微量元素锌在脓毒症中的研究进展
Research Progress of Trace Element Zinc in Sepsis

作者: 来庆兰 , 吴先正 :上海市同济医院急诊科,上海;

关键词: 脓毒症生物标记物动态平衡Zinc Sepsis Biomarker Homeostasis

摘要:
脓毒症被定义为“由宿主对感染的反应失调引起的威胁生命的器官功能障碍”,是全世界主要健康问题之一,目前仍缺乏完全阐明的病理生理学和统一的诊断性测试。研究表明微量元素锌在免疫应答中起着重要的作用,在脓毒症期间,观察到锌从血清重新分布到肝脏,并且目前大量研究表明锌与脓毒症的发生发展具有一定的相关性。此外,锌稳态的变化是显著的,并且与疾病的严重程度相关,这表明锌可以作为评估脓毒症严重程度和预测脓毒症预后的生物标记物。

Abstract: Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” and is one of the major health problems worldwide, and there is still a lack of fully elucidated pathophysiology and uniform diagnostic testing. Studies have shown that trace element zinc plays an important role in the immune response. During sepsis, zinc is redistributed from the serum to the liver, and a large number of studies have shown that zinc has a certain correlation with the development of sepsis. Furthermore, changes in zinc homeostasis are significant and correlated with the severity of the disease, suggesting that zinc can be used as a biomarker to assess the severity of sepsis and predict the prognosis of sepsis.

1. 概述

1.1. 脓毒症

脓毒症每年造成约600万人死亡,成为一种致命性的疾病,也是全球死亡的主要原因之一,在低、中等收入国家,其流行病学负担被认为远远要高的多,全球国民收入影响脓毒症的死亡率 [2] [3] 。最近的共识将脓毒症定义为“由宿主对感染的反应失调引起的威胁生命的器官功能障碍”,为了诊断临床中的器官功能障碍,Singer等人,推荐序贯器官衰竭评估(SOFA),SOFA评分包括呼吸、凝血功能、肝脏、心血管系统、中枢神经系统、肾脏的参数,SOFA评分 > 2分或以上者表明存在器官功能障碍 [1] 。

脓毒症是由感染导致的。病原体触发免疫反应,包括促炎机制与抗炎机制。在脓毒症期间出现的这种免疫反应的失调导致免疫系统的过度反应,可能影响以上两种机制。全身炎症反应综合征(SIRS)形式的过度炎症可导致宿主自身组织的损伤,免疫抑制也称为代偿性抗炎反应综合征(CARS),使宿主更易受到继发性感染 [4] [5] 。

1.2. 锌

锌是人体必需的微量元素。超过300种金属酶需要锌作为催化剂,约2500种转录因子、人类基因组的8%,需要锌的结构完整性。锌还通过反应元件(MRE)结合转录因子-1(MTF-1)调节数千个基因,并且锌通过调节激酶和磷酸化酶活性控制许多细胞信号传导途径 [6] [7] 。缺锌可导致生长迟缓,皮炎和性腺机能减退,伤口愈合延迟,淋巴细胞减少,高感染率等 [8] [9] 。锌的一个特别重要的调节作用就是调节炎症细胞因子的产生 [10] ,此外,锌对几乎所有免疫细胞的功能至关重要,例如,未成熟T细胞的分化及T细胞的成熟均受锌状态的影响,因为胸腺素(一种参与T细胞分化的激素)依赖于锌作为辅因子 [11] [12] 。补锌也被证明可以促进调节性T细胞的发育并抑制Th17细胞的成熟,因此对Th17介导的自身免疫性疾病具有抑制作用。

在分子水平上,锌的功能与其作为免疫细胞中的第二信使的作用有关。细胞内游离锌浓度的变化是由各种配体与它们各自的受体结合而诱导的,例如脂多糖(LPS)与Toll样受体4(TLR-4),或相应的抗原与免疫球蛋白E的结合。不同种类的免疫细胞利用锌的受体表达不同。因此锌信号介导不同的事件,例如,单核细胞形成促炎细胞因子,树突状细胞表面主要组织相容性复合物(MHC)II类分子的呈现,中性粒细胞形成中性粒细胞胞外陷阱粒细胞 [13] ,或T细胞增殖 [14] 。

