, Forchhammer L, M(?)ller P, et al. Indoor particles affect vascular function in the aged: an air filtration-based intervention study. Am J Respir Crit Care Med. 2008 ,177(4):419-25.
118. Peters A, A Doring HE, Wichmann, et al. Increased plasma viscosity during the 1985 air pollution episode: a link to mortality? [J], Lancet, 1997, 349(9065): 1582-1587.
119. Pekkanen J, Brunner EJ, Anderson HR, et al. Daily concentrations of air pollution and plasma fibrinogen in London [J]. Occup Environ Med, 2000, 57(12):818-822.
120. Huang YC, Ghio AJ, Stonehuerner J, et al. The role of soluble components in ambient fine particles- induced changes in human lungs and blood [J]. Inhal Toxicol, 2003, 15(4):327-342.
121. Salvi S., A. Blomberg B. Rudell, et al. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers [J]. Am J Respir Crit Care Med, 1999, 159(3):702-709.
122. Andrej Khandoga MD,Andreas Stampfl MSc, Shinji Takenaka DVM,et al.Ultrafme particles exert prothrombotic but not inflammatory effects on the hepatic microcirculation in healthy mice In vivo [J]. Circulation, 2004, J 09:1320-1325.
123. Alfaro-Moreno E, Lopez-Marure R. Montiel-Davalos A, et al. E-Selectin expression in human endothelial cells exposed to PM10: the role of endotoxin and insoluble fraction [J].Environ Res, 2007,103(2):221-8.
124. Gilmour PS, Ziesenis A, Morrison ER, et al.Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles. Toxicol Appl Pharmacol, 2004,195(1):35-44.
125. Goldsmith IR, Blann AD, Patel RL, et al. Plasma fibrinogen, soluble P-selectin, and von Willebrand factor in aortic valve disease: evidence for abnormal haemorheology, platelet activation, and endothelial dysfunction [J]. Heart, 2000 , 83(5):577-8.
126. Massberg S, Enders G, Leiderer R, et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin [J]. Blood, 1998 , 92(2):507-15.
127. Behzadian MA, Wang XL, Al-Shabrawey M, et al. Effects of hypoxia on glial cell expression of angiogenesis-regulating factors VEGF and TGF-beta [J]. Glia, 1998 , 24(2):216-25.
128. Behzadian MA, Wang XL, Windsor LJ, et al. TGF-beta increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function [J]. Invest Ophthalmol Vis Sci, 2001, 42(3):853-9.
129. Zhu Y, Culmsee C, Klumpp S, et al. Neuroprotection by transforming growth factor-betal involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways [J].Neuroscience, 2004, 123(4):897-906.
130. Ikedo H, Tamaki K, Ueda S, et al. Smad protein and TGF-beta signaling in vascular smooth muscle cells [J]. Int J Mol Med, 2003, 11(5):645-50.
131. Harbord M, Novelli M, Canas B, et al. Yml is a neutrophil granule protein that crystallizes in p47phox-deficient mice [J]. J Biol Chem, 2002, 277: 5468-5475.
132. Cruzado MC, Risler NR, Miatello RM, et al. Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: Effect of angiotensin II and role of insulinlike growth factor-1 receptor transactivation [J]. Am J Hypertens, 2005, 18(1):81-7.
133. Fukuda N, Hu WY, Kubo A, et al. Abnormal regulation of transforming Growth factor-preceptor on vascular smooth muscle cell from Spontaneously hypertension rats by AngII [J]. Hypertension, 1998, 31:672- 677.
134. von Klot S, Peters A, Aalto P, et al. Health Effects of Particles on Susceptible Subpopulations (HEAPSS) Study Group.Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities [J]. Circulation, 2005, 112(20):3073-9.
135. Zanobetti A, Schwartz J. The effect of particulate air pollution on emergency admissions for myocardial infarction: a multicity case-crossover analysis [J]. Environ Health Perspect, 2005, 113(8):978-982.
