纳米氧化锌颗粒诱导BEAS-2B细胞IL-8基因表达的机制
|
摘要
[研究背景]纳米颗粒是尺寸小于100 nm的人造颗粒物,具有广泛的用途。纳米金属氧化物(如纳米氧化锌)是目前世界上纳米产量吨位较高的纳米材料。纳米氧化锌颗粒(Zinc Oxide nanoparticles, ZnO-NPs)可通过呼吸道、皮肤、消化道等途径进入人体。志愿者吸入实验研究结果表明,ZnO-NPs可引起“金属烟雾热”；支气管灌洗液中炎症细胞介素水平如白细胞介素8(Interleukin 8, IL-8)以及中性粒细胞数目均较对照组明显升高。体外研究结果显示,ZnO-NPs可刺激人呼吸道上皮细胞产生过量的IL-8。呼吸道IL-8主要来源于上皮细胞,在介导外源性毒物所致各种肺脏疾病过程中起关键作用。目前,ZnO-NPs所致IL-8基因表达的机制尚不清楚。
[研究目的]阐明国产ZnO-NPs(30 nm)对人支气管上皮细胞IL-8基因表达的影响；揭示纳米氧化锌颗粒诱导IL-8基因表达的分子生物学机制。
[研究方法]以人支气管上皮细胞株(BEAS-2B)为体外模型。用MTT方法测定ZnO-NPs对细胞的损伤作用。用RT-PCR和ELISA方法分别测定ZnO-NPs对IL-8mRNA和蛋白表达水平的影响。使用转录抑制剂和表达突变IL-8基因促进子的BEAS-2B细胞株观察ZnO-NPs对IL-8基因转录的影响。利用IL-8 mRNA降解试验测定ZnO-NPs对转录后IL-8 mRNA稳定性的影响。利用胞噬作用抑制剂观察细胞吞噬作用在ZnO-NPs所致IL-8表达过程中的作用。此外,利用原子吸收光谱手段测定ZnO-NPs在培养液中的溶解水平。
[研究结果]ZnO-NPs刺激可致细胞内IL-8 mRNA水平及培养液上清中IL-8蛋白含量明显升高,该作用呈时间(2 h-4 h)及剂量(1μg/cm2-4μg/cm2)依赖性(P=0.000)。用转录抑制剂放线菌素D (1μg/ml)预处理细胞30 min,可显著降低ZnO-NPs (4μg/cm2,2 h)对IL-8 mRNA表达的诱导作用(P=0.000),表明ZnO-NPs在转录水平调控IL-8基因表达。利用可表达野生型、NFκ,B和C/EBPβ结合位点突变型IL-8促进子的BEAS-2B细胞株,观察到在表达突变IL-8促进子细胞内,ZnO-NPs (4μg/cm2,2 h)对IL-8转录活性的影响较在野生型细胞明显降低(P=0.000),说明转录因子NFκB和C/EBPβ参与调节纳米氧化锌对IL-8基因转录的诱导过程。在用放线菌素D终止IL-8 mRNA合成的前提下,ZnO-NPs(4μg/m2)可明显减缓细胞内IL-8 mRNA的降解,表现为在不同作用时间点(1h,2h,4h), ZnO-NPs处理组IL-8 mRNA水平均较相应对照组(无ZnO-NPs刺激)高(P值分别为0.021、0.002、0.001),说明ZnO-NPs对IL-8 mRNA有稳定作用。用细胞松弛素B(10μg/ml)预处理细胞30 min,可明显降低ZnO-NPs(4μg／cm2,2 h)对IL-8 mRNA表达的诱导作用(抑制率为30.14%)(P=0.000),提示部分ZnO-NPs可通过胞噬作用进入细胞进而诱导IL-8的表达。8μg/ml(相当于24孔培养板一孔内加入4μg/cm2 ZnO-NPs) ZnO-NPs在培养液中37℃温育2 h,有4.3%的ZnO-NPs溶解,培养液上清中锌离子的浓度为3.57μM。
[结论]ZnO-NPs刺激可明显提高人支气管上皮细胞内IL-8 mRNA和蛋白的表达水平；转录因子NFKB和C/EBPβ在ZnO-NPs所致IL-8基因转录过程中起重要调节作用；ZnO-NPs对细胞内IL-8 mRNA具有稳定作用；部分ZnO-NPs可通过胞噬过程进入细胞诱导IL-8基因的表达。
Background:Nanoparticles refer to the manufactured particles less than 100 nm in diameter. They have been used for a wide variety of applications. Metal oxide nanomaterials (such as zinc oxide nanoparticles, ZnO-NPs) have been produced in high tonnage worldwide. ZnO-NPs can enter the human body through inhalation, skin contact, ingestion, and other routes. The results from human volunteer studies have shown that inhaled ZnO-NPs cause metal fume fever, with increased levels in inflammatory mediators, such as IL-8, and elevated number in polymorphonuclear leukocytes in bronchial-alveolar lavage fluid. The in vitro studies have demonstrated that exposure of human airway epithelial cells to ZnO-NPs results in excessive production of IL-8 protein. IL-8 protein in human airways is mainly derived from epithelial cells and plays a critical role in mediating the pathogenesis of exogenous toxicant-induced pulmonary disorders. Thus far, the mechanisms underlying ZnO-NPs-induced IL-8 gene expression in human bronchial epithelial cells remain unclear.
Aims:The aims of this study are to determine the effect of domestic ZnO-NPs (30nm in diameter) on IL-8 expression in human bronchial epithelial cells and to reveal the mechanisms underlying ZnO-NPs-induced IL-8 expression.
Methods:The human bronchial epithelial cell line BEAS-2B was used as the in vitro model. The MTT assay was employed to determine the damage levels of ZnO-NPs to BEAS-2B cells. Real-time PCR and ELISA were used to measure the expression levels of IL-8 mRNA and proteins, respectively. The involvement of transcription regulation in ZnO-NPs-induced IL-8 expression was examined using a selective transcription inhibitor and the BEAS-2B cell lines overexpressing recombinant wild-type or NFκB and C/EBPβbinding site mutated IL-8 promoter constructs. mRNA decay assay was used to determine the effect of ZnO-NPs on IL-8 mRNA stability. The role of phagocytosis in ZnO-NPs-induced IL-8 expression was explored using a phagocytosis inhibitor. The dissolution of ZnO-NPs in culture medium was determined using atom absorption spectrometry.
Results:Exposure of BEAS-2B cells to ZnO-NPs significantly increased the expression levels of IL-8 mRNA and protein in a dose-and time-dependent fashion (1-4μg/cm2,2-4 h) (p=0.000). Pretreatment of BEAS-2B cells with the transcription inhibitor actinomycin D (1μg/ml) for 30min abrogated IL-8 gene expression induced by ZnO-NPs (4μg/cm2,2 h) (p=0.000), implying the involvement of transcriptional regulation. Using the BEAS-2B cells that overexpress wilt-type or mutated IL-8 promoter constructs, we observed that the expression level of luciferase, the IL-8 promoter reporter gene, in ZnO-NPs-treated cells containing mutated IL-8 promoter constructs reduced markedly in compared to that in the cells containing the wild-type IL-8 promoter constructs, indicating that the transcription factors NFκB and C/EBPβwere required for ZnO-NPs-induced IL-8 gene transcription. mRNA decay assay following actinomycin D pretreatment showed that ZnO-NPs stimulation (4μg/cm2,2 h) delayed IL-8 mRNA degradation in BEAS-2B cells in comparison with the control, which suggested that ZnO-NPs exposure stabilized IL-8 mRNA in BEAS-2B cells at the posttranscriptional level. Pretreatment of BEAS-2B cells with the phagocytosis inhibitor cytochalasin B (10μg/ml) for 30 min blocked ZnO-NPs-induced IL-8 expression by 30.14%, implying that phagocytosis was partially involved in ZnO-NPs-induced IL-8 expression (p=0.000). A 8μg/ml concentration of ZnO-NPs (equivalent to 4μg/cm2 ZnO-NPs in one well of a 24 well plate) was dissolved in culture medium and incubated for 2 h at 37℃, resulting in a soluble or dissolved concentration of 4.3%or 3.57μM of Zn2+.
Conclusions:ZnO-NPs exposure increases IL-8 mRNA and protein expression in BEAS-2B cells. The transcription factors NFκB and C/EBPβare required for ZnO-NPs-induced IL-8 gene transcription. In addition, ZnO-NPs treatment can increase IL-8 mRNA stability. The phagocytosis of BEAS-2B cells partially mediates ZnO-NPs-induced IL-8 expression. A small portion of ZnO-NPs can be dissolved into soluble Zn2+ in culture medium.
