Combined viral and bacterial infection and zinc homeostasis in distal lung

病毒和细菌联合感染与远端肺锌稳态

基本信息

批准号：
9043183
负责人：
A. Murat Kaynar
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043183
关键词：
Accounting Acute Acute Lung Injury Adverse effects Affect Aging Alveolar Alveolar Macrophages Apoptosis Apoptotic Bacterial Infections Bacterial Pneumonia Binding Biological Models Breathing Capillary Permeability Cell Death Cell physiology Cells Child Care Clioquinol Coculture Techniques Data Dietary Zinc Disease Distal Electron Microscopy Epidemiologic Studies Epithelial Exposure to Fortified Food Granulocyte-Macrophage Colony-Stimulating Factor Health Homeostasis Human Hydration status Immunity In Situ Infection Infectious Agent Inflammation Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Injury Liver Lower Respiratory Tract Infection Lung Mechanics Mediating Medical Modeling Molecular Morbidity - disease rate Mus Natural Immunity Nitric Oxide Nitrites Nutritional Oral Outcome Phagocytosis Phase Physiological Pneumonia Population Preventive Production Public Health Recovery Resolution Role Sepsis Signal Transduction Site Source Therapeutic Therapeutic Agents Therapeutic Index Transforming Growth Factor beta Treatment Efficacy Uncertainty Viral Viral Cell Proliferation Viral Pneumonia Virus Diseases Water Zinc Zinc deficiency Zinc supplementation adaptive immunity adverse outcome aged airway epithelium alveolar type II cell burden of illness cohort cytokine experience global health influenzavirus insight light microscopy lung injury lung repair macrophage methicillin resistant Staphylococcus aureus mortality novel pandemic influenza pathogen pre-clinical randomized trial research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Zinc deficiency contributes significantly to world wide burden of disease accounting for 10-15% of morbidity and mortality associated with diarrheal disorders and pneumonia. Physiological hypozincemia of aging may account for sensitivity of this population to lower respiratory tract infections. From a pragmatic point of view: a) Zn is involved in innate, adaptive and nutritional immunity; and b) Zn supplementation is inexpensive and has a relatively large therapeutic index. Nonetheless, there is a notable lack of preclinical assessment of mechanisms and therapeutic efficacy of supplemental zinc in the context of pandemic flu (H1N1) with or without secondary bacterial infection (Methicillin-resistant S. aureus, MRSA). In preliminary experiments, we noted that dietary zinc deficiency (Zn-D) did not affect the sensitivity of intact mice to either H1N1 or MRSA, but exposure to both (H1N1/MSRA) resulted in more severe acute lung injury (ALI). Further preliminary data showing that cell death (apoptosis) of distal airway epithelium and inability of alveolar macrophages to phagocytize apoptotic cells (efferocytosis) in Zn-D suggest that mechanistic insight may be obtained in co- culture model system of human alveolar type II cells (ATII) and alveolar macrophages (AM). Additional preliminary data showing that aged mice are Zn-D and sensitive to H1N1 suggest that this is a useful model to consider pharmacotherapeutic potential of Zn. Accordingly, SPECIFIC AIMS are: 1.Determine role of Zn dyshomeostasis in ALI due to H1N1/MRSA. The sensitivity of distal lung to combined infection will be assessed in mice made Zn-D and contrasted to zinc replete (Zn-R) controls. The ability of supplemental Zn to modify injury to and recovery from H1N1/MRSA will be assessed by correcting Zn deficiency prior (preventive) to or after (mitigative) exposure. 2. Determine the molecular mechanisms by which Zn modifies inflammatory response to viral and bacterial infection in cells of distal lung. We will determine: a) if Zn deficiency affects human ATII cells and AM response to H1N1/MRSA; b) the mechanism by which GM-CSF and TGFß affect Zn homeostasis and cellular function in human AM; and c) if Zn supplementation and NO affect human ATII and AM response to H1N1, MRSA or H1N1/MRSA. 3. Determine therapeutic efficacy of Zn in physiological hypozincemia of aging and sensitivity to viral and bacterial infection. Aged (18-22 months) mice will be made Zn replete and the effect of H1N1/MRSA will be assessed. A separate cohort of aged mice will be infected with H1N1/MRSA and intrapulmonary labile levels of zinc will be elevated by inhaled nitrite. Collectively, these studies will provide novel insights into the role of Zn in regulating resolutio of H1N1/MRSA-induced lung injury through modulation of alveolar epithelial apoptosis and macrophage efferocytosis. Such mechanistic insight may help guide the use of zinc in: a) preventive fashion for global health issues regarding sensitive populations to viral and bacterial pneumonia; and b) suggest combined therapies of zinc and nitrite to mitigate pneumonia in aged population.

描述（由申请人提供）：缺锌对世界范围内的疾病负担有显着影响，占腹泻病和肺炎相关发病率和死亡率的 10-15%。衰老引起的生理性低锌血症可能是该人群对下呼吸道感染敏感的原因。从实用的角度来看：a）锌与先天性、适应性和营养性免疫有关；b）补充锌价格低廉且具有相对较大的治疗指数。在大流行性流感（H1N1）伴或不伴继发细菌感染（耐甲氧西林金黄色葡萄球菌，MRSA）的情况下，缺乏对补充锌的机制和治疗效果的临床前评估。 Zn-D）不会影响完整小鼠对 H1N1 或 MRSA 的敏感性，但接触这两种病毒（H1N1/MSRA）会导致更严重的急性肺损伤（ALI）。 Zn-D 中远端气道上皮的细胞死亡（凋亡）和肺泡巨噬细胞无法吞噬凋亡细胞（胞吞作用）表明，可以在人肺泡 II 型细胞（ATII）和肺泡巨噬细胞的共培养模型系统中获得机制见解(AM)。其他初步数据表明，老年小鼠具有 Zn-D 且对 H1N1 敏感，表明这是一个值得考虑的有用模型。因此，具体目标是： 1. 确定锌稳态在 H1N1/MRSA 引起的 ALI 中的作用将在 Zn-D 小鼠中评估远端肺对联合感染的敏感性，并与补充锌 (Zn) 的小鼠进行比较。 -R) 对照，补充锌改善 H1N1/MRSA 损伤和恢复的能力将通过事先纠正锌缺乏来评估。（预防性）暴露或之后（缓解性） 2. 确定锌改变远端肺细胞对病毒和细菌感染的炎症反应的分子机制我们将确定：a) 锌缺乏是否会影响人类 ATII 细胞和 AM 反应。 H1N1/MRSA；b) GM-CSF 和 TGFβ 影响人类 AM 中锌稳态和细胞功能的机制；以及 c) 补充锌和 NO 是否影响人类 ATII 和 AM 的反应H1N1、MRSA 或 H1N1/MRSA 3. 确定 Zn 对衰老和对病毒和细菌感染敏感的生理性低锌血症的治疗效果，对老年（18-22 个月）小鼠补充 Zn，并观察 H1N1/MRSA 的效果。另一组老年小鼠将感染 H1N1/MRSA，吸入亚硝酸盐会使肺内不稳定的锌水平升高。总的来说，这些研究将为锌通过调节肺泡上皮细胞凋亡和巨噬细胞胞吞作用来调节 H1N1/MRSA 诱导的肺损伤的作用提供新的见解，这种机制见解可能有助于指导锌在以下方面的使用：a) 预防方式。针对有关病毒性和细菌性肺炎敏感人群的全球健康问题；b) 建议锌和亚硝酸盐的联合疗法，以减轻老年人群的肺炎。