136. Sullivan J, Sheppard L, Schreuder A, et al. Relation between short-term fine-particulate matter exposure and onset of myocardial infarction [J]. Epidemiology, 2005, 16(1):41-48.
137. Karacalioglu O, Arslan Z, Kilic S, et al. Baseline serum levels of cardiac biomarkers in patients with stable coronary artery disease [J]. Biomarkers, 2007, 12(5):533-40.
138. Reed JC.Double identity for proteins of the bcl-2 family [J], Nature, 1997, 387(6635):773-776.
139. Strasser A, Connor LO, Dixit VM. Apoptosis signaling [J]. Annu Rev Biochem, 2000, 69,217-245.
140. Reed JC. bcl-2 and the regulation of programmed cell death. J. Cell Biol, 1994, 124(1-2), 1-6.
141.Hockenbery D,Nunez G,Miiliman C,et al.bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death[J].Nature,1990,348(6299):334-336.
142.Sato T,Hanada M,Bodrug S,et al.Interactions among members of the bcl-2 protein family analyzed with a yeast two-hybrid system[J].Proc Natl Acad Sci,1994,91(20):9238-9242.
143.Yin XM,Oltvai ZN,Korsmeyer SJ.bhl and bh2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax[J].Nature,1994,369(3478):321-333.
144.Bai J,Meng Z.Expression of apoptosis-related genes in livers from rats exposed to sulfur dioxide[J].Toxicology,2005,216(2-3):253-60.
145.Diez J,Panizo A,Hemandez M,et al.Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats?[J].Hypertension,1997,29(3):776-780.
146.钱华,伏晴艳,马伯文.上海市环境空气中多坏芳烃与苯并[a]芘的监测分析[J].上海环境科学,2003,22(11):779-784.
147.Gutierrez-Castillo ME,Roubicek DA,Cebrian-Garcia ME,et al.Effect of chemical composition on the induction of DNA damage by urban airborne particulate matter [J].Environ Mol Mutagen,2006,47(3):199-211.
148.Steinert SA.Contribution ofapoptosis to observed DNA damage in muscle cells[J].Mar.Environ.Res.1996,42:253-259.
149.Dorszewska,J.,Adamczewska-Goncerzewicz,Z.Oxidative damage to DNA,p53gene expression and p53 protein level in the process of aging in rat brain[J].Res.Physiol Neurobiol,2004,139(3):227-236.
150.Chandra J.,Samali A.,Orrenius S.Triggering and modulation of apoptosis by oxidative stress[J].Free Radical Biol.Med,2000,29(3-4),323-333.
151.Freeman BA,Grapo JD.Biology of disease:free radical and tissue injury[J].Lab.Invest.1982,47(5),412-426.
152.Varughese GI,Patel JV,Lip GY,et al.Novel concepts of statin therapy for cardiovascular risk reduction in hypertension[J].Curr Pharm Des,2006,12(13):1593-609.
153.Elrod JW,Lefer DJ.The effects of statins on endothelium,inflammation and cardioprotection.Timely Top Med Cardiovasc Dis.2005 Aug 1;9:E20.
154.Piconi L.Corgnali M,Da Ros R,et al.The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose[J].J Diabetes Complications,2008,22(1):38-45.
155.Schupp N,Schmid U,Heidland A,et al.Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis.Atherosclerosis.2007.
156.朱鸣雷.他汀类药物在炎性刺激下对脐静脉血管内皮细胞炎性相关分析表达的影响.[D].北京:中国协和医科大学.2002.
157.Omi H,Okayama N,Shimizu M,et al.Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide [J].Microvasc Res,2003,65(2):118-24
158.Okouchi M,Okayama N,Omi H,et al.Cerivastatin ameliorates high insulin-enhanced neutrophil-endothelial cell adhesion and endothelial intercellular adhesion molecule-1expression by inhibiting mitogen-activated protein kinase activation[J].J Diabetes Complications,2003,17(6):380.
159.Bellosta S,Ferri N,Arnaboldi L,et al.Pleiotropic effects of statins in atherosclerosis and diabetes.Diabetes Care.2000,23(Suppl 2):B72-8.