[研究目的]阐明国产ZnO-NPs(30 nm)对人支气管上皮细胞IL-8基因表达的影响；揭示纳米氧化锌颗粒诱导IL-8基因表达的分子生物学机制。
[研究方法]以人支气管上皮细胞株(BEAS-2B)为体外模型。用MTT方法测定ZnO-NPs对细胞的损伤作用。用RT-PCR和ELISA方法分别测定ZnO-NPs对IL-8mRNA和蛋白表达水平的影响。使用转录抑制剂和表达突变IL-8基因促进子的BEAS-2B细胞株观察ZnO-NPs对IL-8基因转录的影响。利用IL-8 mRNA降解试验测定ZnO-NPs对转录后IL-8 mRNA稳定性的影响。利用胞噬作用抑制剂观察细胞吞噬作用在ZnO-NPs所致IL-8表达过程中的作用。此外,利用原子吸收光谱手段测定ZnO-NPs在培养液中的溶解水平。
[研究结果]ZnO-NPs刺激可致细胞内IL-8 mRNA水平及培养液上清中IL-8蛋白含量明显升高,该作用呈时间(2 h-4 h)及剂量(1μg/cm2-4μg/cm2)依赖性(P=0.000)。用转录抑制剂放线菌素D (1μg/ml)预处理细胞30 min,可显著降低ZnO-NPs (4μg/cm2,2 h)对IL-8 mRNA表达的诱导作用(P=0.000),表明ZnO-NPs在转录水平调控IL-8基因表达。利用可表达野生型、NFκ,B和C/EBPβ结合位点突变型IL-8促进子的BEAS-2B细胞株,观察到在表达突变IL-8促进子细胞内,ZnO-NPs (4μg/cm2,2 h)对IL-8转录活性的影响较在野生型细胞明显降低(P=0.000),说明转录因子NFκB和C/EBPβ参与调节纳米氧化锌对IL-8基因转录的诱导过程。在用放线菌素D终止IL-8 mRNA合成的前提下,ZnO-NPs(4μg/m2)可明显减缓细胞内IL-8 mRNA的降解,表现为在不同作用时间点(1h,2h,4h), ZnO-NPs处理组IL-8 mRNA水平均较相应对照组(无ZnO-NPs刺激)高(P值分别为0.021、0.002、0.001),说明ZnO-NPs对IL-8 mRNA有稳定作用。用细胞松弛素B(10μg/ml)预处理细胞30 min,可明显降低ZnO-NPs(4μg／cm2,2 h)对IL-8 mRNA表达的诱导作用(抑制率为30.14%)(P=0.000),提示部分ZnO-NPs可通过胞噬作用进入细胞进而诱导IL-8的表达。8μg/ml(相当于24孔培养板一孔内加入4μg/cm2 ZnO-NPs) ZnO-NPs在培养液中37℃温育2 h,有4.3%的ZnO-NPs溶解,培养液上清中锌离子的浓度为3.57μM。
[结论]ZnO-NPs刺激可明显提高人支气管上皮细胞内IL-8 mRNA和蛋白的表达水平；转录因子NFKB和C/EBPβ在ZnO-NPs所致IL-8基因转录过程中起重要调节作用；ZnO-NPs对细胞内IL-8 mRNA具有稳定作用；部分ZnO-NPs可通过胞噬过程进入细胞诱导IL-8基因的表达。
Background:Nanoparticles refer to the manufactured particles less than 100 nm in diameter. They have been used for a wide variety of applications. Metal oxide nanomaterials (such as zinc oxide nanoparticles, ZnO-NPs) have been produced in high tonnage worldwide. ZnO-NPs can enter the human body through inhalation, skin contact, ingestion, and other routes. The results from human volunteer studies have shown that inhaled ZnO-NPs cause metal fume fever, with increased levels in inflammatory mediators, such as IL-8, and elevated number in polymorphonuclear leukocytes in bronchial-alveolar lavage fluid. The in vitro studies have demonstrated that exposure of human airway epithelial cells to ZnO-NPs results in excessive production of IL-8 protein. IL-8 protein in human airways is mainly derived from epithelial cells and plays a critical role in mediating the pathogenesis of exogenous toxicant-induced pulmonary disorders. Thus far, the mechanisms underlying ZnO-NPs-induced IL-8 gene expression in human bronchial epithelial cells remain unclear.
Aims:The aims of this study are to determine the effect of domestic ZnO-NPs (30nm in diameter) on IL-8 expression in human bronchial epithelial cells and to reveal the mechanisms underlying ZnO-NPs-induced IL-8 expression.
Methods:The human bronchial epithelial cell line BEAS-2B was used as the in vitro model. The MTT assay was employed to determine the damage levels of ZnO-NPs to BEAS-2B cells. Real-time PCR and ELISA were used to measure the expression levels of IL-8 mRNA and proteins, respectively. The involvement of transcription regulation in ZnO-NPs-induced IL-8 expression was examined using a selective transcription inhibitor and the BEAS-2B cell lines overexpressing recombinant wild-type or NFκB and C/EBPβbinding site mutated IL-8 promoter constructs. mRNA decay assay was used to determine the effect of ZnO-NPs on IL-8 mRNA stability. The role of phagocytosis in ZnO-NPs-induced IL-8 expression was explored using a phagocytosis inhibitor. The dissolution of ZnO-NPs in culture medium was determined using atom absorption spectrometry.
Results:Exposure of BEAS-2B cells to ZnO-NPs significantly increased the expression levels of IL-8 mRNA and protein in a dose-and time-dependent fashion (1-4μg/cm2,2-4 h) (p=0.000). Pretreatment of BEAS-2B cells with the transcription inhibitor actinomycin D (1μg/ml) for 30min abrogated IL-8 gene expression induced by ZnO-NPs (4μg/cm2,2 h) (p=0.000), implying the involvement of transcriptional regulation. Using the BEAS-2B cells that overexpress wilt-type or mutated IL-8 promoter constructs, we observed that the expression level of luciferase, the IL-8 promoter reporter gene, in ZnO-NPs-treated cells containing mutated IL-8 promoter constructs reduced markedly in compared to that in the cells containing the wild-type IL-8 promoter constructs, indicating that the transcription factors NFκB and C/EBPβwere required for ZnO-NPs-induced IL-8 gene transcription. mRNA decay assay following actinomycin D pretreatment showed that ZnO-NPs stimulation (4μg/cm2,2 h) delayed IL-8 mRNA degradation in BEAS-2B cells in comparison with the control, which suggested that ZnO-NPs exposure stabilized IL-8 mRNA in BEAS-2B cells at the posttranscriptional level. Pretreatment of BEAS-2B cells with the phagocytosis inhibitor cytochalasin B (10μg/ml) for 30 min blocked ZnO-NPs-induced IL-8 expression by 30.14%, implying that phagocytosis was partially involved in ZnO-NPs-induced IL-8 expression (p=0.000). A 8μg/ml concentration of ZnO-NPs (equivalent to 4μg/cm2 ZnO-NPs in one well of a 24 well plate) was dissolved in culture medium and incubated for 2 h at 37℃, resulting in a soluble or dissolved concentration of 4.3%or 3.57μM of Zn2+.
Conclusions:ZnO-NPs exposure increases IL-8 mRNA and protein expression in BEAS-2B cells. The transcription factors NFκB and C/EBPβare required for ZnO-NPs-induced IL-8 gene transcription. In addition, ZnO-NPs treatment can increase IL-8 mRNA stability. The phagocytosis of BEAS-2B cells partially mediates ZnO-NPs-induced IL-8 expression. A small portion of ZnO-NPs can be dissolved into soluble Zn2+ in culture medium.
