哮喘疾病中锌转运体表达的初步研究
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摘要
研究目的：
通过建立大鼠缺锌哮喘模型来观察饮食锌和地塞米松处理哮喘大鼠后肺组织和外周血白细胞中锌转运体表达的影响；检测正常对照婴儿及哮喘婴儿外周血白细胞中锌转运体mRNA表达的变化,初步探讨哮喘疾病中锌转运体表达的变化。研究方法：
一、20只wistar大鼠(年龄3-4周)随机分为4组：低锌哮喘组、哮喘组、对照组和地塞米松处理组。低锌组饲喂缺锌饲料,其他组饲喂正常饲料；按文献所提供方法获得大鼠哮喘模型；每两天记录一次大鼠的体重、摄食量。五周之后处死动物,检测肺组织和血清锌含量,RT-PCR方法检测肺组织和外周血白细胞中锌转运体mRNA的表达。
二、临床收集9例正常对照婴儿以及9例哮喘婴儿血常规数据、ELISA检测血液中IgE含量、原子吸收分光光度计检测血清锌含量,通过RT-PCR方法检测外周血白细胞中锌转运体mRNA表达。
结果：
一、低锌哮喘组大鼠摄食量较其他组有明显的下降,而对照组、哮喘组以及地塞米松处理组之间没有明显的差别。同样在低锌哮喘组,大鼠体重明显低于其他各组,而对照组、哮喘组和地塞米松组则没有明显的区别；低锌哮喘组大鼠肺组织锌含量显著低于其他各组,而对照组、哮喘组以及地塞米松组之间肺组织锌含量无统计学差别；与对照组相比低锌哮喘组大鼠肺组织ZnT-1mRNA表达下降了45%,哮喘组中ZnT-1mRNA表达上升了67%,地塞米松干预组ZnT-1mRNA表达上升了45%；ZIP-8mRNA和ZIP-13mRNA在对照组中的表达明显低于缺锌哮喘组、哮喘组以及地塞米松干预组；与哮喘组相比,低锌哮喘组中ZnT-1mRNA显著下降了67%, ZIP-8mRNA和ZIP-13mRNA表达升高,地塞米松干预组中ZnT-1mRNA、ZIP-8mRNA和ZIP-13mRNA表达均没有明显的改变。
二、哮喘婴儿血清锌含量显著低于对照组婴儿(P<0.01)；哮喘患儿外周血免疫球蛋白E含量明显高于正常对照组婴儿；哮喘组婴儿和对照组婴儿外周血白细胞中ZnT-1, ZnT-3,ZnT-5, ZIP-1 mRNA表达没有显著的差异；哮喘患儿组外周血白细胞中ZIP-2mRNA表达明显高于对照组婴儿(P<0.01)。
结论：
低锌干预后,低锌哮喘组大鼠肺组织ZnT-1mRNA的表达降低,ZIP-8mRNA和ZIP-13mRNA表达升高；哮喘模型大鼠肺组织ZnT-1mRNA、ZIP-8mRNA和ZIP-13mRNA表达增加,地塞米松干预后,锌转运体表达无明显改变；哮喘儿童外周血白细胞中,ZIP-2mRNA表达明显升高。
意义：
锌是生物体必需的微量元素,六大功能性蛋白家族中超过300种金属酶需要锌作为其关键的结构组分或者是辅助因子,广泛参与生物体代谢,还涉及到细胞的生长、增殖和分化。两个大的基因家族参与了哺乳动物锌的代谢调节：ZnT和ZIP。ZnT蛋白能够促进细胞质锌的外流以及使锌在各细胞器内区室化,从而降低细胞浆锌的含量；ZIP则能够增加锌的内流摄取或者促进细胞器内锌的释放,来增加胞浆中锌的含量。在哺乳动物中,饮食中锌水平不足会导致皮肤病病变,生长迟缓,精神障碍,并损害免疫系统和生殖系统。在动物中,锌平衡的保持主要是通过调节肠吸收率,过量锌的排除,肾重吸收和分配到细胞中,包括细胞内存储。很多文献中提到急性和慢性炎性疾病实验动物模型中锌的代谢发生改变,病例对照研究发现,锌摄入量低的人遗传过敏症,哮喘和过敏性反应型的症状相结合的风险是锌摄入量高的人的4到5倍,哮喘病人血清锌含量要低于健康对照患者。哮喘和锌缺乏都被认为是有利于Th2细胞炎性因子产生,系统性锌缺乏的哮喘病人有可能进一步增加Th2细胞促炎性因子的产生。哮喘是许多慢性炎症疾病中的一种,是世界公认的医学难题,被世界卫生组织列为疾病中四大顽症之一。据调查,在我国至少有2000万以上哮喘患者,哮喘的发病机制和发病原因非常复杂,因此探讨哮喘疾病中锌转运体的表达以及锌对锌转运体表达的影响很有必要。
本课题检测了哮喘婴幼儿外周血白细胞中锌转运体mRNA表达情况,在儿童哮喘的锌研究领域还是首次；同时,使用锌和地塞米松处理哮喘模型大鼠,观察部分锌转运体表达情况,为哮喘的发生,发展机制研究寻找新的突破。
Objective
The zinc deficiency asthmatic rats'models were established in order to explore effects of dietary zinc and dexamethasone on the zinc transporters expression in rats' lung tissue and leucocytes. Changes of zinc transporters'mRNA expression in peripheral blood leukocytes of normal infants and asthmatic infants in asthmatic disease was preliminary studied.