160.Yamakawa T,Tanaka S,Kamei J,et al.Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal-regulated kinases 1/2[J].J Atheroscler Thromb,2003,10(1):37-42.
161.Endres M.Statins:potential new indications in inflammatory conditions[J].Atheroscler Suppl,2006,7(1):31-5.
162.Kishi T,Hirooka Y,Shimokawa H,et al.Clin Exp Hypertens.Atorvastatin reduces oxidative stress in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats[J].Clinical and Experimental Hypertension,2008,30(1):3-11.
163.Chang LT,Sun CK,Chiang CH,et al.Impact of simvastatin and losartan on antiinflammatory effect:in vitro study[J].J Cardiovasc Pharmacol,2007,49(1):20-6.
164.Martinez-Sales V,Vila V,Ferrando M,et al.Atorvastatin neutralizes the up-regulation of thrombospondin-I induced by thrombin in human umbilical vein endothelial cells[J].Endothelium,2007,14(4-5):233-8.
165.Soehnlein O,Eskafi S,Schmeisser A,Kloos H,Daniel WG,Garlichs CD.Atorvastatin induces tissue transglutaminase in human endothelial cells[J].Biochem Biophys Res Commun,2004,322(1):105-9.
166.Ungureanu D,Filip C,Artenie A,Artenie R.Evaluation of simvastatin antioxidant effects[J].Rev Med Chir Soc Med Nat lasi,2003,107(1):66-71.
167.Christ M,Bauersachs J,Liebetrau C,et al.Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation:attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin[J].Diabetes,2002,51(8):2648-52.
168.Wang HR,Li J J,Huang CX,et al.Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein[J].Clin Chim Acta,2005,353(1-2):53-60.
169.Li J-J,Fang C-H,Chen M-Z,et al.Rapid effects on lipid profile and C-reactive protein by simvastatin in patients with hypercholesterolemia[J].Clin Cardiol,2003,26(10):472-476.
170.Li J-J,Fang C-H.Effect of a single high-dose of simvastatin on C-reactive protein in patients with unstable angina.Heart Drug,2004,5:140-145.
171.Wolfrum S,Jensen K,Liao J.Endothelial-dependent effects of statins[J].Arterioscler Thromb Vasc Biol,2003,23(5):729-736.
172.Cooke JP.Therapeutic intervention in endothelial dysfunction:endothelium as a target organ.Clin Cardiol.1997,20:1145-1151.
173.Bonetti PO,Lerman LO,Lerman A.Endothelial dysfunction:A marker of atherosclerotic risk[J].Arterioscler Thromb Vasc Biol,2003,23(2):168-175.
174.Behzadian MA,Wang XL,Windsor L J,et al.TGF-beta increases retinal endothelial cell permeability by increasing MMP-9:possible role of glial cells in endothelial barrier function[J].Invest Ophthalmol Vis Sci,2001,42(3):853-9.
175.张静静,刘廷,王易强,董晓光.转化生长因子β_1对内皮细胞屏障功能的影响.齐鲁医学杂志,2007,22(4):297-300.
176.Thurberg BL,Collins T.The nuclear factor-kappa B/inhibitor of kappa B autoregulatory system and atherosclerosis[J].Curr Opin Lipidol,1998,9(5):387-96.
177.Tokoro,T.,Wang,J.,Kitajima,I.The novel HMG-CoA reductase inhibitor,pitavastatin,induces a protective action in vascular endothelial cells through the production of nitric oxide(NO)[J].Yakugaku Zasshi,2004,124:121-126.
178.Lefer AM,Campbell B,Shin YK,et al.Simvastatin preserves the ischemicreperfused myocardium in normocholesterolemic rat hearts[J].Circulation,1999,100(2):178-184.
179.Mooradian AD,Haas M J,Batejko O,et al.Statins ameliorate endothelial barrier permeability changes in the cerebral tissue of streptozotocin-induced diabetic rats[J].Diabetes,2005,54(10):2977-2982.
