Role of ZIP8 in secondary cigarette smoke exposure-mediated lung injury

ZIP8 在继发性香烟烟雾暴露介导的肺损伤中的作用

• 批准号: 9397646
• 负责人: DAREN Lee KNOELL
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397646
• 关键词: Role; ZIP8; secondary; cigarette; smoke

DESCRIPTION (provided by applicant): Cigarette smoke (CS) exposure is the most important risk factor for developing chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality in men and women in the United States. Importantly, the pathogenesis of CS-related lung disease remains unclear thereby creating a major obstacle to generate improved treatment strategies. Cadmium (Cd) is a major component of cigarette smoke and a leading environmental toxicant with a biological half-life of greater than 20 years. Cd significanty contributes to CS- induced lung disease but it is not known exactly how Cd enters the lung or how it mediates pathological manifestations once in. The long-term goal of this project is to determine the role of the human zinc transporter, ZIP8, a transporter of both zinc and Cd, in lung pathogenesis in the context of first hand (FHS) smoke exposure. Our central hypothesis is that inflammation driven by CS exposure will induce the expression of ZIP8 in lung epithelia thereby increasing Cd entry, immune dysfunction, and lung pathology. This hypothesis is predicated on recent published and preliminary observations by our group demonstrating that ZIP8 expression, not naturally abundant in lung epithelia, is up-regulated by NFkappaB (NF-κB), a key signaling pathway that is activated by CS exposure, and that increased ZIP8 expression enhances Cd uptake into lung epithelia which is further enhanced by zinc deficiency. The rationale for our approach is that establishment of the functional role of ZIP8 within the lung microenvironment in the context of CS exposure, immune activation, and dietary zinc intake, will improve our understanding of CS-related lung disease and foster innovative micronutrient surveillance and treatment strategies. Guided by strong preliminary evidence, this hypothesis will be tested by pursuing two specific aims that: 1) Evaluate the effects of FHS exposure on oxidative status and immune dysfunction in vivo relative to ZIP8 in BTZIP8 overexpressing mice (compared to wild-type matched controls); and 2) Determine the impact of zinc nutrition in vivo as a predisposing factor in ROS formation, immune dysfunction, and lung damage following prolonged FHS exposure. To accomplish the goals of aim 1 and 2 we will pursue novel studies in animal models that explore the role of ZIP8, redox status, immune dysfunction, and zinc nutrition in vivo. The research proposed in this application is innovative because it will for the first time critically evaluate the role of zinc metabolism in the setting of CS-related pathogenesi. This is important because it will define the functional significance of a novel pathway that regulates redox and immune function thereby revealing new molecular insight into CS-related lung disease that will lead to innovative strategies to prevent or better treat this lethal disease

描述（由申请人提供）：接触香烟烟雾 (CS) 是罹患慢性阻塞性肺疾病 (COPD) 的最重要风险因素，慢性阻塞性肺疾病 (COPD) 是美国男性和女性发病和死亡的主要原因。重要的是，CS 相关肺部疾病的发病机制仍不清楚，从而为改进治疗策略造成了主要障碍。镉 (Cd) 是香烟烟雾的主要成分，也是主要的环境毒物，其生物半衰期超过 20 年。 Cd 在很大程度上导致 CS 诱发的肺部疾病，但尚不清楚 Cd 如何进入肺部或进入肺部后如何介导病理表现。该项目的长期目标是确定人类锌转运蛋白 ZIP8（锌和 Cd 的转运蛋白）在第一手 (FHS) 烟雾暴露背景下的肺部发病机制中的作用。我们的中心假设是，CS 暴露引起的炎症会诱导肺上皮细胞中 ZIP8 的表达，从而增加镉的进入、免疫功能障碍和肺部病理。这一假设基于我们小组最近发表的初步观察结果，证明ZIP8表达在肺上皮细胞中并不天然丰富，但会被NFκB（NF-κB）上调，NFκB是CS暴露激活的关键信号通路，并且ZIP8表达增加会增强肺上皮细胞对Cd的吸收，而锌缺乏会进一步增强这种吸收。我们的方法的基本原理是，在 CS 暴露、免疫激活和膳食锌摄入的背景下，确定 ZIP8 在肺部微环境中的功能作用，将提高我们对 CS 相关肺部疾病的理解，并促进创新的微量营养素监测和治疗策略。在强有力的初步证据的指导下，这一假设将通过追求两个具体目标进行检验：1) 评估 FHS 暴露对 BTZIP8 过表达小鼠体内相对于 ZIP8 的氧化状态和免疫功能障碍的影响（与野生型匹配对照相比）； 2) 确定体内锌营养作为长期接触 FHS 后 ROS 形成、免疫功能障碍和肺损伤的诱发因素的影响。为了实现目标 1 和 2，我们将在动物模型中进行新颖的研究，探索 ZIP8、氧化还原状态、免疫功能障碍和体内锌营养的作用。本申请中提出的研究具有创新性，因为它将首次批判性地评估锌代谢在 CS 相关发病机制中的作用。这很重要，因为它将定义调节氧化还原和免疫功能的新途径的功能意义，从而揭示对 CS 相关肺部疾病的新分子见解，从而产生预防或更好地治疗这种致命疾病的创新策略

项目成果

Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia.

• DOI: 10.4049/jimmunol.2001395
• 发表时间: 2021-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hall SC;Smith DR;Dyavar SR;Wyatt TA;Samuelson DR;Bailey KL;Knoell DL
• 通讯作者: Knoell DL

Essential Role of Zinc and Zinc Transporters in Myeloid Cell Function and Host Defense against Infection.

• DOI: 10.1155/2018/4315140
• 发表时间: 2018
• 期刊: Journal of immunology research
• 影响因子: 4.1
• 作者: Sapkota M;Knoell DL
• 通讯作者: Knoell DL