引文
[1] G. Oberdorster, E. Oberdorster, J. Oberdorster, et al. Nanotoxicology:An emerging discipline evolving from studies of ultrafine particles [J], Environ. Health Perspect, 2005,113(7):823～839 [2] Masciangioli T, Zhang WX. Environmental technologies at the nanoscale [J]. Environ Sci Technol,2003,37(5):102～108 [3] Colvin VL, The potential environmental impact of engineered nanomaterials [J]. Nat Biotechnol,2003,21:1166～1170 [4] Gunter Oberdorster, Eva Oberdorster, Jan Oberdorster.Nanotoxicology:An Emerging Discipline Evolving from Studies of Ultrafine Particles [J]. Environ Health Perspect, 2005,113:823～839 [5] Vicki Stone, Helinor Johnston, Martin J. D. Clift. Air Pollution, Ultrafine and Nanoparticle Toxicology:Cellular and Molecular Interactions [J]. IEEE Trans nanobioscience,2007,6(4):331～340 [6] H. M. Kipen, D. L. Laskin. Smaller is not always better:Nanotechnology yields nanotoxicology [J]. Amer J Physio Lung Cell Mol Physiol,2005,289:696～697 [7] Ma H, Bertsch PM, Glenn TC, et al. Toxicity of manufactured zinc oxide nanoparticles in the nematode Caenorhabditis elegans [J]. Environ Toxicol Chem,2009,28(6): 1324～1330 [8] Xia T, Kovochich M, Liong M, et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties [J]. ACS Nano,2008,2(10):2121～2134 [9] Blanc PD, Boushey HA, Wong H, et al. Cytokines in metal fume fever [J]. Am Rev Respir Dis,1993,147(1):134～138 [10]Gordon T, Chen LC, Fine JM, et al. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits [J]. Am Ind Hyg Assoc J,1992,53:503～509 [11]Kuschner WG, D'Alessandro A, Wong H, et al. Early pulmonary cytokine responses to zinc oxide fume inhalation [J]. Environ Res,1997,75:7-11 [12]Kuschner WG, D'Alessandro A, Wintermeyer SF, et al. Pulmonary responses to purified zinc oxide fume [J]. J Investig Med,1995,43(4):371-378 [13]Sayes CM, Reed KL, Warheit DB. Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles [J]. Toxicol Sci, 2007,97(1):163～180 [14]Warheit DB, Sayes CM, Reed KL. Nanoscale and fine zinc oxide particles:can in vitro assays accurately forecast lung hazards following inhalation exposures [J], Environ Sci Technol,2009,43(20):739～745
[15]Strieter RM. Interleukin-8:a very important chemokine of the human airway epithelium [J]. Am J Physiol Lung Cell Mol Physiol,2002,283:688～689
[16]Fritz EA, Jacobs JJ, Glant TT, et al. Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-kappaB [J]. J Orthop Res,2005,23:1249-1257
[17]Hirota R, Akimaru K, Nakamura H. In vitro toxicity evaluation of diesel exhaust particles on human eosinophilic cell [J]. Toxicol In Vitro,2008,22:988～994
[18]Kafoury RM, Kelley J. Ozone enhances diesel exhaust particles (DEP)-induced interleukin-8 (IL-8) gene expression in human airway epithelial cells through activation of nuclear factors-kappaB (NF-kappaB) and IL-6 (NF-IL6) [J]. Int J Environ Res Public Health,2005,2:403～410
[19]Sonoda Y, Kasahara T, Yamaguchi Y, et al. Stimulation of interleukin-8 production by okadaic acid and vanadate in a human promyelocyte cell line, an HL-60 subline. Possible role of mitogenactivated protein kinase on the okadaic acid-induced NF-kappaB activation [J]. J Biol Chem,1997,272:15366～15372
[20]Kasahara T, Mukaida N, Yamashita K, et al. IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line [J]. Immunology,1991,74:60～67
[21]Hobbie S, Chen LM, Davis RJ,et al. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells [J]. J Immunol,1997,159:5550～5559
[22]Johnston SL, Papi A, Bates PJ, et al. Low grade rhinovirus infection induces a prolonged release of IL-8 in pulmonary epithelium [J]. J Immunol,1998,160: 6172～6181
[23]Holtmann H, Enninga J, Kalble S, et al. The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation [J]. J Biol Chem,2001,276:3508-3516
[24]Holtmann H, Winzen R, Holland P, et al. Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine-or stress-activated signal transduction pathways [J]. Mol Cell Biol,1999,19:6742～6753
[25]Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism [J]. Embo J,1999,18:4969～4980
[26]Roebuck KA, Carpenter LR, Lakshminarayanan V, et al. Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kappaB [J]. J Leukoc Biol,1999,65:291～298
[27]Luster AD. Chemokines--chemotactic cytokines that mediate inflammation [J]. N Engl J Med,1998,338:436-445
[28]Wu GD, Lai EJ, Huang N, et al. Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor [J]. J Biol Chem,1997,272:2396～2403
[29]Medin CL, Rothman AL. Cell type-specific mechanisms of interleukin-8 induction by dengue virus and differential response to drug treatment [J]. J Infect Dis,2006,193: 1070～1077
[30]Madl AK, Pinkerton KE. Health effects of inhaled engineered and incidental nanoparticles [J].Crit Rev Toxicol,2009,39(8):629～58
[31]张巧,徐磊,任文杰,等.二氧化硅对人呼吸道上皮细胞及巨噬细胞内IL-8和TNFα的诱导作用[J].环境与职业医学,2009,26(4)：337～339
[32]赵嘉惠,张华屏,王春芳.MTT法在检测细胞增殖方面的探讨[J].山西医科大学学报,2007,38(3)：262～263
[33]Weidong Wu, James M. Samet, David B. Peden,et al. Phosphorylation ofp65 Is Required for Zinc Oxide Nanoparticle-induced Interlcukin 8 Expression in Human Bronchial Epithelial Cells [J]. Environ Health Perspect,2010,3:210～223
[34]Kaja Kasemets,Angela Ivask, Henri-Charles Dubourguier,et al. Toxicity of nanoparticles of ZnO, CuO and TiO2 to yeast Saccharomyces cerevisiae[J]. Toxicology in Vitro,2009, 23:1116～1122
[35]Weidong Wu,Robert A. Silbajoris,Dongsun Cao,et al. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc[J]. Toxicology and Applied Pharmacology,2008,231:260～266
[36]Yu-Mee Kim,William Reed,Weidong Wu,et al. Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells[J]. Am J Physiol Lung Cell Mol Physiol,2006,290:1028～1035
[37]Nair S, Sasidharan A, Divya Rani VV, et al. Role of size scale of ZnO nanoparticles and microparticles on toxicity toward bacteria and osteoblast cancer cells [J]. J Mater Sci Mater Med,2009,1:235～241
[38]Bischoff DS, Zhu JH, Makhijani NS, et al.Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (intedeukin-8), in human adult mesenchymal stem cells via the extracellular signd-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways [J]. J Cell biochem,2008,104(4):1378～1392
[39]Stemeek E, Zhu S, Ramirez A, et al. Conditional ablation qf C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis[J].Oncogene,2006,5(8):1272～1276
[40]Cloutier A, Guindi C, Larivee P, et al. Inflammatory cytokine production by human neutrophils involves C/EBP transcription factors [J]. J Immunol,2009,182(1):563～571
[41]Novoa I, Gallego J, Ferreira PG, et al. Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control [J]. Nat Cell Biol,2010,4:119-129
[42]White NM, Chow TF, Mejia-Guerrero S, et al.4.Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer [J]. Br J Cancer,2010,30: 119～126
[43]Lee HH, Vo MT, Kim HJ, et al. Stability of the lats2 tumor suppressor gene is regulated by tristetraprolin [J]. J Biol Chem,2010,285(15):101～126
[44]Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction [J]. Nat Rev Mol Cell Biol,2010,11(4):252～63
[45]Todd PK, Paulson HL. RNA-mediated neurodegeneration in repeat expansion disorders [J]. Ann Neural,2010,67(3):291～300
[46]Malecova B, Morris KV. Transcriptional gene silencing through epigenetic changes mediated by noncoding RNAs [J]. Curr Opin Mol Ther,2010,12(2):214～222
[47]Chong MM, Simpson N, Ciofani M, et al. Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells [J]. Genes Dev,2010,24(7): 659～669
[48]Zhao N, Guo Y, Zhang M, et al. Akt-mTOR signaling is involved in Notch-1-mediated glioma cell survival and proliferation [J]. Oncol Rep,2010,23(5):1443～1447
[49]Kim JY, Park HK, Yoon JS, et al. Molecular mechanisms of cellular proliferation in acute myelogenous leukemia by leptin [J]. Oncol Rep,2010,23(5):1369～1374
[50]Wu W, Silbajoris RA, Cao D, et al. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc [J]. Toxicol Appl Pharmacol,2008 231(2):260～266
[51]Cornell TT, Hinkovska-Galcheva V, Sun L, et al. Ceramide-dependent PP2A regulation of TNFalpha-induced IL-8 production in respiratory epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol,2009,296(5):849～856
[52]Rasmussen MK,lvemen L,Johansen C, et al.IL-8 and p53are inversely regulmed through JNK,p38 and NF-kappaB p65 in HepG2 cells during an inflammatory response[J]. Inflamm Res,2008,57(7):329～339
[53]Choi EY, Park zY, Choi FJ, et al.Transcriptional regulation of IL-8 by iron chelator in human epithelial cells is independent from NF-kappaB but involves ERK1/2-and p38 kinase-dependent activation of AP-1[J]. J Cell biochem,2007,102(6):1442～1457