2. 锌与脓毒症

2.1. 锌水平与脓毒症的关系

在人类脓毒症患者和临床模型中,已发现低水平锌在SIRS和脓毒症的敏感性之间有直接联系 [15] 。通常在幼儿,老年人和糖尿病患者中发现锌血清水平低。这些人的锌缺乏是否构成他们患脓毒症的风险的基础尚不清楚。SIRS患者不仅血锌低,而且硒,铜和铁血值低于正常值 [16] 。与锌和硒相比,SIRS死亡率的相关性特别显著。据报道,在小鼠模型中低锌饮食在SIRS和脓毒症中动物较敏感,并在这些模型中有致死性。Knoell [17] 描述了在小鼠多微生物CLP脓毒症模型中的敏感性。小鼠中的锌耗尽也导致对感染的敏感性增加,当小鼠接受CLP时,响应于Zip14(Slc39a14)表达的上调,血清锌水平急剧下降至CLP发作后9h-24h,肝脏中的锌水平显着降低。在脓毒症的急性期中锌的这种重新分布对于确保急性期蛋白的转录和翻译,为含锌蛋白质提供锌并保护肝细胞免受氧化应激和炎症是必要的。低锌食物对内毒素血症和CLP的致敏作用被发现与炎症因子(IL6, TNF)增加,中性粒细胞趋化性降低,吞噬作用减少,肝和肺细胞死亡增加以及蛋白质氧化增加有关 [18] [19] 。缺锌明显导致多个保护性反应降低。锌对肠上皮细胞(IEC)屏障很重要,并且已发现锌缺乏导致IEC屏障失效 [20] ,这可能导致食物过敏、腹泻、吸收不良,还会使肠道菌群易位,从而对SIRS和脓毒症敏感性增加。

2.2. 锌对脓毒症机制的作用

2.2.1. 锌与炎症信号转导

在脓毒症中,炎症在多种细胞中被激活,包括白细胞,内皮细胞和上皮细胞。在细菌性脓毒症中,炎症的主要诱因是细菌的细胞壁组分,这些组分被宿主的Pattern识别受体识别 [21] 。结果,许多转录因子被激活,主要的炎症转录因子是NFκB,其在脓毒症患者中的活性增加,并且与较高的死亡率相关 [22] 。研究发现Zn对NFκB的影响存在矛盾的结果。表明Zn诱导NFκB抑制的不同机制。1)Zn通过抑制IKB蛋白导致其蛋白酶体降解的IKKβ亚基直接抑制IκB激酶(IKK)复合物 [23] 。2)Zn抑制环核苷酸磷酸二酯酶(PDE),导致cGMP增加,蛋白激酶A(PKA)活化和Raf磷酸化,后者抑制NFκB活化 [24] 。3)Zn也对蛋白质TNFAIP3产生重大影响,这种蛋白质称为A20,是一种去泛素化酶,是NFκB活化的主要调节因子 [25] 。Zn证明可以诱导A20启动子的表观遗传修饰 [26] 。

2.2.2. 锌与趋化性和吞噬作用

感染后,固有免疫系统的激活导致特定白细胞募集到感染的主要部位。PMN(主要是中性粒细胞),巨噬细胞和自然杀伤(NK)细胞是第一个被感染的细胞,是病原体清除所必需的。然而,在脓毒症中,经常观察到中性粒细胞趋化性降低和吞噬作用受损 [27] [28] 。在锌缺乏中也观察到第一线防御缺陷。体外游离锌的螯合作用可以减少中性粒细胞的趋化性和吞噬作用 [29] ,证实了锌在这些过程中的重要作用。感染后,巨噬细胞被吸引到感染部位,在那里它们清除感染因子并产生大量的促炎细胞因子。然而,在脓毒症期间,单核细胞上HLA-DR的表达降低,巨噬细胞极化成所谓的M2巨噬细胞,包括已经观察到抗炎表型,其特征在于细胞因子表达降低 [30] 。NK细胞是固有免疫反应的另一重要防御线,脓毒症期间,NK细胞的细胞毒性功能降低,因此IFNγ的产生减少,这可以通过Zn处理恢复,Zn也可以促进CD34+细胞祖细胞向NK细胞的发育 [31] 。