Methods
20 male wistar rats were randomly divided into 4 groups:zinc-lower ova group、ova group、control group and dexamethasone treated group. Zinc-lower group was given the low-zinc feed and the other group was given normal feed. The asthmatic rats'models were established according to the literature. The body weight and food intake of the rats were recorded every two days. The animals were killed after 5 weeks, and the content of zinc in the lung and serum was measured, and the mRNA expression of zinc transporter of the lung tissue and peripheral blood leukocytes were tested via RT-PCR method.
A routine blood test data、IgE data、serum zinc concentration data as well as fresh blood of 9 normal infants and 9 infants with bronchial asthma were collected. The mRNA expression of zinc transporter of peripheral blood lymphocytes was tested via RT-PCR method.
Results
Weight of zinc deficient asthmatic rats was significantly lower than the control groups', and there was no significant change between asthmatic group and control group, as well as dexamethasone group. Compared with the control group, ZnT-1 mRNA expression of zinc-lower asthmatic rats in lung tissue decreased by 45%, ZnT-1mRNA expression of asthmatic group increased by 67%, ZnT-1mRNA expression of the dexamethasone intervention group increased by 45%. ZIP-8mRNA and ZIP-13mRNA expression in the control group was significantly lower than zinc deficiency asthmatic group, asthmatic group and dexamethasone intervention group. Compared with the asthmatic group, ZnT-1mRNA expression of zinc deficiency asthmatic group significantly decreased by 67%, ZIP-8mRNA and ZIP-13mRNA expression increased. ZnT-1mRNA, ZIP-8mRNA and ZIP-13mRNA expression of the dexamethasone intervention group were not obviously changed.
Serum zinc content of asthmatic infants was significantly lower than control group infants (P<0.01);there are no significant differences in peripheral blood lymphocytes ZnT-1, ZnT-3, ZnT-5, ZIP-1 mRNA expression between asthmatic infants and the control group infants; peripheral blood lymphocytes ZIP-2mRNA expression of asthmatic infants was significantly higher than the control infants group (P<0.01).
Conclusion
Zinc is essential to cell growth and is cofactor for more than 300 enzymes, representing over 50 different enzyme classes. Also it is involved in diverse cellular processes, from catalysis to gene expression to cell proliferation. Several proteins and genes involved in cellular zinc transport, which belong to two gene families:ZnT and ZIP. ZnT transporters reduce intracellular zinc by promoting zinc efflux from cells or into intracellular vesicles, while ZIP transporters increase intracellular zinc by promoting intracellular zinc uptake and, perhaps, vesicular zinc release into the cytoplasm. In mammals, inadequate levels of zinc in the diet lead to dermatologic lesions, growth retardation, mental disorders, and compromised function of the immune and reproductive systems. In animals, zinc balance is primarily maintained through a regulated rate of intestinal uptake, fecal elimination of excess zinc, renal reabsorption and distribution to cells, including intracellular storage. A large number of studies documented changes in zinc metabolism in experimental animal models of acute and chronic inflammatory disease, and asthma is one of these chronic inflammatory diseases. Case-control studies found that the combined risk of atopy, bronchial reactivity and allergic-type symptoms were four to five fold higher in individuals with low zinc intake as compared to those with higher zinc intake.Asthmatic patients were shown to have lower plasma zinc than healthy controls. Both asthma and Zn deficiency are thought to favor the T-helper-2 (Th2) inflammatory cytokine profile, and asthmatic individuals with systemic zinc deficiency may have further increases in Th2 proinflammatory cytokines. Asthma is one of chronic inflammatory diseases, which is recognized as one of the world medical problems. According to the survey, there are at least more than 20 million patients with asthma in China; Therefore, it is necessary to explore the zinc transporters'expression and the influences of zinc on zinc transporters in asthma.