[54]Zhang M, Zhu LJ, Jia ZY, et al. Chrysotile fibers induced apoptosis of human bronchial epithelial cells and effect of oxidation [J]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi,2009,27(1):11～15
[55]Baroli B, Ennas MG, Loffredo F, et al. Penetration of metallic nanoparticles in human full-thickness skin [J]. J Invest Dermatol,2007,127(7):1701～1712
[56]Yu-Mee Kim,William Reed, Weidong Wu, et al.Zn2+-induced IL-8 expression involves AP-1,JNK, and ERK activities in human airway epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol,2006,290:1028～1035
[57]Zhang Q, Wu W, Zhang T, et al. Involvement of EGF receptor and PI3K in ICAM-1 expression in human airway epithelial cells exposed to zinc sulfate [J]. Wei Sheng Yan Jiu,2008,37(5):552～557
[1]Williams D. Nanotechnology:a new look [J]. Med Device Technol,2004,15(8):9-10
[2]S. E. McNeil. Nanotechnology for the biologist [J]. J Leukoc Biol,2005,78:585～594
[3]R. F. Service. Nanotoxicology. nanotechnology grows up [J]. Science,2004,304:1732～1734
[4]P. H. Hoet, A. Nemmar, B. Nemery. Health impact of nanomaterials [J]? Nature Biotechnol, 2004,22:19～23
[5]G. Oberdorster, E. Oberdorster, J. Oberdorster, et al. Nanotoxicology:An emerging discipline evolving from studies of ultrafine particles [J]. Environ Health Perspect,2005,113:823～839
[6]G. M. Whitesides. The 'right' size in nanobiotechnology [J]. Nature Biotechnol,2003,21: 1161～1165
[7]G. A. Silva. Neuroscience nanotechnology:Progress, opportunities and challenges [J]. Nature Rev. Neurosci.,2006,7:65～74
[8]K. L. Dreher. Health and environmental impact of nanotechnology:Toxicological assessment of manufactured nanoparticles [J]. Toxicol Sci.,2004,77:3-5
[9]J. S. Tsuji, A. D. Maynard, P. C. Howard, et al. Research strategies for safety evaluation of nanomaterials, part Ⅳ:Risk assessment of nanoparticles [J]. Toxicol. Sci,2006,89:42～50
[10]M. C. Powell, M. S. Kanarek. Nanomaterial health effects-part 1:Background and current knowledge [J]. WMJ,2006,105:16～20
[11]R. Duncan. The dawning era of polymer therapeutics [J]. Nature Rev. Drug. Discov,2003,2: 347～360
[12]P. Sharma, S. Brown, G.Walter, et al. Nanoparticles for bioimaging [J]. Adv. Colloid Interface Sci,2006,123:471～485
[13]E. Hood. Nanotechnology:Looking as we leap [J]. Environ Health Perspect,2004,112: 740～749
[14]P. J. Borm, D. Robbins, S. Haubold, et al. The potential risks of nanomaterials:A review carried out for ECETOC [J]. Part Fibre. Toxicol,2006,3:11～20
[15]B. I. Lee, L. Qu, T. Copeland. Nanoparticle for materials design:Present and future [J]. J. Ceram. Process. Res.,2005,6:31～40
[16]K.Donaldson, V. Stone, C. L. Tran, et al. Nan-otoxicology [J]. Occup. Environ. Med,2004, 61:727～728
[17]Schmid K, Danuser B, Riediker M. Nanoparticle usage and protection measures in the manufacturing industry--a representative survey [J]. J Occup Environ Hyg,2010,7(4): 224～32
[18]R. J. Aitken,M. Q. Chaudhry, A. B. Boxall, et al. Manufacture and use of nanomaterials: Current status in the UK and global trends [J]. Occup. Med. (Lond.),2006,56:300～306
[19]Q. Chaudhry, M. Thomas, A. Boxall, et al. Ascoping study into the manufacture and use of nanomaterials in the UK Central Science Laboratory [D]. Sand Hutton, York, U.K.,2005
[20]A. Seaton. Nanotechnology and the occupational physician [J]. Occup. Med. (Lond.),2006, 56:312～316
[21]J. Schwartz. Air pollution and dailymortality:Areviewandmeta analysis [J]. Environ. Res., 1994,64:36～52
[22]D. W. Dockery, C. A. Pope, X. Xu, et al. An association between air pollution and mortality in six U.S. cities [J]. N. Engl. J. Med,1993,329:1753～1759
[23]C. A. Pope, Ⅲ, D. W. Dockery, et al. Respiratory health and PM10 pollution. A daily time series analysis [J]. Amer. Rev. Respir. Dis.,1991,144:668-674
[24]K. Donaldson, V. Stone. Current hypotheses on the mechanisms of toxicity of ultrafine particles [J]. Ann.1st Super Sanita,2003,39(3):405～410
[25]V. Stone. Environmental air pollution [J]. Amer. J. Respir. Crit. Care. Med.,2000,162: 44～47
[26]N. L. Mills, H. Tornqvist, S. D. Robinson, et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis [J]. Circulation,2005,112:3930～3936
[27]C. A. Pope, Ⅲ. Particulate pollution and health:A review of the utah valley experience [J]. J. Expo. Anal. Environ. Epidemiol,1996,6:23～34
[28]L. Clancy, P. Goodman, H. Sinclair, et al. Effect of air-pollution control on death rates in Dublin, Ireland:An intervention study [J]. Lancet,2002,360:1210～1214
[29]A. J. Ghio, R. B. Devlin. Inflammatory lung injury after bronchial instillation of air pollution particles [J]. Amer. J. Respir. Crit. Care.Med.,2001,164:704～708
[30]X. Y. Li, D. Brown, S. Smith, et al. Shortterm inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats [J]. Inhal. Toxicol,1999,11:709～731
[31]P. S. Gilmour, I. Rahman, K. Donaldson, et al. Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress from environmental particles [J]. Amer. J. Physiol Lung Cell Mol. Physiol,2003,284:533-540
[32]D. M. Brown, L. Hutchison, K. Donaldson, et al. The effects of PM10 particles and oxidative stress onmacrophages and lung epithelial cells:Modulating effects of calcium signalling antagonists [J]. Amer. J. Physiol Lung Cell Mol. Physiol,2007,292(6):1444～1452
[33]M. W. Frampton, A. J. Ghio, J. M. Samet, et al. Effects of aqueous extracts of PM(10) filters from the utah valley on human airway epithelial cells [J]. Amer. J. Physiol,1999,277: 960～967
[34]G. R. Hutchison, D.M. Brown, L. R. Hibbs, et al. The effect of refurbishing a UK steel plant on PM10 metal composition and ability to induce inflammation [J]. Respir. Res.,2005,6: 43～49
[35]R. P. Schins, J. H. Lightbody, P. J. Borm, et al. Inflammatory effects of coarse and fine particulate matter in relation to chemical and biological constituents [J]. Toxicol. Appl. Pharmacol.,2004,195:1～11
[36]A. Seaton, W. MacNee, K. Donaldson, et al. Particulate air pollution and acute health effects [J]. Lancet,1995,345:176～178
[37]A. Peters, A. Doring, H. E. Wichmann, et al. Increased plasma viscosity during an air pollution episode:A link to mortality? Lancet,1997,349:1582～1587
[38]J. Ferin, G. Oberdorster, D. P. Penney. Pulmonary retention of ultrafine and fine particles in rats [J]. Amer. J. Respir. Cell. Mol. Biol.,1992,6:535～542
[39]N. Li, M. Karin. Is NF-kappaB the sensor of oxidative stress [J]? FASEB J.,1999,13: 1137～1143
[40]D. M. Brown, V. Stone, P. Findlay, et al. Increased inflammation and intracellular calcium caused by ultrafine carbon black is independent of transition metals or other soluble com-ponents [J]. Occup. Environ. Med.,2000,57:685～691
[41]T. Stoeger, C. Reinhard, S. Takenaka, et al. Instillation of six different ultrafine carbon particles indicates a surface area threshold dose for acute lung inflam-mation in mice [J]. Environ. Health Perspect,2006,114:328～333
[42]D.M. Brown, M. R.Wilson, W.MacNee, et al. Size-dependent proinflammatory effects of ultrafine polystyrene par-ticles:A role for surface area and oxidative stress in the enhanced activity of ultrafines [J]. Toxicol. Appl. Pharmacol.,2001,175:191～199
[43]P. S.Gilmour, P. H. Beswick, D.M. Brown,et al. Detection of surface free radical activity of respirable industrial fibres using supercoiled phi X174 RF1 plasmid DNA [J]. Carcinogenesis, 1995,16:2973～2979
[44]P. S.Gilmour, D.M. Brown, T.G. Lindsay, et al. Adverse health effects of PM10 particles: Involvement of iron in generation of hydroxyl radical [J]. Occup. Environ. Med.,1996,53: 817～822
[45]V. Stone, J. Shaw, D. M. Brown, et al. The role of oxidative stress in the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function [J]. Toxicol. In Vitro,1998,12: 649～659
[46]C.A.Dick, D.M. Brown, K.Donaldson, et al. The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types [J]. Inhal. Toxicol,2003,15: 39～52
[47]M. R. Wilson, J. H. Lightbody, K. Donaldson, et al. Interactions between ultrafine particles and transition metals in vivo and in vitro [J]. Toxicol. Appl. Pharmacol.,2002,184:172～179
[48]R. Cathcart, E. Schwiers, B. N. Ames. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay [J]. Anal. Biochem,1983,134:111～116
[49]H. Zhu,G. L. Bannenberg, P.Moldeus, et al. Oxidation pathways for the intracellular probe 2', 7'-dichlorofluorescein. Arch. Toxicol.,1994,68:582-587
[50]W. MacNee, I. Rahman. Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease [J]? Trends Mol. Med.,2001,7:55～62
[51]C. M. Sayes, A. M. Gobin, K. D. Ausman, et al. Nano-C60 cytotoxicity is due to lipid peroxidation [J]. Biomaterials,2005,26:7587～7595