3. 补锌

低血清锌浓度与较高死亡率或复发机会之间的相关性提出了一个问题,如果补充锌可能是改善败血症结果的治疗选择。在研究中,在脓毒症发生后进行补锌。其中一些表现出锌的有益作用,其形式是较低的死亡率和新生儿更好的神经发育 [32] [33] [34] 。然而,也观察到补充锌剂没有导致锌组和对照组之间的任何显着差异,或甚至显示出有害作用 [35] 。在诱导脓毒症之前补充锌显示出有益效果,例如与对照组相比,存活率提高,促炎细胞因子血清浓度降低,细菌负荷降低或肺功能改善 [36] [37] 。锌补充的阴性结果可以通过以下事实来解释:脓毒症期间锌水平的降低可能由于某种原因而发生,高剂量的锌被证明具有促炎作用,并因此可能加重炎症,或锌补充可能潜在地干扰营养免疫,这是基于血清中锌短缺的内源性防御机制之一。

4. 血清锌浓度作为脓毒症可能的生物标志物

除了锌补充剂的潜在治疗价值之外,锌稳态的改变有可能用于基于患者的血清锌水平建立生物标志物。在脓毒症的猪模型中,血清锌浓度的下降是炎症的第一标志物,在诱导脓毒症后1小时已经具有统计学意义。因此,它是炎症的早期指标,而不是促炎细胞因子IL-6和TNF-α的增加,其在诱导脓毒症后2小时达到统计学显著性 [38] 。到目前为止,关于脓毒症患者和危重病对照组,手术对照组或创伤患者的血清锌浓度是否存在显着差异的研究结果不同 [39] 。需要进一步的研究来评估血清锌浓度作为败血症生物标志物的潜力,包括大型临床研究和临床数据集的评估,以证明其有效性和预期价值。

在脓毒症中使用锌作为标记物的一个障碍可能是必要的基础设施。目前,原子吸收光谱法或电感耦合等离子体质谱法用于量化锌。即使有所需的仪器,结果的质量也很大程度上取决于执行人员或实验室的分析能力 [40] 。如果没有这种复杂的设备,例如在农村地区或基础设施欠发达的国家,将样品送到外部实验室可能会导致获得这些时间敏感结果的显着延迟,从而使早期诊断标记的优势无效。已经报道了一些关于更容易的护理点装置来测量血清锌浓度的基本工作,但这些仍然必须达到临床应用。

关于调节锌重新分布的机制的一些方面尚未完全揭示。它们可能有助于更好地利用锌稳态作为脓毒症的诊断参数。Wessels等。报告诱导后9小时脓毒症模型中血清锌浓度最低,而诱导后第9小时观察到肝脏中ZIP14的上调和肝脏锌的增加 [41] 。这些研究提出了进一步的问题,主要是关于血清锌浓度的下降如何在初始阶段介导,以及锌是否可能位于身体的其他部分,从血清中消失到最终检测到在肝脏。

5. 小结

在脓毒症中,宿主的锌稳态被改变,是宿主抵抗病原体防御机制的一部分,有迹象表明,患者的锌供应和血清锌浓度与脓毒症的严重程度、预后有关。锌似乎有可能被用作生物标志物或甚至作为治疗方法的起点。需要进一步研究以扩大对脓毒症期间锌稳态的理解及其潜在机制,以及评估该知识可能的临床适用性。

基金项目

急诊与危重重点薄弱学科(2016ZB0204)。

参考文献

NOTES

*通讯作者。

文章引用: 来庆兰 , 吴先正 (2018) 微量元素锌在脓毒症中的研究进展。 临床医学进展, 8, 790-795. doi: 10.12677/ACM.2018.89132

参考文献

[1] Singer, M., Deutschman, C.S., Seymour, C.W., et al. (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315, 801-810.
https://doi.org/10.1001/jama.2016.0287

[2] (2017) WHA Resolution A70/13—Improving the Prevention, Diagnosis and Clinical Management of Sepsis. WHO, Geneva, Swit-zerland.