180.Takemoto M,Liao JK.Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors[J].Arterioscler Thromb Vasc Biol.2001,21(11):1712-1719.
181.Hasegawa H,Yamamoto R,Takano H,et al.3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats[J].J Mol Cell Cardiol,2003,35(8):953-60.
1.Ostro B,Feng WY,Broadwin R,et al.The effects of components of fine particulate air pollution on mortality in califomia:results from CALFINE[J].Environ Health Perspect,2007,115(1):13-9.
2.Kan H,London S J,Chen G,Zhang Y,et al.Differentiating the effects of fine and coarse particles on daily mortality in Shanghai,China[J].Environ Int.2007,33(3):376-84.
3.Pope Ⅲ CA,Bumett RT.,Thun MJ,et al.Lung cancer,cardiopulmonary mortality,and long-term exposure to fine particulate air pollution[J].JAMA,2002,287:1132-1141.
4.Goldberg MS,Bumett RT,Bailar JC Ⅲ,et al.Identification of persons with cardiorespiratory conditions who are at risk of dying from the acute effects of ambient air particles[J].Environ Health Perspect,2001,109(suppl 4):487-494.
5.Samet JM,Dominici F,Curriero FC,et al.Fine particulate air pollution and mortality in 20 U.S.cities,1987-1994[J].N Engl J Med,2000,343(16):1742-1749.
6.Dominici F,McDermott A,Daniels M,et al.Revised analyses of the National Morbidity,Mortality,and Air Pollution Study:mortality among residents of 90 cities [J].J Toxicol Environ Health A,2005,68(13-14):1071-92.
7.Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies:part Ⅰ[J].Circulation,2003,108(15):1664-1672.
8.Schwartz J,Dockery D W,Neas L M.Is daily mortality associated specifically with fine particles? J Air Waste Manag Assoc[J].1996,46(10):927-939.
9.Barnett AG,Williams GM,Schwartz J,et al.The effects of air pollution on hospitalizations for cardiovascular disease in elderly people in Australian and New Zealand cities[J].Environ Health Perspect,2006,114(7):1018-23.
10.Braga AL,Zanobetti A,Schwartz J.The lag structure between particulate air pollution and respiratory and cardiovascular deaths in 10 US cities [J]. Occup. Environ. Med, 2001, 43(11): 927-933.
11. Harrison RM, Yin J. Particulate matter in the atmosphere:which particle properties are important for its effect on health? [J]. Sci Total Environ, 2000, 249(1-3):85 -101.
12. de Hartog JJ, Hoek G, Peters A, et al. Effects of fine and ultrafine particles on cardiorespiratory symptoms in elderly subjects with coronary heart disease [J]. American Journal of Epidemiology, 2003, 157(7):613-623.
13. Gilmour PS, Ziesenis A, Morrison ER, et al. Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles [J]. Toxicol Appl Pharmacol, 2004,195(1):35-44.
14. Singh S, Shi T, Duffin R, et al. Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles [J]. Toxicol Appl Pharmacol, 2007,222(2): 141-51..
15. Karoly ED, Li Z, Dailey LA, et al.Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure [J]. Environ Health Perspect,2007, 115(4):535-40.
16. Kodavanti UP., Moyer CF., Ledbetter AD., er al. Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat [J]. Toxicol Sci, 2003,71(2):237-245.
17. Zhang Q.W., Kusaka Y., Zhu X.Q., et al. Comparative toxicity of standard nickel and ultrafine nickel in lung after intratracheal instillation [J]. Occ Health, 2003, 45(1): 23-30.
18. Nemmar A, Hoet PHM, Vanquickenborne B, et al. Passage of inhaled particles into the blood circulation in humans [J]. Circulation, 2002,105(4): 411-414.
19. Nemmar A, Vanbilloen H, Hoylaerts MF, et al. Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster [J]. Am J Respir Crit Care Med, 2001,164(9): 1665-1668.
20. Oberdorster G, Sharp Z, Atudorei V, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats [J]. J Toxicol Environ Health A, 2002, 65(20): 1531-1543.