[52]X. Y. Li, P. S. Gilmour, K. Donaldson, et al. In vivo and in vitro proinflammatory effects of particulate air pollution (PM10) Environ [J]. Health Perspect.105 Suppl.,1997,5: 1279～1283
[53]V. Stone, M. Tuinman, J. E. Vamvakopoulos, et al. Increased calcium influx in a monocytic cell line on ex-posure to ultrafine carbon black [J]. Eur. Respir. J.,2000,15:297～303
[54]L. A. Jimenez, E. M. Drost, P. S. Gilmour, et al. PM(10)-exposed macrophages stimulate a proinflammatory response in lung epithelial cells via TNF-alpha [J]. Amer. J. Physiol. Lung. Cell. Mol. Physiol.,2002,282:237～248
[55]D. M. Brown, K. Donaldson, V. Stone. Role of calcium in the induction of TNF expression by macrophages on exposure to ultrafine particles [J]. Ann. Occup. Hyg,2002,46:219～222
[56]I. Rahman. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases [J]. J. Biochem. Mol. Biol.,2003,36:95～109
[57]M. S. Byun, K. I. Jeon, J. W. Choi, et al. Dual effect of oxidative stress onNF-kappakB activation inHeLa cells [J]. Exp. Mol. Med.,2002,34:332-339
[58]M. J. Berridge. Calciumsignal transduction and cellular controlmech-anisms [J]. Biochim. Biophys. Acta,2004,1742:3-7
[59]S. Orrenius, M. J. Burkitt, G. E. Kass, et al. Calcium ions and oxidative cell injury [J]. Ann. Neurol.,1992,32:33～42
[60]K. A. Barnes, S. E. Samson, A. K. Grover. Sarco/endoplasmic reticulum Ca-pump isoform SERCA3a is more resistant to superoxide damage than SERCA2b [J]. Mol. Cell. Biochem, 2000,203:17～21
[61]J. I. Kourie. Interaction of reactive oxygen species with ion transport mechanisms [J]. Amer. J.Physiol.,1998,275:1-24
[62]I. V. Deaciuc, J. A. Spitzer. Calcium content in liver and heart and its intracellular distribution in liver during endotoxicosis and sepsis in rats [J]. Cell. Calcium,1987,8: 365～376
[63]V. Stone, D. M. Brown, N. Watt,et al. Ultrafine particle-mediated activation of macrophages: Intracellular calcium signaling and oxidative stress [J]. Inhal. Toxicol,2000,12:345～351
[64]D. M. Brown, K. Donaldson, P. J. Borm, et al. Calcium and reactive oxygen species-mediated activation of transcription factors and TNFa cytokine gene expression in macrophages exposed to ultrafine particles [J]. Amer. J. Physiol. Lung. Cell. Mol. Physiol., 2004,286:344-353
[65]A. Baulig, M. Garlatti, V. Bonvallot, et al. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Amer. J. Physiol. Lung [J]. Cell. Mol. Physiol.,2003,285:671～679
[66]T. Ishii, K. Itoh, H. Sato, et al. Oxidative stress-inducible proteins inmacrophages. Free Radic. Res.,1999,31:351～355
[67]T. Ishii, K. Itoh, S. Takahashi, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages [J]. J. Biol. Chem.,2000,275: 16023～16029
[68]N. Li, J. Alam, M. I. Venkatesan, A. Eiguren-Fernandez, et al. Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells:Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals [J]. J. Immunol.,2004,173:3467～3481
[69]D. Ng, N. Kokot, T. Hiura, et al. Macrophage activation by polycyclic aromatic hydrocarbons:Evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements [J]. J. Immunol.,1998,161:942～951
[70]L. C. Renwick, K. Donaldson, A. Clouter. Impairment of alveolar macrophage phagocytosis by ultrafine particles [J]. Toxicol. Appl. Pharmacol.,2001,172:119～127
[71]P. H. Hoet, B. Nemery. Stimulation of phagocytosis by ultrafine particles [J]. Toxicol. Appl. Pharmacol.,2001,176:203-211
[72]M. Geiser, N. Kapp, S. Schurch, et al. Ultrafine particles cross cellular membranes by non-phagocytic mechanisms in lungs and in cultured cells [J]. Environ.Health Perspect., 2005,113(11):1555～1560
[73]C.Montellier, C. L. Tran, W.MacNee, et al. The pro-inflammatory effects of low solublity low toxicity particles, nanoparticles and fine particles on epithelial cells in vitro:The role of surface area and surface reactivity [J]. Occup. Environ. Med.,2006,12:23-31
[74]R. P. Schins, A.McAlinden, W.MacNee, et al. Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles [J]. Toxicol. Appl. Pharmacol.,2000,167:107～117
[75]L. Ramage, K. Guy. Expression of C-reactive protein and heatshock protein-70 in the lung epithelial cell line A549, in response to PM10 exposure [J]. Inhal. Toxicol,2004,16: 447～452
[76]L. Ramage, L. Proudfoot, K. Guy. Expression of C-reactive protein in human lung epithelial cells and upregulation by cytokines and carbon particles [J]. Inhal. Toxicol,2004,16: 607～613
[77]N. R. Madamanchi, S. Li, C. Patterson, et al. Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. Arterioscler [J]. Thromb. Vasc. Biol.,2001,21: 321～326
[78]G. Kohn, H. R. Wong, K. Bshesh, et al. Heat shock inhibits tnf-induced ICAM-1 expression in human endothelial cells via I kappa kinase in-hibition [J]. Shock,2002,17:91～97
[79]C. R. Timblin, Y. M. Janssen, J. L. Goldberg,et al. GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed to asbestos, cadmium, or H2O2 [J]. Free Radic. Biol. Med.,1998,24:632～642
[80]A. Asea, S. K. Kraeft, E. A. Kurt-Jones, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine [J]. Nature Med.,2000,6:435～442
[81]A. G. Pockley, A. Georgiades, T. Thulin, et al. Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension [J]. Hypertension, 2003,42:235～238
[82]K. L. Dreher. Health and environmental impact of nanotechnology:Toxicological assessment of manufactured nanoparticles [J]. Toxicol Sci,2004,77:3-5
[83]J. S. Tsuji, A. D. Maynard, P. C. Howard, et al. Research strategies for safety evaluation of nanomaterials, part Ⅳ:Risk assessment of nanoparticles [J].Toxicol Sci,2006,89:42～50.
[84]M. C. Powell, M. S. Kanarek. Nanomaterial health effects-part 1:Background and current knowledge [J]. WMJ,2006,105:16～20
[85]Tian Xia, Michael Kovochich, Monty Liong, et al. Comparison of the Mechanism of Toxicity of Zinc Oxide and Cerium Oxide Nanoparticles Based on Dissolution and Oxidative Stress Properties [J]. ACS Nano,2008,2:2121～2134
[86]G. A. Silva. Neuroscience nanotechnology:Progress, opportunities and challenges [J]. Nature Rev Neurosci,2006,7:65～74
[87]Gordon T, Chen LC, Fine JM, et al. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits [J]. Am Ind Hyg Assoc J,1992,53:503～509
[88]Kuschner WG, D'Alessandro A, Wong H, et al. Early pulmonary cytokine responses to zinc oxide fume inhalation [J]. Environ Res,1997,75:7-11
[89]Blanc PD, Boushey HA, Wong H, et al. Cytokines in metal fume fever [J]. Am Rev Respir Dis,1993,147:134-138
[90]Kuschner WG, D'Alessandro A, Wintermeyer SF, et al. Pulmonary responses to purified zinc oxide fume [J]. J Investig Med,1995,43:371～378
[91]吴诚,文利新,袁慧.纳米氧化锌对小鼠的毒性试验[J].粮食与饲料工业,2008,(05)：38～39
[92]Wang B, Feng WY, Wang TC, et al. Acute toxicity of nano-and micro-scale zinc powder in healthy adult mice [J]. Toxicol Lett,2008,10:263～276
[93]杨辉,刘超,杨丹凤,等.碳、氧化锌和碳载氧化锌复合纳米颗粒对小鼠胚胎成纤维细胞活性抑制及DNA损伤的研究[J].卫生研究,2008,37(1)：12-15
[94]Nel A, Xia T, Madler L, et al. Toxic Potential of Materials at the Nanolevel [J]. Science,2006, 311:622～627
[95]Donaldson K, Stone V. Borm P J, et al. Oxidative Stress and Calcium Signaling in the Adverse Effects of Environmental Particles (PM10) [J]. Free Radical Biol Med,2003,34: 1369-1382
[96]Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology:An Emerging Discipline Evolving from Studies of Ultrafine Particles [J]. Environ Health Perspect,2005,113: 823～839
[97]Xia T, Kovochich M, Nel A. The Role of Reactive Oxygen Species and Oxidative Stress in Mediating Particulate Matter Injury [J]. Clin Occup Environ Med,2006,5:817～836
[98]Hongbo MA, Paul M.Bertsch, Travis C. Glenn, et al. Toxicity of Manufactured Zinc Oxide Nanoparticles in the Nematode Caenorhabditis Elegans. Environmental [J] Toxicology and Chemistry,2009,28(6):1324～1330
[99]Holsapple MP, Farland WH, Landry TD, et al. Research strategies for safety evaluation of nanomaterials, Part Ⅱ:Toxicological and safety evaluation of nanomaterials, current challenges and data needs [J].Toxicol Sci,2005,88:12～17
[100]Stella W. Y. Wong, Priscilla T. Y. Leung, A. B. Djurisic, et al. Toxicities of nano zinc oxide to five marine organisms:influences of aggregate size and ion solubility [J]. Anal Bioanal Chem,2010,396:609～618
[101]Franklin NM, Rogers NJ, Apte SC, et al. Comparative toxicity of nanoparticulate ZnO, bulk ZnO, and ZnCl to a freshwater microalga (Pseudokirchneriella subcapitata):the importance of particle solubility [J]. Environ Sci Technol,2007,41:8484～8490
[102]Wang H, Wick RL, Xing B. Toxicity of nanoparticulate and bulk ZnO, A12O3 and TiO2 to the nematode Caenorhabditis elegans [J]. Environ Pollut,2009,157:1171～1177
