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: 9894841
• 负责人: Rebecca M Baron
• 金额: $ 69.43万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894841
• 关键词: Admission activity; Adult Respiratory Distress Syndrome; 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; Pharmacology; Phenotype; Plasma; Population Heterogeneity; Predisposition; Prevalence; Prevention strategy; Randomized Controlled Trials; Recommendation; Regulation; Respiratory physiology; 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; 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.

项目摘要 急性呼吸窘迫综合征每年影响多达19万人， 尽管改善了机械通气策略的旁道管理，但仍高达46%。有 目前尚无针对ARDS的特异性治疗方法，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凋亡过程中发挥抗炎和细胞保护作用， 拉伸在体外和呼吸机诱导的肺损伤在体内，并在人类受试者与ARDS。我们的中央 假设/前提是肺牵张启动锌依赖性肺保护性分子应答。一个关键 这一假设的一个推论是，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。特别是低 血浆锌水平不一定反映锌的低组织储存， 危重病人的锌代谢。因此，定制安全有效的锌补充剂 针对ARDS的策略需要机制和临床数据。我们建议检查生物和临床 在从细胞到人类的研究中，锌缺乏和对锌补充的反应的终点。目标1： 将确定锌补充对体外细胞拉伸反应的影响， 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 与人类ARDS相似在目标2中，我们将确定锌缺乏的化学拯救的效果， 使用人ARDS的鼠模型检测对细胞拉伸的反应，以检查药代动力学，时间过程， 给药策略/间隔、组织/细胞锌储备和锌缺乏恢复的潜在机制 在雄性和雌性小鼠中。在目标3中，我们将确定缺锌的发病率和影响， 通过全面分析ARDS受试者在整个治疗过程中的锌水平， 疾病，这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， 氧化应激、上皮损伤、锌转运体状态和宿主防御。这些研究将揭示，首先， 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 哪些患者在ARDS期间可能受益于锌补充。我们的长期目标是发展第一个 针对性治疗和预防ARDS的策略。重要的是，最近完成的一项1期试验 招募测试锌补充剂，以增强脓毒症的免疫反应，提供了基础， 快速临床翻译这个项目。