[3] Bloos, F., Thomas-Rüddel, D., Rüddel, H., Engel, C., Schwarzkopf, D., Marshall, J.C., et al. (2014) Im-pact of Compliance with Infection Management Guidelines on Outcome in Patients with Severe Sepsis: A Prospective Observational Multi-Center Study. Crit Care, 18, R42.

[4] Angus, D.C. and van der Poll, T. (2013) Severe Sepsis and Septic Shock. New England Journal of Medicine, 369, 840-851.
https://doi.org/10.1056/NEJMra1208623

[5] Bone, R.C., Grodzin, C.J. and Balk, R.A. (1997) Sepsis: A New Hypothesis for Pathogenesis of the Disease Process. Chest, 112, 235-243.
https://doi.org/10.1378/chest.112.1.235

[6] Liuzzi, J.P. and Cousins, R.J. (2004) Mammalian Zinc Transporters. Annual Review of Nutrition, 24, 151-172.
https://doi.org/10.1146/annurev.nutr.24.012003.132402

[7] Lukacik, M., Thomas, R.L. and Aranda, J.V. (2008) A Meta-Analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea. Pediatrics, 121, 326-336.
https://doi.org/10.1542/peds.2007-0921

[8] King, L.E., Frentzel, J.W., Mann, J.J. and Fraker, P.J. (2005) Chronic Zinc Deficiency in Mice Disrupted T Cell Lymphopoiesis and Erythropoiesis While B Cell Lymphopoiesis and Myelopoiesis Were Maintained. Journal of the American College of Nutrition, 24, 494-502.
https://doi.org/10.1080/07315724.2005.10719495

[9] Prasad, A.S., Meftah, S., Abdallah, J., Kaplan, J., Brewer, G.J., Bach, J.F. and Dardenne, M. (1988) Serum Thymulin in Human Zinc Deficiency. Journal of Clinical Investigation, 82, 1202-1210.
https://doi.org/10.1172/JCI113717

[10] Mayer, L.S., Uciechowski, P., Meyer, S., Schwerdtle, T., Rink, L. and Haase, H. (2014) Differential Impact of Zinc Deficiency on Phagocytosis, Oxidative Burst, and Production of Pro-Inflammatory Cytokines by Human Monocytes. Metallomics, 6, 1288-1295.
https://doi.org/10.1039/c4mt00051j

[11] Dardenne, M., Pléau, J.M., Nabarra, B., Lefrancier, P., Derrien, M., Choay, J. and Bach, J.F. (1982) Contribution of Zinc and Other Metals to the Biological Activity of the Serum Thymic Factor. Proceedings of the National Academy of Sciences of USA, 79, 5370-5373.
https://doi.org/10.1073/pnas.79.17.5370

[12] Incefy, G.S., Mertelsmann, R., Yata, K., Dardenne, M., Bach, J.F. and Good, R.A. (1980) Induction of Differentiation in Human Marrow T Cell Precursors by the Synthetic Serum Thymic Factor, FTS. Clinical & Experimental Immunology, 40, 396-406.

[13] Hasan, R., Rink, L. and Haase, H. (2013) Zinc Signals in Neutrophil Granulocytes Are Required for the Formation of Neutrophil Extracellular Traps. Innate Immunity, 19, 253-264.
https://doi.org/10.1177/1753425912458815

[14] Kaltenberg, J., Plum, L.M., Ober-Blbaum, J.L., Hnscheid, A., Rink, L. and Haase, H. (2010) Zinc Signals Promote IL-2-Dependent Proliferation of T Cells. European Journal of Immunology, 40, 1496-1503.
https://doi.org/10.1002/eji.200939574

[15] I. Wessels, R.J. (2015) Cousins Zinc Dyshomeostasis during Polymi-crobial Sepsis in Mice Involves Zinc Transporter Zip14 and Can Be Overcome by Zinc Supplementation. American Journal of Physiology-Gastrointestinal and Liver Physiology, 309, G768-G778.
https://doi.org/10.1152/ajpgi.00179.2015