In this study, we explore the zinc transporters'expression in the leukocytes of asthmatic infants. This is the first report, which detects the zinc transporters expression in asthma infants. At the same time, we explore the expression of zinc transporters after the asthmatic rats treated by zinc and dexamethasone, to make some effect in the study of zinc transporter regulation in asthma.
通过建立大鼠缺锌哮喘模型来观察饮食锌和地塞米松处理哮喘大鼠后肺组织和外周血白细胞中锌转运体表达的影响；检测正常对照婴儿及哮喘婴儿外周血白细胞中锌转运体mRNA表达的变化,初步探讨哮喘疾病中锌转运体表达的变化。研究方法：
一、20只wistar大鼠(年龄3-4周)随机分为4组：低锌哮喘组、哮喘组、对照组和地塞米松处理组。低锌组饲喂缺锌饲料,其他组饲喂正常饲料；按文献所提供方法获得大鼠哮喘模型；每两天记录一次大鼠的体重、摄食量。五周之后处死动物,检测肺组织和血清锌含量,RT-PCR方法检测肺组织和外周血白细胞中锌转运体mRNA的表达。
二、临床收集9例正常对照婴儿以及9例哮喘婴儿血常规数据、ELISA检测血液中IgE含量、原子吸收分光光度计检测血清锌含量,通过RT-PCR方法检测外周血白细胞中锌转运体mRNA表达。
结果：
一、低锌哮喘组大鼠摄食量较其他组有明显的下降,而对照组、哮喘组以及地塞米松处理组之间没有明显的差别。同样在低锌哮喘组,大鼠体重明显低于其他各组,而对照组、哮喘组和地塞米松组则没有明显的区别；低锌哮喘组大鼠肺组织锌含量显著低于其他各组,而对照组、哮喘组以及地塞米松组之间肺组织锌含量无统计学差别；与对照组相比低锌哮喘组大鼠肺组织ZnT-1mRNA表达下降了45%,哮喘组中ZnT-1mRNA表达上升了67%,地塞米松干预组ZnT-1mRNA表达上升了45%；ZIP-8mRNA和ZIP-13mRNA在对照组中的表达明显低于缺锌哮喘组、哮喘组以及地塞米松干预组；与哮喘组相比,低锌哮喘组中ZnT-1mRNA显著下降了67%, ZIP-8mRNA和ZIP-13mRNA表达升高,地塞米松干预组中ZnT-1mRNA、ZIP-8mRNA和ZIP-13mRNA表达均没有明显的改变。
二、哮喘婴儿血清锌含量显著低于对照组婴儿(P<0.01)；哮喘患儿外周血免疫球蛋白E含量明显高于正常对照组婴儿；哮喘组婴儿和对照组婴儿外周血白细胞中ZnT-1, ZnT-3,ZnT-5, ZIP-1 mRNA表达没有显著的差异；哮喘患儿组外周血白细胞中ZIP-2mRNA表达明显高于对照组婴儿(P<0.01)。
结论：
低锌干预后,低锌哮喘组大鼠肺组织ZnT-1mRNA的表达降低,ZIP-8mRNA和ZIP-13mRNA表达升高；哮喘模型大鼠肺组织ZnT-1mRNA、ZIP-8mRNA和ZIP-13mRNA表达增加,地塞米松干预后,锌转运体表达无明显改变；哮喘儿童外周血白细胞中,ZIP-2mRNA表达明显升高。
意义：
锌是生物体必需的微量元素,六大功能性蛋白家族中超过300种金属酶需要锌作为其关键的结构组分或者是辅助因子,广泛参与生物体代谢,还涉及到细胞的生长、增殖和分化。两个大的基因家族参与了哺乳动物锌的代谢调节：ZnT和ZIP。ZnT蛋白能够促进细胞质锌的外流以及使锌在各细胞器内区室化,从而降低细胞浆锌的含量；ZIP则能够增加锌的内流摄取或者促进细胞器内锌的释放,来增加胞浆中锌的含量。在哺乳动物中,饮食中锌水平不足会导致皮肤病病变,生长迟缓,精神障碍,并损害免疫系统和生殖系统。在动物中,锌平衡的保持主要是通过调节肠吸收率,过量锌的排除,肾重吸收和分配到细胞中,包括细胞内存储。很多文献中提到急性和慢性炎性疾病实验动物模型中锌的代谢发生改变,病例对照研究发现,锌摄入量低的人遗传过敏症,哮喘和过敏性反应型的症状相结合的风险是锌摄入量高的人的4到5倍,哮喘病人血清锌含量要低于健康对照患者。哮喘和锌缺乏都被认为是有利于Th2细胞炎性因子产生,系统性锌缺乏的哮喘病人有可能进一步增加Th2细胞促炎性因子的产生。哮喘是许多慢性炎症疾病中的一种,是世界公认的医学难题,被世界卫生组织列为疾病中四大顽症之一。据调查,在我国至少有2000万以上哮喘患者,哮喘的发病机制和发病原因非常复杂,因此探讨哮喘疾病中锌转运体的表达以及锌对锌转运体表达的影响很有必要。
本课题检测了哮喘婴幼儿外周血白细胞中锌转运体mRNA表达情况,在儿童哮喘的锌研究领域还是首次；同时,使用锌和地塞米松处理哮喘模型大鼠,观察部分锌转运体表达情况,为哮喘的发生,发展机制研究寻找新的突破。
Objective
The zinc deficiency asthmatic rats'models were established in order to explore effects of dietary zinc and dexamethasone on the zinc transporters expression in rats' lung tissue and leucocytes. Changes of zinc transporters'mRNA expression in peripheral blood leukocytes of normal infants and asthmatic infants in asthmatic disease was preliminary studied.
