Zinc deficiency primes the lung for ventilator-induced injury
Zinc deficiency primes the lung for ventilator-induced injury
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DOI：
10.1172/jci.insight.86507
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发表时间：
2017-06-02
期刊：
影响因子：
8
通讯作者：
Baron, Rebecca M.
中科院分区：
文献类型：
--
作者：
Boudreault, Francis;Pinilla-Vera, Miguel;Baron, Rebecca M.
机械通气对支持急性肺损伤患者是必要的，但也通过机械应激激活的信号通路加重损伤。我们发现，STRAGE应用于培养的人类细胞和体内的小鼠肺，可以诱导金属硫蛋白的强烈表达，金属硫蛋白是一种对细胞锌稳态至关重要的有效抗氧化剂和细胞保护分子。此外，小鼠金属硫蛋白基因的遗传缺陷加剧了高潮气量机械通气引起的肺损伤，确认了这些基因在限制肺损伤方面的适应性作用。金属硫蛋白的拉伸诱导需要锌和锌结合转录因子MTF1。我们进一步表明，小鼠膳食缺锌加剧了呼吸机诱导的肺损伤，与健康和非ARDS重症监护病房(ICU)对照组以及其他没有ARDS的ICU患者相比，继续发展为急性呼吸窘迫综合征(ARDS)的人类患者的血浆锌水平显著降低。综上所述，我们的发现确定了肺对拉伸的潜在新的适应性反应，以及锌在定义肺对机械通风的耐受性中的关键作用。这些结果表明，拉伸适应性反应的失败在加重机械呼吸机诱导的肺损伤中起着重要作用，并将锌和金属硫蛋白确定为需要机械通气的患者进行肺保护干预的靶点。
Mechanical ventilation is necessary to support patients with acute lung injury, but also exacerbates injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by high tidal volume mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF1. We further show that mouse dietary zinc deficiency potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients who go on to develop acute respiratory distress syndrome (ARDS) compared with healthy and non-ARDS intensive care unit (ICU) controls, as well as with other ICU patients without ARDS. Taken together, our findings identify a potentially novel adaptive response of the lung to stretch and a critical role for zinc in defining the lung's tolerance for mechanical ventilation. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating mechanical ventilator-induced lung injury, and identify zinc and metallothionein as targets for lung-protective interventions in patients requiring mechanical ventilation.