[16] Rech, M., et al. (2014) Heavy Metal in the Intensive Care Unit: A Review of Current Literature on Trace Element Supplementation in Critically Ill Patients. Nutrition in Clinical Practice, 29, 78-89.
https://doi.org/10.1177/0884533613515724

[17] Knoell, D.L., et al. (2009) Zinc Deficiency Increases Organ Damage and Mortality in a Murine Model of Polymicrobial Sepsis. Critical Care Medicine, 37, 1380-1388.
https://doi.org/10.1097/CCM.0b013e31819cefe4

[18] Shea-Budgell, M., et al. (2006) Marginal Zinc Deficiency Increased the Susceptibility to Acute Lipopolysaccharide-Induced Liver Injury in Rats. Experimental Biology and Medicine (Maywood), 231, 553-558.
https://doi.org/10.1177/153537020623100509

[19] Crowell, K.T., et al. (2016) Marginal Dietary Zinc Deprivation Augments Sepsis-Induced Alterations in Skeletal Muscle TNF-α But Not Protein Synthesis. Physiological Reports, 4, pii: e13017.

[20] Skrovanek, S., et al. (2014) Zinc and Gastrointestinal Disease. World Journal of Gastrointestinal Pathophysiology, 5, 496-513.
https://doi.org/10.4291/wjgp.v5.i4.496

[21] Crouser, E., et al. (2008) Sepsis: Links between Pathogen Sensing and Organ Damage. Current Pharmaceutical Design, 14, 1840-1852.
https://doi.org/10.2174/138161208784980572

[22] Abraham, E. (2003) Nuclear Factor-kappaB and Its Role in Sepsis-Associated Organ Failure. The Journal of Infectious Diseases, 187, S364-S369.
https://doi.org/10.1086/374750

[23] Liu, M.J., et al. (2013) ZIP8 Regulates Host Defense through Zinc-Mediated Inhibition of NF-κB. Cell Reports, 3, 386-400.
https://doi.org/10.1016/j.celrep.2013.01.009

[24] von Bülow, V., et al. (2007) Zinc-Dependent Suppression of TNF-alpha Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1: I kappa B kinase Beta, and NF-kappa B. The Journal of Immunology, 179, 4180-4186.
https://doi.org/10.4049/jimmunol.179.6.4180

[25] Lork, M., Verhelst, K. and Beyaert, R. (2017) CYLD, A20 and OTULIN Deubiquitinases in NF-κB Signaling and Cell Death: So Similar, Yet So Different. Cell Death & Differentia-tion, 24, 1172-1183.
https://doi.org/10.1038/cdd.2017.46

[26] Li, C., et al. (2015) Maternal High-Zinc Diet At-tenuates Intestinal Inflammation by Reducing DNA Methylation and Elevating H3K9 Acetylation in the A20 Promoter of Offspring Chicks. The Journal of Nutritional Biochemistry, 26, 173-183.
https://doi.org/10.1016/j.jnutbio.2014.10.005

[27] Arraes, S.M., et al. (2006) Impaired Neutrophil Chemotaxis in Sepsis Associates with GRK Expression and Inhibition of Actin Assembly and Tyrosine Phosphorylation. Blood, 108, 2906-2913.
https://doi.org/10.1182/blood-2006-05-024638

[28] Kovach, M.A. and Standiford, T.J. (2012) The Function of Neutrophils in Sepsis. Current Opinion in Infectious Diseases, 25, 321-327.
https://doi.org/10.1097/QCO.0b013e3283528c9b

[29] Hasan, R., Rink, L. and Haase, H. (2016) Chelation of Free Zn2+ Impairs Chemotaxis, Phagocytosis, Oxidative Burst, Degranulation, and Cytokine Production by Neutrophil Granulocytes. Biological Trace Element Research, 171, 79-88.
https://doi.org/10.1007/s12011-015-0515-0

[30] Watanabe, N., et al. (2016) Sepsis Induces Incomplete M2 Phe-notype Polarization in Peritoneal Exudate Cells in Mice. Journal of Intensive Care, 4, 6.
https://doi.org/10.1186/s40560-015-0124-1