21. Suwa T, Hogg JC, Quinlan, K.B, et al. Particulate air pollution induces progression of atherosclerosis [J]. Am. Coll. Cardiol, 2002, 39(6):935-942.
22. Nurkiewicz TR, Porter DW, Barger M, et al. Particulate Matter Exposure Impairs Systemic Microvascular Endothelium-Dependent Dilation.2004,112(13): 1299-1306.
23. Kreyling W., Semmler M., Erbe F, et al. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low [J]. Toxicol Environ. Health A, 2002, 65(20): 1513-1530.
24. Donaldson K, Stone V, Seaton A, et al. Ambient particle inhalation and the cardiovascular system: potential mechanisms [J]. Environ Health Perspect, 2001, 109(suppl 4):523-527.
25. Elder AC, Gelein R, Azadniv M, et al.Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains [J]. Inhal Toxicol, 2004, 16(6-7):461-71.
26. Gerlofs-Nijland ME, Boere AJ, Leseman DL, et al. Effects of particulate matter on the pulmonary and vascular system: time course in spontaneously hypertensive rats [J]. Part Fibre Toxicol, 2005,2(1):2.
27. Rivero DH, Soares SR, Lorenzi-Filho G, et al. Acute cardiopulmonary alterations induced by fine particulate matter of Sao Paulo, Brazil [J]. Toxicol Sci. 2005, 85(2):898-905.
28. Haley K.J., Lilly C.M., Yang J.H., et al. Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation [J]. Circulation, 2000, 102(18):2185- 2189.
29. van Eeden SF, Hogg JC. Systemic inflammatory response induced by particulate matter air pollution: the importance of bone-marrow stimulation [J]. J Toxicol Environ Health A, 2002,65(20): 1597-613.
30. Riediker M, Devlin RB, Griggs TR, et al. Cardiovascular effects in patrol officers are associated with fine particulate matter from brake wear and engine emissions [J].Part Fibre Toxicol, 2004, 1(1):2.
31. Pope CA, Hansen ML, Long RW, et al. Ambient particulate air pollution, heart rate variability, and blood markers of inflammation in a panel of elderly subjects.Environ Health Perspect [J]. 2004, 112(3):339-45.
32. Driscoll KE, Simpson L, Carter J, et al. Ozone inhalation stimulates expression of a neutrophil chemotactic protein, macrophage inflammatory protein 2[J]. Toxicol Appl Pharmacol. 1993, 119(2): 306-309.
33. Kodavanti UP, Schladweiler MC, Richards JR,et al. Acute lung injury from intratracheal exposure to fugitive residual oil fly ash and its constituent metals in normo- and spontaneously hypertensive rats. Inhal Toxicol. 2001, 13(1):37-54.
34. Kodavanti UP, Jaskot RH, Costa DL, et al: Pulmonary proinflammatory gene induction following acute exposure to residual oil fly ash: roles of particle associated metals [J]. Inhal Toxicol .1997, 9:679-701.
35. Kodavanti UP,Schladweiler MC,Ledbetter AD, et al. The spontaneously hypertensive rat as a model of human cardiovascular disease:evidence of exacerbated cardiopulmonary injury and oxidative stress from inhaled emission particulate matter [J]. Toxicol Appl Pharmacol, 2000, 164(3):250-63.
36. Nadadur SS, Kodavanti UP. Altered gene expression profiles of rat lung in response to an emission particulate and its metal constituents [J].J Toxicol Environ Health A. 2002, 65(18): 1333-50.
37. Adamson IY, Prieditis H, Vincent R. Soluble and insoluble air particle fractions induce differential production of tumor necrosis factor alpha in rat lung [J].Exp Lung Res, 2004,30(5):355-68.
38. Shaw CA,Taylor EL,Megson IL,et al. Nitric oxide and the resolution of inflammation: implications for atherosclerosis[J]. Mem Inst Oswaldo Cruz, 2005,100:67
39. Hirano S, Furuyama A, Koike E, et al. Oxidative-stress potency of organic extracts of diesel exhaust and urban fine particles in rat heart microvessel endothelial cells [J]. Toxicology, 2003,187(2-3): 161-70.
