Therapeutic modulation of zinc for lung injury and mechanobiology

锌对肺损伤和机械生物学的治疗调节

• 批准号: 10378503
• 负责人: Rebecca M Baron
• 金额: $ 68.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378503
• 关键词: Acute Respiratory Distress Syndrome; Admission activity; Affect; Animals; Anti-Inflammatory Agents; Area; Biological; Biological Markers; Cells; Cessation of life; Chemicals; Clinical; Clinical Data; Clinical Practice Guideline; Clinical Trials; Complex; Confidence Intervals; Critical Illness; Cytoprotection; Data; Development; Dose; Drug Kinetics; Enrollment; Excretory function; Exhibits; Failure; Female; Foundations; Gender; Goals; Heme; Heterogeneity; Host Defense; Human; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Intervention; Investigation; Life; Lung; Mechanical ventilation; Mechanics; Metabolism; Metallothionein; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Oxygenases; Parenteral Nutrition; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Plasma; Population Heterogeneity; Predisposition; Prevalence; Prevention strategy; Randomized Controlled Trials; Recommendation; Regulation; Risk; Safety; Savings; Sepsis; Stretching; Syndrome; Testing; Therapeutic; Time; Tissues; Ventilator-induced lung injury; Zinc; Zinc deficiency; Zinc supplementation; cecal ligation puncture; cell type; clinical research site; clinical translation; cohort; cost; epithelial injury; high reward; human model; human subject; in vivo; indexing; lung injury; male; mortality; mouse model; novel; novel therapeutics; oxidant stress; patient response; phase I trial; preservation; prevent; pulmonary function; response; restoration; septic patients; targeted treatment; therapeutic candidate; treatment strategy; zinc-binding protein

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.

项目概要 急性呼吸窘迫综合症每年影响多达 190,000 人，死亡率极高 尽管机械通气策略的管理有所改善，但该比率仍高达 46%。有 ARDS 尚无特效疗法，迫切需要新的治疗理念。我们发现 锌依赖性金属硫蛋白途径在细胞过程中发挥抗炎和细胞保护作用 在体外、呼吸机引起的体内肺损伤期间以及患有 ARDS 的人类受试者中进行拉伸。我们的中央 假设/前提是肺拉伸启动锌依赖性肺保护分子反应。一把钥匙 这一假设的推论是，补充锌代表了一种低风险、高回报的治疗方法 预防和/或治疗 ARDS。然而，锌储存/代谢的调节很复杂。特别是，低 血浆锌水平并不一定反映锌的组织储存量低，并且不同组织之间存在很大的异质性。 危重病人的锌代谢。因此，制定安全有效的锌补充剂 ARDS 策略需要机制和临床数据。我们建议检查生物学和临床 从细胞到人类的研究中锌缺乏的终点和对补充锌的反应。在目标 1 中，我们 将确定锌补充对体外细胞拉伸反应的影响，检查 使用模型研究锌补充的药代动力学、时间进程和锌输入/输出机制 反映人类 ARDS。在目标 2 中，我们将确定化学救援对缺锌的效果 使用人类 ARDS 小鼠模型对细胞拉伸的反应来检查药代动力学、时间过程、 给药策略/间隔、组织/细胞锌储存以及恢复锌缺乏的潜在机制 在雄性和雌性小鼠中。在目标 3 中，我们将确定缺锌的发生率和影响 通过对 ARDS 受试者整个过程中锌水平的综合分析 疾病将使我们能够将锌水平与临床结果以及炎症生物标志物相关联， 氧化应激、上皮损伤、锌转运蛋白状态和宿主防御。这些研究将首次揭示 时间，锌缺乏对 ARDS 发病机制和治疗的影响，使我们能够确定 哪些患者可能会在 ARDS 期间从补充锌中受益。我们的长期目标是开发第一 ARDS 的针对性治疗和预防策略。重要的是，第一阶段试验最近完成 入组测试补充锌以增强败血症的免疫反应，为 该项目的快速临床转化。