[31] Muzzioli, M., et al. (2007) Zinc Improves the Development of Human CD34+ Cell Progenitors towards Natural Killer Cells and Induces the Expression of GATA-3 Transcription Factor. The International Journal of Biochemistry & Cell Biology, 39, 955-965.
https://doi.org/10.1016/j.biocel.2007.01.011

[32] Newton, B., Ballambattu, V.B., Bosco, D.B., Gopalakrishna, S.M. and Subash, C.P. (2017) Efficacy of Zinc Supplementation on Serum Calprotectin, Inflammatory Cytokines and Outcome in Neonatal Sepsis—A Randomized Controlled Trial. The Journal of Maternal-Fetal & Neonatal Medicine, 30, 1627-1631.
https://doi.org/10.1080/14767058.2016.1220524

[33] Newton, B., Bhat, B.V., Bosco Dhas, B., Mondal, N. and Gopalakrishna, S.M. (2016) Effect of Zinc Supplementation on Early Outcome of Neonatal Sepsis—A Randomized Controlled Trial. Indian Journal of Pediatrics, 83, 289-293.
https://doi.org/10.1007/s12098-015-1939-4

[34] Newton, B., Bhat, B.V., Bosco Dhas, B., Christina, C., Gopala-krishna, S.M. and Subhash Chandra, P. (2018) Short Term Oral Zinc Supplementation among Babies with Neonatal Sepsis for Reducing Mortality and Improving Outcome—A Double-Blind Randomized Controlled Trial. Indian Journal of Pediatrics, 85, 5-9.
https://doi.org/10.1007/s12098-017-2444-8

[35] Mehta, K., Bhatta, N.K., Majhi, S., Shrivastava, M.K. and Singh, R.R. (2013) Oral Zinc Supplementation for Reducing Mortality in Probable Neonatal Sepsis: A Double Blind Ran-domized Placebo Controlled Trial. Indian Pediatrics, 50, 390-393.
https://doi.org/10.1007/s13312-013-0120-2

[36] Ganatra, H.A., Varisco, B.M., Harmon, K., Lahni, P., Opoka, A. and Wong, H.R. (2017) Zinc Supplementation Leads to Immune Modulation and Improved Survival in a Juvenile Model of Murine Sepsis. Innate Immunity, 23, 67-76.
https://doi.org/10.1177/1753425916677073

[37] Nowak, J.E., Harmon, K., Caldwell, C.C. and Wong, H.R. (2012) Prophylactic Zinc Supplementation Reduces Bacterial Load and Improves Survival in a Murine Model of Sepsis. Pedi-atric Critical Care Medicine, 13, e323-e329.

[38] Hoeger, J., Simon, T.-P., Doemming, S., Thiele, C., Marx, G., Schuerholz, T. and Haase, H. (2015) Alterations in Zinc Binding Capacity, Free Zinc Levels and Total Serum Zinc in a Porcine Model of Sepsis. BioMetals, 28, 693-700.
https://doi.org/10.1007/s10534-015-9858-4

[39] Jang, J.Y., Shim, H., Lee, S.H. and Lee, J.G. (2014) Serum Se-lenium and Zinc Levels in Critically Ill Surgical Patients. Journal of Critical Care, 29, 317.e5-317.e8.
https://doi.org/10.1016/j.jcrc.2013.12.003

[40] Trame, S., Wessels, I., Haase, H. and Rink, L. (2018) A Short 18 Items Food Frequency Questionnaire Biochemically Validated to Estimate Zinc Status in Humans. Journal of Trace Elements in Medicine and Biology, 49, 285-295.
https://doi.org/10.1016/j.jtemb.2018.02.020

[41] Wessels, I. and Cousins, R.J. (2015) Zinc Dyshomeostasis during Polymicrobial Sepsis in Mice Involves Zinc Transporter Zip14 and Can Be Overcome by Zinc Supplementation. American Journal of Physiology-Gastrointestinal and Liver Physiology, 309, G768-G778.
https://doi.org/10.1152/ajpgi.00179.2015

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