40. Brauner EV, Forchhammer L, M(?)ller P, et al. Indoor particles affect vascular function in the aged: an air filtration-based intervention study [J]. Am J Respir Crit Care Med, 2008, 177(4):419-25.
41. Heart rate variability standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [J].Circulation, 1996, 93(5): 1043 -1065.
42. Devlin RB, Ghio AL Kelhd H, et al. Elderly humans exposed to Concentrated air polution particles have decreased heart rate variability [J]. Eur respair j,2003,21: 69,76-80
43. Chen LC, Hwang JS. Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice IV, Characterization of acute and chronic effects of ambient air fine particulate matter exposures on heart-rate variability [J]. Inhal Toxicol 2005, 17(4-5):209-216.
44. Wichers LB, Nolan JP, Winsett DW, et al. Effects of instilled combustion-derived particles in spontaneously hypertensive rats [J] . Part I: Cardiovascular responses. Inhal Toxicol, 2004, 16(6-7):391-405.
45. Bagate K, Meiring JJ, Gerlofs-Nijland ME, et al.Vascular effects of ambient particulate matter instillation in spontaneous hypertensive rats [J]. Toxicol Appl Pharmacol, 2004, 197(1):29-39.
46. Mills NL, Tornqvist H, Gonzalez MC, et al. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease [J].N Engl J Med. 2007 ,357(11): 1075-82.
47. Peters A, Liu E, Verrier RL, et al. Air pollution and incidence of cardiac arrhythmia [J]. Epidemiology, 2000, 11(1): 11-17.
48. Schulz H. Fine particulate matter-a health hazard for lungs and other organs? [J] Pneumologie, 2006, 60(10):611-5.
49. Wellenius GA, Saldiva PH, Batalha JR, et al. Electrocardiographic changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction [J]. Toxicol Sci, 2002, 66(2): 327- 335.
50. Wang B, Feng WY, Wang M, et al.Transport of intranasally instilled fine Fe_2O_3 particles into the brain: micro-distribution, chemical states, and histopathological observation [J]. Biol Trace Elem Res, 2007,118(3):233-43.
51. Campbell A, Oldham M, Becaria A, et al. Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain [J]. Neurotoxicology, 2005, 26(1):133-40.
52. UN Environment Program and WHO Report. Air pollution in the world's megacities. A Report from the U.N. Environment Programme and WHO. Environment, 1994, 36, 5-37.
53. Bell ML, Samet JM, Dominici F: Time-series studies of particulate matter [J]. Annu Rev Public Health, 2004,25:247-280.
54. Sorensen M, Daneshvar B, Hansen M, et al. Personal PM2.5 exposure and markers of oxidative stress in blood [J]. Environ Health Perspect, 2003, 111 (2): 161—166.
1.Stoll LL,McCormick ML,Denning GM,et al.Antioxidant effects of statins[J].Drugs Today(Barc) 2004,40(12):975-90.
2.Lauts V,La Fata V,PlutzkyJ,et al.Upregulation of endothelial nitric Oxide synthase by HMG CoS reductase inhibitors[J].Greulation.1998,97(5):1129-1135.
3.Bates K,Ruggeroli CE,Goldman S,Gaballa MA.Simvastatin restores endothelial NO-mediated vasorelaxation in large arteries after myocardial infarction[J].Am J Physiol Heart Circ Physiol,2002,283(2):H768-775.
4.Wei CM,Lerman A,Rodeheffer RJ,et al.Endothelin in human congestive heart failure[J].Circulation,1994,89(4):1580-6.
5.Seljeflot I,Tonstad S,Hjermann I,Amesen H.Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease[J].Atherosclerosis,2002,162(1):179-85.
6.Hemandez-Perera O,Perez-Sala D,Navarro-Antolin J,et al.Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors,atorvastatin and simvastatin,on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells[J].J Clin Invest 1998,101(12):2711-2719.