Methods
20 male wistar rats were randomly divided into 4 groups:zinc-lower ova group、ova group、control group and dexamethasone treated group. Zinc-lower group was given the low-zinc feed and the other group was given normal feed. The asthmatic rats'models were established according to the literature. The body weight and food intake of the rats were recorded every two days. The animals were killed after 5 weeks, and the content of zinc in the lung and serum was measured, and the mRNA expression of zinc transporter of the lung tissue and peripheral blood leukocytes were tested via RT-PCR method.
A routine blood test data、IgE data、serum zinc concentration data as well as fresh blood of 9 normal infants and 9 infants with bronchial asthma were collected. The mRNA expression of zinc transporter of peripheral blood lymphocytes was tested via RT-PCR method.
Results
Weight of zinc deficient asthmatic rats was significantly lower than the control groups', and there was no significant change between asthmatic group and control group, as well as dexamethasone group. Compared with the control group, ZnT-1 mRNA expression of zinc-lower asthmatic rats in lung tissue decreased by 45%, ZnT-1mRNA expression of asthmatic group increased by 67%, ZnT-1mRNA expression of the dexamethasone intervention group increased by 45%. ZIP-8mRNA and ZIP-13mRNA expression in the control group was significantly lower than zinc deficiency asthmatic group, asthmatic group and dexamethasone intervention group. Compared with the asthmatic group, ZnT-1mRNA expression of zinc deficiency asthmatic group significantly decreased by 67%, ZIP-8mRNA and ZIP-13mRNA expression increased. ZnT-1mRNA, ZIP-8mRNA and ZIP-13mRNA expression of the dexamethasone intervention group were not obviously changed.
Serum zinc content of asthmatic infants was significantly lower than control group infants (P<0.01);there are no significant differences in peripheral blood lymphocytes ZnT-1, ZnT-3, ZnT-5, ZIP-1 mRNA expression between asthmatic infants and the control group infants; peripheral blood lymphocytes ZIP-2mRNA expression of asthmatic infants was significantly higher than the control infants group (P<0.01).