[103]Zhu X, Zhu L, Duan Z, et al. Comparative toxicity of several metal oxide nanoparticles aqueous suspensions to zebrafish (Danio rerio) early developmental stage [J]. J Environ Sci Heal A,2008,43:278～284
[104]Aruoja V, Dubourguier H, Kasemets K, et al. Toxicity of nanoparticles of CuO, ZnO and TiO2 to microalgae Pseudokirchneriella subcaptitata [J]. Sci Total Environ,2009,407: 1461～1468
[105]Handy RD, Owen R, Valsami-Jones E. The ecotoxicology of nanoparticles and nanomaterials:current status, knowledge gaps, challenges, and future needs [J]. Ecotoxicology,2008,17:315～325
[106]Xiaoyong Deng, Qixia Luan, Wenting Chen, et al. Nanosized zinc oxide particles induce neural stem cell apoptosis [J]. Nanotechnology,2009,20:1-7
[107]K M Reddy, Kevin feris, Jason Bell,et al. Selective toxicity of zinc oxide nanoparticles to prokaryotic and eukaryotic systems [J]. Appl Phys Lett,2007,90:1-3
[108]Vyom Sharmaa, Ritesh K. Shuklaa, Neha Saxenab, et al. DNA damaging potential of zinc oxide nanoparticles in human epidermal cells [J]. Oxicology Letters,2009,185: 211～218
[15]Strieter RM. Interleukin-8:a very important chemokine of the human airway epithelium [J]. Am J Physiol Lung Cell Mol Physiol,2002,283:688～689
[16]Fritz EA, Jacobs JJ, Glant TT, et al. Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-kappaB [J]. J Orthop Res,2005,23:1249-1257
[17]Hirota R, Akimaru K, Nakamura H. In vitro toxicity evaluation of diesel exhaust particles on human eosinophilic cell [J]. Toxicol In Vitro,2008,22:988～994
[18]Kafoury RM, Kelley J. Ozone enhances diesel exhaust particles (DEP)-induced interleukin-8 (IL-8) gene expression in human airway epithelial cells through activation of nuclear factors-kappaB (NF-kappaB) and IL-6 (NF-IL6) [J]. Int J Environ Res Public Health,2005,2:403～410
[19]Sonoda Y, Kasahara T, Yamaguchi Y, et al. Stimulation of interleukin-8 production by okadaic acid and vanadate in a human promyelocyte cell line, an HL-60 subline. Possible role of mitogenactivated protein kinase on the okadaic acid-induced NF-kappaB activation [J]. J Biol Chem,1997,272:15366～15372
[20]Kasahara T, Mukaida N, Yamashita K, et al. IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line [J]. Immunology,1991,74:60～67
[21]Hobbie S, Chen LM, Davis RJ,et al. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells [J]. J Immunol,1997,159:5550～5559
[22]Johnston SL, Papi A, Bates PJ, et al. Low grade rhinovirus infection induces a prolonged release of IL-8 in pulmonary epithelium [J]. J Immunol,1998,160: 6172～6181
[23]Holtmann H, Enninga J, Kalble S, et al. The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation [J]. J Biol Chem,2001,276:3508-3516
[24]Holtmann H, Winzen R, Holland P, et al. Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine-or stress-activated signal transduction pathways [J]. Mol Cell Biol,1999,19:6742～6753
[25]Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism [J]. Embo J,1999,18:4969～4980
[26]Roebuck KA, Carpenter LR, Lakshminarayanan V, et al. Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kappaB [J]. J Leukoc Biol,1999,65:291～298
[27]Luster AD. Chemokines--chemotactic cytokines that mediate inflammation [J]. N Engl J Med,1998,338:436-445
[28]Wu GD, Lai EJ, Huang N, et al. Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor [J]. J Biol Chem,1997,272:2396～2403
[29]Medin CL, Rothman AL. Cell type-specific mechanisms of interleukin-8 induction by dengue virus and differential response to drug treatment [J]. J Infect Dis,2006,193: 1070～1077
[30]Madl AK, Pinkerton KE. Health effects of inhaled engineered and incidental nanoparticles [J].Crit Rev Toxicol,2009,39(8):629～58
[31]张巧,徐磊,任文杰,等.二氧化硅对人呼吸道上皮细胞及巨噬细胞内IL-8和TNFα的诱导作用[J].环境与职业医学,2009,26(4)：337～339
[32]赵嘉惠,张华屏,王春芳.MTT法在检测细胞增殖方面的探讨[J].山西医科大学学报,2007,38(3)：262～263
[33]Weidong Wu, James M. Samet, David B. Peden,et al. Phosphorylation ofp65 Is Required for Zinc Oxide Nanoparticle-induced Interlcukin 8 Expression in Human Bronchial Epithelial Cells [J]. Environ Health Perspect,2010,3:210～223
[34]Kaja Kasemets,Angela Ivask, Henri-Charles Dubourguier,et al. Toxicity of nanoparticles of ZnO, CuO and TiO2 to yeast Saccharomyces cerevisiae[J]. Toxicology in Vitro,2009, 23:1116～1122
[35]Weidong Wu,Robert A. Silbajoris,Dongsun Cao,et al. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc[J]. Toxicology and Applied Pharmacology,2008,231:260～266
[36]Yu-Mee Kim,William Reed,Weidong Wu,et al. Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells[J]. Am J Physiol Lung Cell Mol Physiol,2006,290:1028～1035
[37]Nair S, Sasidharan A, Divya Rani VV, et al. Role of size scale of ZnO nanoparticles and microparticles on toxicity toward bacteria and osteoblast cancer cells [J]. J Mater Sci Mater Med,2009,1:235～241
[38]Bischoff DS, Zhu JH, Makhijani NS, et al.Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (intedeukin-8), in human adult mesenchymal stem cells via the extracellular signd-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways [J]. J Cell biochem,2008,104(4):1378～1392
[39]Stemeek E, Zhu S, Ramirez A, et al. Conditional ablation qf C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis[J].Oncogene,2006,5(8):1272～1276
[40]Cloutier A, Guindi C, Larivee P, et al. Inflammatory cytokine production by human neutrophils involves C/EBP transcription factors [J]. J Immunol,2009,182(1):563～571
[41]Novoa I, Gallego J, Ferreira PG, et al. Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control [J]. Nat Cell Biol,2010,4:119-129
[42]White NM, Chow TF, Mejia-Guerrero S, et al.4.Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer [J]. Br J Cancer,2010,30: 119～126
[43]Lee HH, Vo MT, Kim HJ, et al. Stability of the lats2 tumor suppressor gene is regulated by tristetraprolin [J]. J Biol Chem,2010,285(15):101～126
[44]Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction [J]. Nat Rev Mol Cell Biol,2010,11(4):252～63
[45]Todd PK, Paulson HL. RNA-mediated neurodegeneration in repeat expansion disorders [J]. Ann Neural,2010,67(3):291～300
[46]Malecova B, Morris KV. Transcriptional gene silencing through epigenetic changes mediated by noncoding RNAs [J]. Curr Opin Mol Ther,2010,12(2):214～222
[47]Chong MM, Simpson N, Ciofani M, et al. Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells [J]. Genes Dev,2010,24(7): 659～669
[48]Zhao N, Guo Y, Zhang M, et al. Akt-mTOR signaling is involved in Notch-1-mediated glioma cell survival and proliferation [J]. Oncol Rep,2010,23(5):1443～1447
[49]Kim JY, Park HK, Yoon JS, et al. Molecular mechanisms of cellular proliferation in acute myelogenous leukemia by leptin [J]. Oncol Rep,2010,23(5):1369～1374
[50]Wu W, Silbajoris RA, Cao D, et al. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc [J]. Toxicol Appl Pharmacol,2008 231(2):260～266
[51]Cornell TT, Hinkovska-Galcheva V, Sun L, et al. Ceramide-dependent PP2A regulation of TNFalpha-induced IL-8 production in respiratory epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol,2009,296(5):849～856
[52]Rasmussen MK,lvemen L,Johansen C, et al.IL-8 and p53are inversely regulmed through JNK,p38 and NF-kappaB p65 in HepG2 cells during an inflammatory response[J]. Inflamm Res,2008,57(7):329～339
[53]Choi EY, Park zY, Choi FJ, et al.Transcriptional regulation of IL-8 by iron chelator in human epithelial cells is independent from NF-kappaB but involves ERK1/2-and p38 kinase-dependent activation of AP-1[J]. J Cell biochem,2007,102(6):1442～1457
[54]Zhang M, Zhu LJ, Jia ZY, et al. Chrysotile fibers induced apoptosis of human bronchial epithelial cells and effect of oxidation [J]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi,2009,27(1):11～15
[55]Baroli B, Ennas MG, Loffredo F, et al. Penetration of metallic nanoparticles in human full-thickness skin [J]. J Invest Dermatol,2007,127(7):1701～1712
[56]Yu-Mee Kim,William Reed, Weidong Wu, et al.Zn2+-induced IL-8 expression involves AP-1,JNK, and ERK activities in human airway epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol,2006,290:1028～1035
[57]Zhang Q, Wu W, Zhang T, et al. Involvement of EGF receptor and PI3K in ICAM-1 expression in human airway epithelial cells exposed to zinc sulfate [J]. Wei Sheng Yan Jiu,2008,37(5):552～557
[1]Williams D. Nanotechnology:a new look [J]. Med Device Technol,2004,15(8):9-10
[2]S. E. McNeil. Nanotechnology for the biologist [J]. J Leukoc Biol,2005,78:585～594
[3]R. F. Service. Nanotoxicology. nanotechnology grows up [J]. Science,2004,304:1732～1734
[4]P. H. Hoet, A. Nemmar, B. Nemery. Health impact of nanomaterials [J]? Nature Biotechnol, 2004,22:19～23