7.Aukrust P,Ueland T,Muller F,et al.Elevated circulating levels ofC-C chemokines in patients with congestive heart failure[J].Circulation,1998,97(12):1136-43.
8.Christ M,Bauersachs J,Liebetrau C,et al.Glucose increases endothelial- dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation:attenuation by the 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor atorvastatin[J].Diabetes,2002,51:2648-2652.
9.Wassmann S,Laufs U,Muller K,et al.Cellular antioxidant effects of atorvastatin in vitro and in vivo[J].Arterioscler Thromb Vasc Biol,2002,22(2):300-5.
10.Carneado J,Alvarez de Sotomayor M,Perez-Guerrero C,et al.Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect [J]. J Hypertens, 2002, 20(3):429-37.
11. Grosser N, Erdmann K, Hemmerle A, et al. Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1 [J]. Biochem Biophys Res Commun, 2004, 325(3):871-6.
12. Hsu M, Muchova L, Morioka I, et al. Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo [J]. Biochem Biophys Res Commun, 2006, 343(3):738-744.
13. Berton G, Cordiano R, Palmieri R, Pianca S, Pagliara V, Palatini P. C-reactive protein in acute myocardial infarction: association with heart failure [J]. Am Heart J, 2003, 145(6): 1094-1101.
14. Blanco-Colio LM, Tunon J, Martin-Ventura JL, et al. Antiinflammatory and immunomodulatory effects of statins [J]. Kidney Int, 2003, 63(1): 12-23.
15. Hasegawa H, Yamamoto R, Takano H, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats [J]. J Mol Cell Cardiol, 2003, 35(8):953-60.
16. Wang HR, Li JJ, Huang CX, Jiang H. Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein [J]. Clin Chim Acta, 2005, 353(1-2):53-60.
17. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future [J]. Circ Res, 2002,91(11):988-98.
18. Namazi MR. Decreasing the expression of LFA-1 and ICAM-1 as well as hindering their interaction as the major mechanism for statin-induced neutrophil dysfunction [J]. Ann Thorac Surg, 2007, 84(6):2137-8.
19. Kimura M, Kurose I, Russell J, et al. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats [J]. Arterioscler Thromb Vasc Biol, 1997, 17(8): 1521-6.
20. Niwa S, Totsuka T, Hayashi S. Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line [J]. Int J Immunopharmacol, 1996, 18(11):669-75.
21. Serebruany VL, Murugesan SR, Pothula A, et al. Increased soluble platelet/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy [J]. Eur J Heart Fail, 1999, 1(3):243-9.
22.Amoroso G,van Veldhuisen DJ Tio RA,et al.Pathophysiology of vascular endothelium and circulating platelets:implications for coronary revascularization and treatment[J].Int J Cardiol,2001,79(3).265-275.
23.Joukhadar C,Klein N,Prinz M,et al.Similar effects of atorvastatin,simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia[J].Thromb Haemost,2001,85(1):47-51
24.Schafer A,Fraccarollo D,Eigenthaler M,et al.Rosuvastatin reduces platelet activation in heart failure:role of NO bioavailability[J].Arterioscler Thromb Vasc Biol,2005,25(5):1071-7.
25.Tousoulis D,Antoniades C,Bosinakou E,et al.Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure[J].Heart,2005,91(1):27-31.
26.徐成斌.冠心病防治在调脂领域.的某些进展与动向.心血管病学进展,2002,23(1):1-5.
27.Node K,Fujita M,Kitakaze M,et al.Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy[J].Circulation,2003,108(7):839-43.
28.Bellosta S,Via D,Canavesi M,et al.HMG-CoA reductase inhibitors reduce MMP-9secretion by macrophages[J].Arterioscler Thromb Vasc Biol,1998,18(11):1671-1678.
29.Rossig L,Haendeler J,Mallat Z,et al.Congestive heart failure induces endothelial cell apoptosis:protective role of carvedilol[J].J Am Coil Cardiol,2000,36(7):2081-9.