Conclusion
Zinc is essential to cell growth and is cofactor for more than 300 enzymes, representing over 50 different enzyme classes. Also it is involved in diverse cellular processes, from catalysis to gene expression to cell proliferation. Several proteins and genes involved in cellular zinc transport, which belong to two gene families:ZnT and ZIP. ZnT transporters reduce intracellular zinc by promoting zinc efflux from cells or into intracellular vesicles, while ZIP transporters increase intracellular zinc by promoting intracellular zinc uptake and, perhaps, vesicular zinc release into the cytoplasm. In mammals, inadequate levels of zinc in the diet lead to dermatologic lesions, growth retardation, mental disorders, and compromised function of the immune and reproductive systems. In animals, zinc balance is primarily maintained through a regulated rate of intestinal uptake, fecal elimination of excess zinc, renal reabsorption and distribution to cells, including intracellular storage. A large number of studies documented changes in zinc metabolism in experimental animal models of acute and chronic inflammatory disease, and asthma is one of these chronic inflammatory diseases. Case-control studies found that the combined risk of atopy, bronchial reactivity and allergic-type symptoms were four to five fold higher in individuals with low zinc intake as compared to those with higher zinc intake.Asthmatic patients were shown to have lower plasma zinc than healthy controls. Both asthma and Zn deficiency are thought to favor the T-helper-2 (Th2) inflammatory cytokine profile, and asthmatic individuals with systemic zinc deficiency may have further increases in Th2 proinflammatory cytokines. Asthma is one of chronic inflammatory diseases, which is recognized as one of the world medical problems. According to the survey, there are at least more than 20 million patients with asthma in China; Therefore, it is necessary to explore the zinc transporters'expression and the influences of zinc on zinc transporters in asthma.
In this study, we explore the zinc transporters'expression in the leukocytes of asthmatic infants. This is the first report, which detects the zinc transporters expression in asthma infants. At the same time, we explore the expression of zinc transporters after the asthmatic rats treated by zinc and dexamethasone, to make some effect in the study of zinc transporter regulation in asthma.
引文
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31.Keen CL, Gerswin ME. Zinc deficiency and immune function. Annu Rev Nutr 1990; 10:415-431
32.Odeh M. The role of zinc in acquired immunodeficiency syndrome. J Intern Med.1992 May;231 (5):463-9
33. Chvapil M. Effect of Zinc on cells and biomembranes.Med. Clin.North.Am. 1976;60:799～812
34.孟晋雄,梁哲等.锌对人体生理功能的影响及作用机制[J].微量元素与健康研究.1997,14(3)：54—56
35.徐迪雄,吴嘉急.锌的主要生物学作用及生物学意义[J]国外医学医学地理分册.1995,16(1)：8—11)
36.Venter J. C., Adams M. D., Myers E. W., Li P. W., Mural R. J., Sutton G. G. et al. (2001) The sequence of the human genome.Science 291:1304-1351
37.周毅峰,吴永尧,唐巧玉等.锌的生物学功能.氨基酸和生物资源2004,26(2)：11～15
38.Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine production by superantigens and lipopolysaccaride. Immunology 1995;84:272-277
39. Wellinghousen N, Rink L. The significance of zinc for leukocuyte biology. J Leukocyte Biol 1998;64:571-577
40. Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW. Interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C. Proc Natl Acad Sci USA 1992;89:7752-7756
41.Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993;73:79-118
42.Fraker PJ, King LE. A distinct role for apoptosis in the changes in the lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J 2001; 15:2572-2578
43. Prasad AS. Effects of zinc deficiency on Thl and Th2 cytokine shifts. J Infect Dis 2000; 182:562-568
44.Truong-Tran AQ, Ho LH and Chai F. Cellular zinc fluxes and the regulation of apoptosis/gene-directed cell death. J Nutr.2000;130 (5S Suppl):1459S-66S.
45.Beyersmann D, Haase H. Functions of zinc in signaling,proliferation and differentiation of mammalian cells.Biometals.2001 Sep-Dec;14(3-4):331-341
46.Vallee BL,Falchuk KH.The biochemical basis of zinc physiology. Physiol Rev.1993 Jan;(1):79-118
47.Hambidge M.Human zinc deficiency. J Nutr.2000 May;130(5S Suppl): 1344S-1349S
48.Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW.The role of zinc in selective neuronal death after transient global cerebral ischemia. Science.1996 May 17;272(5264):1013-1016
49.Krebs NF.Overview of zinc absorption and excretion in the human gastrointestinal tract. J Nutr.2000 May;130(5S Suppl):1374S-1377S.