[5]G. Oberdorster, E. Oberdorster, J. Oberdorster, et al. Nanotoxicology:An emerging discipline evolving from studies of ultrafine particles [J]. Environ Health Perspect,2005,113:823～839
[6]G. M. Whitesides. The 'right' size in nanobiotechnology [J]. Nature Biotechnol,2003,21: 1161～1165
[7]G. A. Silva. Neuroscience nanotechnology:Progress, opportunities and challenges [J]. Nature Rev. Neurosci.,2006,7:65～74
[8]K. L. Dreher. Health and environmental impact of nanotechnology:Toxicological assessment of manufactured nanoparticles [J]. Toxicol Sci.,2004,77:3-5
[9]J. S. Tsuji, A. D. Maynard, P. C. Howard, et al. Research strategies for safety evaluation of nanomaterials, part Ⅳ:Risk assessment of nanoparticles [J]. Toxicol. Sci,2006,89:42～50
[10]M. C. Powell, M. S. Kanarek. Nanomaterial health effects-part 1:Background and current knowledge [J]. WMJ,2006,105:16～20
[11]R. Duncan. The dawning era of polymer therapeutics [J]. Nature Rev. Drug. Discov,2003,2: 347～360
[12]P. Sharma, S. Brown, G.Walter, et al. Nanoparticles for bioimaging [J]. Adv. Colloid Interface Sci,2006,123:471～485
[13]E. Hood. Nanotechnology:Looking as we leap [J]. Environ Health Perspect,2004,112: 740～749
[14]P. J. Borm, D. Robbins, S. Haubold, et al. The potential risks of nanomaterials:A review carried out for ECETOC [J]. Part Fibre. Toxicol,2006,3:11～20
[15]B. I. Lee, L. Qu, T. Copeland. Nanoparticle for materials design:Present and future [J]. J. Ceram. Process. Res.,2005,6:31～40
[16]K.Donaldson, V. Stone, C. L. Tran, et al. Nan-otoxicology [J]. Occup. Environ. Med,2004, 61:727～728
[17]Schmid K, Danuser B, Riediker M. Nanoparticle usage and protection measures in the manufacturing industry--a representative survey [J]. J Occup Environ Hyg,2010,7(4): 224～32
[18]R. J. Aitken,M. Q. Chaudhry, A. B. Boxall, et al. Manufacture and use of nanomaterials: Current status in the UK and global trends [J]. Occup. Med. (Lond.),2006,56:300～306
[19]Q. Chaudhry, M. Thomas, A. Boxall, et al. Ascoping study into the manufacture and use of nanomaterials in the UK Central Science Laboratory [D]. Sand Hutton, York, U.K.,2005
[20]A. Seaton. Nanotechnology and the occupational physician [J]. Occup. Med. (Lond.),2006, 56:312～316
[21]J. Schwartz. Air pollution and dailymortality:Areviewandmeta analysis [J]. Environ. Res., 1994,64:36～52
[22]D. W. Dockery, C. A. Pope, X. Xu, et al. An association between air pollution and mortality in six U.S. cities [J]. N. Engl. J. Med,1993,329:1753～1759
[23]C. A. Pope, Ⅲ, D. W. Dockery, et al. Respiratory health and PM10 pollution. A daily time series analysis [J]. Amer. Rev. Respir. Dis.,1991,144:668-674
[24]K. Donaldson, V. Stone. Current hypotheses on the mechanisms of toxicity of ultrafine particles [J]. Ann.1st Super Sanita,2003,39(3):405～410
[25]V. Stone. Environmental air pollution [J]. Amer. J. Respir. Crit. Care. Med.,2000,162: 44～47
[26]N. L. Mills, H. Tornqvist, S. D. Robinson, et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis [J]. Circulation,2005,112:3930～3936
[27]C. A. Pope, Ⅲ. Particulate pollution and health:A review of the utah valley experience [J]. J. Expo. Anal. Environ. Epidemiol,1996,6:23～34
[28]L. Clancy, P. Goodman, H. Sinclair, et al. Effect of air-pollution control on death rates in Dublin, Ireland:An intervention study [J]. Lancet,2002,360:1210～1214
[29]A. J. Ghio, R. B. Devlin. Inflammatory lung injury after bronchial instillation of air pollution particles [J]. Amer. J. Respir. Crit. Care.Med.,2001,164:704～708
[30]X. Y. Li, D. Brown, S. Smith, et al. Shortterm inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats [J]. Inhal. Toxicol,1999,11:709～731
[31]P. S. Gilmour, I. Rahman, K. Donaldson, et al. Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress from environmental particles [J]. Amer. J. Physiol Lung Cell Mol. Physiol,2003,284:533-540
[32]D. M. Brown, L. Hutchison, K. Donaldson, et al. The effects of PM10 particles and oxidative stress onmacrophages and lung epithelial cells:Modulating effects of calcium signalling antagonists [J]. Amer. J. Physiol Lung Cell Mol. Physiol,2007,292(6):1444～1452
[33]M. W. Frampton, A. J. Ghio, J. M. Samet, et al. Effects of aqueous extracts of PM(10) filters from the utah valley on human airway epithelial cells [J]. Amer. J. Physiol,1999,277: 960～967
[34]G. R. Hutchison, D.M. Brown, L. R. Hibbs, et al. The effect of refurbishing a UK steel plant on PM10 metal composition and ability to induce inflammation [J]. Respir. Res.,2005,6: 43～49
[35]R. P. Schins, J. H. Lightbody, P. J. Borm, et al. Inflammatory effects of coarse and fine particulate matter in relation to chemical and biological constituents [J]. Toxicol. Appl. Pharmacol.,2004,195:1～11
[36]A. Seaton, W. MacNee, K. Donaldson, et al. Particulate air pollution and acute health effects [J]. Lancet,1995,345:176～178
[37]A. Peters, A. Doring, H. E. Wichmann, et al. Increased plasma viscosity during an air pollution episode:A link to mortality? Lancet,1997,349:1582～1587
[38]J. Ferin, G. Oberdorster, D. P. Penney. Pulmonary retention of ultrafine and fine particles in rats [J]. Amer. J. Respir. Cell. Mol. Biol.,1992,6:535～542
[39]N. Li, M. Karin. Is NF-kappaB the sensor of oxidative stress [J]? FASEB J.,1999,13: 1137～1143
[40]D. M. Brown, V. Stone, P. Findlay, et al. Increased inflammation and intracellular calcium caused by ultrafine carbon black is independent of transition metals or other soluble com-ponents [J]. Occup. Environ. Med.,2000,57:685～691
[41]T. Stoeger, C. Reinhard, S. Takenaka, et al. Instillation of six different ultrafine carbon particles indicates a surface area threshold dose for acute lung inflam-mation in mice [J]. Environ. Health Perspect,2006,114:328～333
[42]D.M. Brown, M. R.Wilson, W.MacNee, et al. Size-dependent proinflammatory effects of ultrafine polystyrene par-ticles:A role for surface area and oxidative stress in the enhanced activity of ultrafines [J]. Toxicol. Appl. Pharmacol.,2001,175:191～199
[43]P. S.Gilmour, P. H. Beswick, D.M. Brown,et al. Detection of surface free radical activity of respirable industrial fibres using supercoiled phi X174 RF1 plasmid DNA [J]. Carcinogenesis, 1995,16:2973～2979
[44]P. S.Gilmour, D.M. Brown, T.G. Lindsay, et al. Adverse health effects of PM10 particles: Involvement of iron in generation of hydroxyl radical [J]. Occup. Environ. Med.,1996,53: 817～822
[45]V. Stone, J. Shaw, D. M. Brown, et al. The role of oxidative stress in the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function [J]. Toxicol. In Vitro,1998,12: 649～659
[46]C.A.Dick, D.M. Brown, K.Donaldson, et al. The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types [J]. Inhal. Toxicol,2003,15: 39～52
[47]M. R. Wilson, J. H. Lightbody, K. Donaldson, et al. Interactions between ultrafine particles and transition metals in vivo and in vitro [J]. Toxicol. Appl. Pharmacol.,2002,184:172～179
[48]R. Cathcart, E. Schwiers, B. N. Ames. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay [J]. Anal. Biochem,1983,134:111～116
[49]H. Zhu,G. L. Bannenberg, P.Moldeus, et al. Oxidation pathways for the intracellular probe 2', 7'-dichlorofluorescein. Arch. Toxicol.,1994,68:582-587
[50]W. MacNee, I. Rahman. Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease [J]? Trends Mol. Med.,2001,7:55～62
[51]C. M. Sayes, A. M. Gobin, K. D. Ausman, et al. Nano-C60 cytotoxicity is due to lipid peroxidation [J]. Biomaterials,2005,26:7587～7595
[52]X. Y. Li, P. S. Gilmour, K. Donaldson, et al. In vivo and in vitro proinflammatory effects of particulate air pollution (PM10) Environ [J]. Health Perspect.105 Suppl.,1997,5: 1279～1283
[53]V. Stone, M. Tuinman, J. E. Vamvakopoulos, et al. Increased calcium influx in a monocytic cell line on ex-posure to ultrafine carbon black [J]. Eur. Respir. J.,2000,15:297～303
[54]L. A. Jimenez, E. M. Drost, P. S. Gilmour, et al. PM(10)-exposed macrophages stimulate a proinflammatory response in lung epithelial cells via TNF-alpha [J]. Amer. J. Physiol. Lung. Cell. Mol. Physiol.,2002,282:237～248
[55]D. M. Brown, K. Donaldson, V. Stone. Role of calcium in the induction of TNF expression by macrophages on exposure to ultrafine particles [J]. Ann. Occup. Hyg,2002,46:219～222
[56]I. Rahman. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases [J]. J. Biochem. Mol. Biol.,2003,36:95～109
[57]M. S. Byun, K. I. Jeon, J. W. Choi, et al. Dual effect of oxidative stress onNF-kappakB activation inHeLa cells [J]. Exp. Mol. Med.,2002,34:332-339
