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（由适用提供）：锌缺乏症对全球疾病的燃烧产生了重大贡献，占与腹泻疾病和肺炎相关的发病率和死亡率的10-15％。衰老的生理缺血可能是该人群对下呼吸道感染的敏感性。从务实的角度来看：a）Zn参与了先天，适应性和营养免疫； b）补充Zn是廉价的，具有相对较大的治疗指数。尽管如此，在大流行流感（H1N1）的背景下，缺乏对机制和治疗效率的临床前评估，有或没有继发性细菌感染（耐甲氧西林的S. aureus，MRSA）。在初步实验中，我们注意到饮食锌缺乏症（Zn-D）并不影响完整小鼠对H1N1或MRSA的敏感性，但暴露于两者（H1N1/MSRA）会导致更严重的急性肺损伤（ALI）。进一步的初步数据表明，远端气道上皮的细胞死亡（凋亡）和肺泡巨噬细胞无法吞噬Zn-D中凋亡细胞（efferocytosis）的能力，这表明可以在人肺泡II型细胞（ATIII）和Alve Alve Alve Alve Alve Alve Macrages（AmaClage）和AmAlve Martage（Am）中获得机理洞察力。其他初步数据表明，老年小鼠对H1N1敏感，这表明这是考虑Zn的药物治疗潜力的有用模型。根据以下内容，具体目的是：1。由于H1N1/MRSA，Zn Dyshomeostasis在ALI中的确定作用。将评估Zn-D的小鼠中远端肺对组合感染的敏感性，并与锌替换（Zn-R）对照对比。补充Zn修改H1N1/MRSA的损伤和恢复的能力将通过纠正Zn缺乏（预防性）或之后（缓解）暴露。 2。确定锌通过改变不同肺细胞中对病毒和细菌感染的炎症反应的分子机制。我们将确定：a）锌缺乏是否影响人ATII细胞并对H1N1/MRSA的反应； b）GM-CSF和TGFß影响Zn稳态和人类AM中细胞功能的机制； c）如果补充锌，没有影响人ATII，并且对H1N1，MRSA或H1N1/MRSA的反应。 3。确定Zn在衰老和对病毒和细菌感染敏感性的物理性低血症中的治疗有效性。将使年龄（18-22个月）的小鼠替换为Zn替换，并评估H1N1/MRSA的效果。单独的老年小鼠队列将被H1N1/MRSA感染，锌内不稳定水平将通过遗传亚硝酸盐升高。总的来说，这些研究将通过调节肺泡上皮细胞凋亡和巨噬细胞诱导的巨噬细胞凋亡来提供有关Zn在调节H1N1/MRSA诱导的肺损伤中的作用的新见解。这种机械洞察力可能有助于指导锌的使用：a）关于敏感人群对病毒和细菌性肺炎的全球健康问题的预防性方式； b）建议将锌和亚硝酸盐的综合疗法减轻年龄人群的肺炎。