50.T.Kambe,Y.Yamaguchi-Iwai,R.Sasaki,M.Nagao. Overview of mammalian zinc t ransporters[J]. Cell Mol Life Sci,2004,61:49-68
51.Gaither L. A. and Eide D. J. Eukaryotic zinc transporters and their regulation.Biometals.2001 Sep-Dec;14 (3-4):251-270
52. Taylor KM,Morgan HE,Johnson A,etc. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters.Biochem J.2003 Oct 1;375 (Pt 1):51-59
53. Gaither LA, Eide DJ.Functional expression of the human hZIP2 zinc transporter. J. Biol. Chem.2000 Feb 25;275 (8):5560-5564
54. Liuzzi JP, Cousins RJ.Mammalian zinc transporters.Annu Rev Nutr.2004; 24:151-172
55. Guffanti AA, Wei Y, Rood SV, Krulwich TA. An antiport mechanism for a member of the cation diffusion facilitator family:divalent cations efflux in exchange for K+ and H+.Mol Microbiol.2002 Jul;45 (1):145-153
56. Palmiter RD, Cole TB, Findley SD.ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration.Embo J.1996 Apr 15; 15 (8):1784-1791
57. de Luis DA, Izaola O, Aller R, Armentia A, Cuellar L, Antioxidant and fat intake in patients with polinic asthma, Med Clin(Barc) 2003 Nov 15;121(17):653-4
58.Soutar A,Seaton A,Brown K, Bronchial reactivity and dietaryantioxidants, Thorax.1997 Feb;52(2):166-170
59.Kadrabova J, Madaric A, Podivinsky F, Gazdik F, Ginter F. Plasma zinc, copper copper/zinc ratio in intrinsic asthma. J Trace Elem Med Biol 1996;10:50-53
60.Richter M, Bonneau R, Girard MA, Beaulieu C, Larivee P. Zinc status modulates bronchopulmonary eosinophil infiltration in a murine model of allergic inflammation. Chest 2003; 123:446
61.Powell SR. The anti-oxidant properties of zinc. J Nutr 2000; 130:1447-1457
62.Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radic Biol Med 1990;8:281-291
63.Prasad AS. Zinc and immunity. Mol Cell Biochem 1998;188:63-69.51
64.Truong-Tran AQ, Ruffin RE, Foster PS, Koskinen AM, Coyle P,Philcox JC, Rofe AM, Zalewski PD:Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation.Am J Respir Cell Mol Biol 2002,27:286-296
65.A.Q. Truong-Tran, R.E. Ruffin, P.S. Foster, A.M. Koskinen, P.Coyle, J.C. Philcox, A.M. Rofe, P.D. Zalewski, Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation, Am. J. Respir. Cell Mol. Biol.27 (2002) 286-296
66. Filley WV, Holley KE, Kephart GM, Gleich GJ. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma. Lancet 2:11-16,1982.26
67. Murgia C, Vespignani I, Rami R, Zalewski PD, Perozzi G. The ZnT4 mutation in lethal milk mice affects intestinal zinc homeostasis through the expression of other Zn transporters. Genes Nutr 1:51-70,2006
68. C.J. Lang, C. Murgia, M. Leong, L.W. Tan, G. Perozzi, D. Knight, R.E. Ruffin, P.D. Zalewski. Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse models of allergic inflammation. Am J Physiol Lung Cell Mol Physiol Physiol.2007 Feb;292(2):L577-84
69.Peter J Barnes, Ian M Adcock. Glucocorticoid resistance in inflammatory diseases. Lancet 2009;373:1905-17
70. Cristiana Stellato, Baltimore. Glucocorticoid actions on airway epithelial responses in immunity:Functional outcomes responses in immunity:Functional outcomes and molecular targets and molecular targets. J ALLERGY CLIN IMMUNOL 2007; 120(6):1247-63
71.A.M. Sadowskaa*, B. Klebeb, P. Germonprea, W.A. De Backera. Glucocorticosteroids as antioxidants in treatment of asthma and COPD New application for an old medication? Steroids 2007;72(1):1-6
72. Fulya Tahan, Cigdem Karakukcu.Zinc Status in Infantile Wheezing.Pediatric Pulmonology 2006;41:630-634