[58]M. J. Berridge. Calciumsignal transduction and cellular controlmech-anisms [J]. Biochim. Biophys. Acta,2004,1742:3-7
[59]S. Orrenius, M. J. Burkitt, G. E. Kass, et al. Calcium ions and oxidative cell injury [J]. Ann. Neurol.,1992,32:33～42
[60]K. A. Barnes, S. E. Samson, A. K. Grover. Sarco/endoplasmic reticulum Ca-pump isoform SERCA3a is more resistant to superoxide damage than SERCA2b [J]. Mol. Cell. Biochem, 2000,203:17～21
[61]J. I. Kourie. Interaction of reactive oxygen species with ion transport mechanisms [J]. Amer. J.Physiol.,1998,275:1-24
[62]I. V. Deaciuc, J. A. Spitzer. Calcium content in liver and heart and its intracellular distribution in liver during endotoxicosis and sepsis in rats [J]. Cell. Calcium,1987,8: 365～376
[63]V. Stone, D. M. Brown, N. Watt,et al. Ultrafine particle-mediated activation of macrophages: Intracellular calcium signaling and oxidative stress [J]. Inhal. Toxicol,2000,12:345～351
[64]D. M. Brown, K. Donaldson, P. J. Borm, et al. Calcium and reactive oxygen species-mediated activation of transcription factors and TNFa cytokine gene expression in macrophages exposed to ultrafine particles [J]. Amer. J. Physiol. Lung. Cell. Mol. Physiol., 2004,286:344-353
[65]A. Baulig, M. Garlatti, V. Bonvallot, et al. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Amer. J. Physiol. Lung [J]. Cell. Mol. Physiol.,2003,285:671～679
[66]T. Ishii, K. Itoh, H. Sato, et al. Oxidative stress-inducible proteins inmacrophages. Free Radic. Res.,1999,31:351～355
[67]T. Ishii, K. Itoh, S. Takahashi, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages [J]. J. Biol. Chem.,2000,275: 16023～16029
[68]N. Li, J. Alam, M. I. Venkatesan, A. Eiguren-Fernandez, et al. Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells:Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals [J]. J. Immunol.,2004,173:3467～3481
[69]D. Ng, N. Kokot, T. Hiura, et al. Macrophage activation by polycyclic aromatic hydrocarbons:Evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements [J]. J. Immunol.,1998,161:942～951
[70]L. C. Renwick, K. Donaldson, A. Clouter. Impairment of alveolar macrophage phagocytosis by ultrafine particles [J]. Toxicol. Appl. Pharmacol.,2001,172:119～127
[71]P. H. Hoet, B. Nemery. Stimulation of phagocytosis by ultrafine particles [J]. Toxicol. Appl. Pharmacol.,2001,176:203-211
[72]M. Geiser, N. Kapp, S. Schurch, et al. Ultrafine particles cross cellular membranes by non-phagocytic mechanisms in lungs and in cultured cells [J]. Environ.Health Perspect., 2005,113(11):1555～1560
[73]C.Montellier, C. L. Tran, W.MacNee, et al. The pro-inflammatory effects of low solublity low toxicity particles, nanoparticles and fine particles on epithelial cells in vitro:The role of surface area and surface reactivity [J]. Occup. Environ. Med.,2006,12:23-31
[74]R. P. Schins, A.McAlinden, W.MacNee, et al. Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles [J]. Toxicol. Appl. Pharmacol.,2000,167:107～117
[75]L. Ramage, K. Guy. Expression of C-reactive protein and heatshock protein-70 in the lung epithelial cell line A549, in response to PM10 exposure [J]. Inhal. Toxicol,2004,16: 447～452
[76]L. Ramage, L. Proudfoot, K. Guy. Expression of C-reactive protein in human lung epithelial cells and upregulation by cytokines and carbon particles [J]. Inhal. Toxicol,2004,16: 607～613
[77]N. R. Madamanchi, S. Li, C. Patterson, et al. Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. Arterioscler [J]. Thromb. Vasc. Biol.,2001,21: 321～326
[78]G. Kohn, H. R. Wong, K. Bshesh, et al. Heat shock inhibits tnf-induced ICAM-1 expression in human endothelial cells via I kappa kinase in-hibition [J]. Shock,2002,17:91～97
[79]C. R. Timblin, Y. M. Janssen, J. L. Goldberg,et al. GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed to asbestos, cadmium, or H2O2 [J]. Free Radic. Biol. Med.,1998,24:632～642
[80]A. Asea, S. K. Kraeft, E. A. Kurt-Jones, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine [J]. Nature Med.,2000,6:435～442
[81]A. G. Pockley, A. Georgiades, T. Thulin, et al. Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension [J]. Hypertension, 2003,42:235～238
[82]K. L. Dreher. Health and environmental impact of nanotechnology:Toxicological assessment of manufactured nanoparticles [J]. Toxicol Sci,2004,77:3-5
[83]J. S. Tsuji, A. D. Maynard, P. C. Howard, et al. Research strategies for safety evaluation of nanomaterials, part Ⅳ:Risk assessment of nanoparticles [J].Toxicol Sci,2006,89:42～50.
[84]M. C. Powell, M. S. Kanarek. Nanomaterial health effects-part 1:Background and current knowledge [J]. WMJ,2006,105:16～20
[85]Tian Xia, Michael Kovochich, Monty Liong, et al. Comparison of the Mechanism of Toxicity of Zinc Oxide and Cerium Oxide Nanoparticles Based on Dissolution and Oxidative Stress Properties [J]. ACS Nano,2008,2:2121～2134
[86]G. A. Silva. Neuroscience nanotechnology:Progress, opportunities and challenges [J]. Nature Rev Neurosci,2006,7:65～74
[87]Gordon T, Chen LC, Fine JM, et al. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits [J]. Am Ind Hyg Assoc J,1992,53:503～509
[88]Kuschner WG, D'Alessandro A, Wong H, et al. Early pulmonary cytokine responses to zinc oxide fume inhalation [J]. Environ Res,1997,75:7-11
[89]Blanc PD, Boushey HA, Wong H, et al. Cytokines in metal fume fever [J]. Am Rev Respir Dis,1993,147:134-138
[90]Kuschner WG, D'Alessandro A, Wintermeyer SF, et al. Pulmonary responses to purified zinc oxide fume [J]. J Investig Med,1995,43:371～378
[91]吴诚,文利新,袁慧.纳米氧化锌对小鼠的毒性试验[J].粮食与饲料工业,2008,(05)：38～39
[92]Wang B, Feng WY, Wang TC, et al. Acute toxicity of nano-and micro-scale zinc powder in healthy adult mice [J]. Toxicol Lett,2008,10:263～276
[93]杨辉,刘超,杨丹凤,等.碳、氧化锌和碳载氧化锌复合纳米颗粒对小鼠胚胎成纤维细胞活性抑制及DNA损伤的研究[J].卫生研究,2008,37(1)：12-15
[94]Nel A, Xia T, Madler L, et al. Toxic Potential of Materials at the Nanolevel [J]. Science,2006, 311:622～627
[95]Donaldson K, Stone V. Borm P J, et al. Oxidative Stress and Calcium Signaling in the Adverse Effects of Environmental Particles (PM10) [J]. Free Radical Biol Med,2003,34: 1369-1382
[96]Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology:An Emerging Discipline Evolving from Studies of Ultrafine Particles [J]. Environ Health Perspect,2005,113: 823～839
[97]Xia T, Kovochich M, Nel A. The Role of Reactive Oxygen Species and Oxidative Stress in Mediating Particulate Matter Injury [J]. Clin Occup Environ Med,2006,5:817～836
[98]Hongbo MA, Paul M.Bertsch, Travis C. Glenn, et al. Toxicity of Manufactured Zinc Oxide Nanoparticles in the Nematode Caenorhabditis Elegans. Environmental [J] Toxicology and Chemistry,2009,28(6):1324～1330
[99]Holsapple MP, Farland WH, Landry TD, et al. Research strategies for safety evaluation of nanomaterials, Part Ⅱ:Toxicological and safety evaluation of nanomaterials, current challenges and data needs [J].Toxicol Sci,2005,88:12～17
[100]Stella W. Y. Wong, Priscilla T. Y. Leung, A. B. Djurisic, et al. Toxicities of nano zinc oxide to five marine organisms:influences of aggregate size and ion solubility [J]. Anal Bioanal Chem,2010,396:609～618
[101]Franklin NM, Rogers NJ, Apte SC, et al. Comparative toxicity of nanoparticulate ZnO, bulk ZnO, and ZnCl to a freshwater microalga (Pseudokirchneriella subcapitata):the importance of particle solubility [J]. Environ Sci Technol,2007,41:8484～8490
[102]Wang H, Wick RL, Xing B. Toxicity of nanoparticulate and bulk ZnO, A12O3 and TiO2 to the nematode Caenorhabditis elegans [J]. Environ Pollut,2009,157:1171～1177
[103]Zhu X, Zhu L, Duan Z, et al. Comparative toxicity of several metal oxide nanoparticles aqueous suspensions to zebrafish (Danio rerio) early developmental stage [J]. J Environ Sci Heal A,2008,43:278～284
[104]Aruoja V, Dubourguier H, Kasemets K, et al. Toxicity of nanoparticles of CuO, ZnO and TiO2 to microalgae Pseudokirchneriella subcaptitata [J]. Sci Total Environ,2009,407: 1461～1468
[105]Handy RD, Owen R, Valsami-Jones E. The ecotoxicology of nanoparticles and nanomaterials:current status, knowledge gaps, challenges, and future needs [J]. Ecotoxicology,2008,17:315～325
[106]Xiaoyong Deng, Qixia Luan, Wenting Chen, et al. Nanosized zinc oxide particles induce neural stem cell apoptosis [J]. Nanotechnology,2009,20:1-7
[107]K M Reddy, Kevin feris, Jason Bell,et al. Selective toxicity of zinc oxide nanoparticles to prokaryotic and eukaryotic systems [J]. Appl Phys Lett,2007,90:1-3
[108]Vyom Sharmaa, Ritesh K. Shuklaa, Neha Saxenab, et al. DNA damaging potential of zinc oxide nanoparticles in human epidermal cells [J]. Oxicology Letters,2009,185: 211～218