Therapeutic modulation of zinc for lung injury and mechanobiology

项目摘要 急性呼吸窘迫综合征每年影响多达19万人，并导致 尽管在机械通风策略的辅助管理方面有所改善，但比率仍高达46%。的确有 ARDS没有特效的治疗方法，迫切需要新的治疗概念。我们发现， 锌依赖的金属硫蛋白途径在细胞内发挥抗炎和细胞保护作用 在体外和体内呼吸机诱导的肺损伤期间以及患有ARDS的人类受试者中拉伸。我们的中央 假设/前提是肺拉伸启动锌依赖的肺保护性分子反应。一把钥匙 这一假设的推论是，锌补充代表了一种低风险、高回报的治疗方法 预防和/或治疗ARDS。然而，锌储存/代谢的调节是复杂的。特别是，Low， 血浆锌水平并不一定反映锌的组织储存量低，而且血浆锌水平存在显著的异质性。 危重病人的锌代谢。因此，量身定做安全有效的锌补充剂 ARDS的治疗策略需要机械学和临床数据。我们建议对其进行生物学和临床检查 从细胞到人类的研究中缺锌的终点和对锌补充的反应。在目标1中，我们 将在体外确定锌补充对细胞拉伸反应的影响，检查 利用模型研究锌再利用的药代动力学、时间进程和锌进出口机制 与人类急性呼吸窘迫综合征相似。在目标2中，我们将确定化学拯救缺锌的效果。 用人ARDS小鼠模型检测药物动力学、时间进程、 补锌策略/间隔、组织/细胞锌储备和恢复缺锌的潜在机制 在雄性和雌性小鼠中都是如此。在目标3中，我们将确定缺锌的发生率和影响 通过对ARDS受试者整个病程中锌水平的综合分析，了解人类ARDS 这种疾病将使我们能够将锌水平与临床结果以及炎症的生物标志物联系起来， 氧化应激，上皮损伤，锌转运蛋白状态，以及宿主防御。这些研究将首次揭示 时间，锌缺乏对ARDS的发病机制和治疗的影响，使我们能够确定 哪些患者可能受益于ARDS期间的锌补充。我们的长远目标是发展第一 ARDS的针对性治疗和预防策略。重要的是，最近完成了一项第一阶段试验 登记测试补充锌以增强脓毒症患者的免疫反应，为 该项目的快速临床翻译。

Project Summary The Acute Respiratory Distress Syndrome affects as many as 190,000 people each year and has a mortality rate as high as 46% despite improvement in beside management of mechanical ventilation strategies. There is no specific therapy for ARDS, and novel therapeutic concepts are urgently needed. We have discovered that the zinc-dependent metallothionein pathway exerts anti-inflammatory and cytoprotective effects during cell stretch in vitro and during ventilator-induced lung injury in vivo, and in human subjects with ARDS. Our central hypothesis/premise is that lung stretch initiates zinc-dependent lung protective molecular responses. A key corollary of this hypothesis is that zinc repletion represents a low-risk, high reward therapeutic approach to prevent and/or treat ARDS. However, regulation of zinc stores/metabolism is complex. In particular, low plasma zinc levels do not necessarily reflect low tissue stores of zinc, and there is substantial heterogeneity in zinc metabolism amongst critically ill patients. Thus, tailoring a safe and effective zinc supplementation strategy for ARDS requires mechanistic and clinical data. We propose to examine the biologic and clinical endpoints of zinc deficiency and response to zinc repletion in studies spanning cells to humans. In Aim 1, we will determine the impact of zinc repletion on the response to cell stretch in vitro, examining the pharmacokinetics, time course, and zinc import/export mechanisms underlying zinc repletion using models mirroring human ARDS. In Aim 2, we will determine the effect of chemical rescue of zinc deficiency in response to cell stretch using murine models of human ARDS to examine the pharmacokinetics, time course, dosing strategy/interval, tissue/cellular zinc stores, and underlying mechanism of restoration of zinc deficiency in both male and female mice. In Aim 3, we will determine the incidence and impact of zinc deficiency in human ARDS through a comprehensive analysis of zinc levels in ARDS subjects throughout the course of illness that will enable us to correlate zinc levels with clinical outcomes, as well as biomarkers of inflammation, oxidant stress, epithelial injury, zinc transporter status, and host defense. These studies will reveal, for the first time, the impact of zinc deficiency on the pathogenesis and therapy of ARDS and enable us to determine which patients might benefit from zinc repletion during ARDS. Our long-term goal is to develop the first targeted therapeutic and preventive strategy for ARDS. Importantly a Phase 1 trial recently completed enrollment testing zinc supplementation to augment the immune response in sepsis, providing a foundation for rapid clinical translation of this project.