73.Besecker B, Bao S, Bohacova B, Papp A, Sadee W, Knoell DL.The human zinc transporter SLC39A8 (ZIP8) is critical in zinc-mediated cytoprotection in lung epithelia. Am J Physiol Lung Cell Mol Physiol 2008; 294(6):L1127-36
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21.Vallee BL,Falchuk KH. The biochemical basis of zinc physiology.Physiol Rev.1993 Jan;73 (1):79-118
22.Koh JY,Suh SW,Gwag BJ,He YY,Hsu CY,Choi DW. The role of zinc in selective neuronal death after transient global cerebral ischemia.Science.1996 May 17;272 (5264):1013-1016
23. Krebs NF.Overview of zinc absorption and excretion in the human gastrointestinal tract.J Nutr.2000 May; 130 (5S Suppl):1374S-1377S
24. Gaither LA, Eide DJ.Eukaryotic zinc transporters and their regulation.Biometals.wfe 2001 Sep-Dec; 14 (3-4):251-270
25.Tucker HF, Salmon WD. Parakeratosis or zinc deficiency disease in the pig. Proc Soc Exp Biol Med 1955;88:613-616
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27.Prasad AS. Zinc in human nutrition. Boca Raton, FL:CRC Press; 1979 Sep;8(1):1-80
28.Hambidge KM, Neldner KH, Walravens PA. Zinc, Acrodermatitis Enteropathica and congenital malformations. Lancet 1975; 1:577-578
29.Zalewski PD. A review. Zinc and immunity:implications for growth, survival and function of lymphoid cells. J Nutr Immun 1996;4:39-101
30.Allen JL, Perri RT, McClain CJ, Kay NE. Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency. J Lab Clin Med 1983; 102:577-589
31.Keen CL, Gerswin ME. Zinc deficiency and immune function. Annu Rev Nutr 1990; 10:415-431
32.Odeh M. The role of zinc in acquired immunodeficiency syndrome. J Intern Med.1992 May;231 (5):463-9
33. Chvapil M. Effect of Zinc on cells and biomembranes.Med. Clin.North.Am. 1976;60:799～812
34.孟晋雄,梁哲等.锌对人体生理功能的影响及作用机制[J].微量元素与健康研究.1997,14(3)：54—56
35.徐迪雄,吴嘉急.锌的主要生物学作用及生物学意义[J]国外医学医学地理分册.1995,16(1)：8—11)
36.Venter J. C., Adams M. D., Myers E. W., Li P. W., Mural R. J., Sutton G. G. et al. (2001) The sequence of the human genome.Science 291:1304-1351
37.周毅峰,吴永尧,唐巧玉等.锌的生物学功能.氨基酸和生物资源2004,26(2)：11～15
38.Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine production by superantigens and lipopolysaccaride. Immunology 1995;84:272-277
39. Wellinghousen N, Rink L. The significance of zinc for leukocuyte biology. J Leukocyte Biol 1998;64:571-577
40. Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW. Interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C. Proc Natl Acad Sci USA 1992;89:7752-7756
41.Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993;73:79-118
42.Fraker PJ, King LE. A distinct role for apoptosis in the changes in the lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J 2001; 15:2572-2578
43. Prasad AS. Effects of zinc deficiency on Thl and Th2 cytokine shifts. J Infect Dis 2000; 182:562-568
44.Truong-Tran AQ, Ho LH and Chai F. Cellular zinc fluxes and the regulation of apoptosis/gene-directed cell death. J Nutr.2000;130 (5S Suppl):1459S-66S.
45.Beyersmann D, Haase H. Functions of zinc in signaling,proliferation and differentiation of mammalian cells.Biometals.2001 Sep-Dec;14(3-4):331-341
46.Vallee BL,Falchuk KH.The biochemical basis of zinc physiology. Physiol Rev.1993 Jan;(1):79-118
47.Hambidge M.Human zinc deficiency. J Nutr.2000 May;130(5S Suppl): 1344S-1349S
48.Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW.The role of zinc in selective neuronal death after transient global cerebral ischemia. Science.1996 May 17;272(5264):1013-1016
49.Krebs NF.Overview of zinc absorption and excretion in the human gastrointestinal tract. J Nutr.2000 May;130(5S Suppl):1374S-1377S.
