Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-κB
Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-κB
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DOI：
10.1152/ajplung.00368.2009
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发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Knoell, Daren L.
中科院分区：
文献类型：
--
作者：
Bao, Shengying;Liu, Ming-Jie;Knoell, Daren L.
包S，刘明杰，李B，贝塞克B，赖志平，古特里奇DC，诺埃尔DL。锌通过调节核因子-kappa B调节体内对多菌败血症的先天免疫反应。2010年3月5日首次出版；DOI：10.1152/ajpeng.00368.2009。-锌是促进宿主对感染反应期间免疫激活协调的基本元素。我们最近报道，在一种小动物脓毒症模型中，缺锌会增加全身炎症、重要器官损伤和死亡率。为了研究导致这些现象的潜在机制，我们使用了相同的动物模型，观察到缺锌增加了细菌负荷，并增强了包括肺在内的重要器官中的核因子-kappaB活性。我们在肺部进行了进一步的研究，以确定缺锌的整体影响。在分子水平上，锌缺乏可增强核因子-kappa B p65的DNA结合活性，以响应多菌败血症。此外，缺锌还上调了核因子-kappa B靶向基因IL-1β、肿瘤坏死因子α、ICAM-1和急性期反应基因SAA1/2的表达。缺锌小鼠肺组织包括肺泡上皮细胞中的核因子-kappaBp65基因和蛋白表达均显著增加。这些事件发生时，与对照组相比，缺锌小鼠在脓毒症发病24小时内caspase-3活性显著增加。短期补锌逆转了这些影响。肺上皮细胞培养中锌缺乏的重建导致了类似的结果，对肿瘤坏死因子α的反应。综上所述，锌缺乏系统性地增强了感染的传播和体内核因子-kappaB的激活，以应对多菌败血症，导致炎症增加，肺损伤，以及先前报道的死亡。在脓毒症开始之前立即补充锌可以逆转这些影响，从而支持了未来探索锌补充策略以预防脓毒症引起的发病率和死亡率的研究的合理性。
Bao S, Liu M-J, Lee B, Besecker B, Lai J-P, Guttridge DC, Knoell DL. Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-kappa B. Am J Physiol Lung Cell Mol Physiol 298: L744-L754, 2010. First published March 5, 2010; doi:10.1152/ajplung.00368.2009.-Zinc is an essential element that facilitates coordination of immune activation during the host response to infection. We recently reported that zinc deficiency increases systemic inflammation, vital organ damage, and mortality in a small animal model of sepsis. To investigate potential mechanisms that cause these phenomena, we used the same animal model and observed that zinc deficiency increases bacterial burden and enhances NF-kappa B activity in vital organs including the lung. We conducted further studies in the lung to determine the overall impact of zinc deficiency. At the molecular level, NF-kappa B p65 DNA-binding activity was enhanced by zinc deficiency in response to polymicrobial sepsis. Furthermore, expression of the NF-kappa B-targeted genes IL-1 beta, TNF alpha, ICAM-1, and the acute phase response gene SAA1/2 were elevated by zinc deficiency. Unexpectedly, the amount of NF-kappa B p65 mRNA and protein was increased in the lung including alveolar epithelia of zinc-deficient mice. These events occurred with a significant and concomitant increase in caspase-3 activity within 24 h of sepsis onset in zinc-deficient mice relative to control group. Short-term zinc supplementation reversed these effects. Reconstitution of zinc deficiency in lung epithelial cultures resulted in similar findings in response to TNF alpha. Taken together, zinc deficiency systemically enhances the spread of infection and NF-kappa B activation in vivo in response to polymicrobial sepsis, leading to enhanced inflammation, lung injury, and, as reported previously, mortality. Zinc supplementation immediately before initiation of sepsis reversed these effects thereby supporting the plausibility of future studies that explore zinc supplementation strategies to prevent sepsis-mediated morbidity and mortality.