50.T.Kambe,Y.Yamaguchi-Iwai,R.Sasaki,M.Nagao. Overview of mammalian zinc t ransporters[J]. Cell Mol Life Sci,2004,61:49-68
51.Gaither L. A. and Eide D. J. Eukaryotic zinc transporters and their regulation.Biometals.2001 Sep-Dec;14 (3-4):251-270
52. Taylor KM,Morgan HE,Johnson A,etc. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters.Biochem J.2003 Oct 1;375 (Pt 1):51-59
53. Gaither LA, Eide DJ.Functional expression of the human hZIP2 zinc transporter. J. Biol. Chem.2000 Feb 25;275 (8):5560-5564
54. Liuzzi JP, Cousins RJ.Mammalian zinc transporters.Annu Rev Nutr.2004; 24:151-172
55. Guffanti AA, Wei Y, Rood SV, Krulwich TA. An antiport mechanism for a member of the cation diffusion facilitator family:divalent cations efflux in exchange for K+ and H+.Mol Microbiol.2002 Jul;45 (1):145-153
56. Palmiter RD, Cole TB, Findley SD.ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration.Embo J.1996 Apr 15; 15 (8):1784-1791
57. de Luis DA, Izaola O, Aller R, Armentia A, Cuellar L, Antioxidant and fat intake in patients with polinic asthma, Med Clin(Barc) 2003 Nov 15;121(17):653-4
58.Soutar A,Seaton A,Brown K, Bronchial reactivity and dietaryantioxidants, Thorax.1997 Feb;52(2):166-170
59.Kadrabova J, Madaric A, Podivinsky F, Gazdik F, Ginter F. Plasma zinc, copper copper/zinc ratio in intrinsic asthma. J Trace Elem Med Biol 1996;10:50-53
60.Richter M, Bonneau R, Girard MA, Beaulieu C, Larivee P. Zinc status modulates bronchopulmonary eosinophil infiltration in a murine model of allergic inflammation. Chest 2003; 123:446
61.Powell SR. The anti-oxidant properties of zinc. J Nutr 2000; 130:1447-1457
62.Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant. Free Radic Biol Med 1990;8:281-291
63.Prasad AS. Zinc and immunity. Mol Cell Biochem 1998;188:63-69.51
64.Truong-Tran AQ, Ruffin RE, Foster PS, Koskinen AM, Coyle P,Philcox JC, Rofe AM, Zalewski PD:Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation.Am J Respir Cell Mol Biol 2002,27:286-296
65.A.Q. Truong-Tran, R.E. Ruffin, P.S. Foster, A.M. Koskinen, P.Coyle, J.C. Philcox, A.M. Rofe, P.D. Zalewski, Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation, Am. J. Respir. Cell Mol. Biol.27 (2002) 286-296
66. Filley WV, Holley KE, Kephart GM, Gleich GJ. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma. Lancet 2:11-16,1982.26
67. Murgia C, Vespignani I, Rami R, Zalewski PD, Perozzi G. The ZnT4 mutation in lethal milk mice affects intestinal zinc homeostasis through the expression of other Zn transporters. Genes Nutr 1:51-70,2006
68. C.J. Lang, C. Murgia, M. Leong, L.W. Tan, G. Perozzi, D. Knight, R.E. Ruffin, P.D. Zalewski. Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse models of allergic inflammation. Am J Physiol Lung Cell Mol Physiol Physiol.2007 Feb;292(2):L577-84
69.Peter J Barnes, Ian M Adcock. Glucocorticoid resistance in inflammatory diseases. Lancet 2009;373:1905-17
70. Cristiana Stellato, Baltimore. Glucocorticoid actions on airway epithelial responses in immunity:Functional outcomes responses in immunity:Functional outcomes and molecular targets and molecular targets. J ALLERGY CLIN IMMUNOL 2007; 120(6):1247-63
71.A.M. Sadowskaa*, B. Klebeb, P. Germonprea, W.A. De Backera. Glucocorticosteroids as antioxidants in treatment of asthma and COPD New application for an old medication? Steroids 2007;72(1):1-6
72. Fulya Tahan, Cigdem Karakukcu.Zinc Status in Infantile Wheezing.Pediatric Pulmonology 2006;41:630-634
73.Besecker B, Bao S, Bohacova B, Papp A, Sadee W, Knoell DL.The human zinc transporter SLC39A8 (ZIP8) is critical in zinc-mediated cytoprotection in lung epithelia. Am J Physiol Lung Cell Mol Physiol 2008; 294(6):L1127-36