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

• 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
• 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

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.

说明(申请人提供)：缺锌严重造成世界范围的疾病负担，占与腹泻疾病和肺炎相关的发病率和死亡率的10%-15%。老龄化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。从实用角度看：a)锌参与先天免疫、适应性免疫和营养免疫；b)补锌价格低廉，治疗指数较大。然而，在有或没有继发性细菌感染(耐甲氧西林金黄色葡萄球菌，MRSA)的大流行性流感(H1N1)背景下，明显缺乏对补充锌的机制和治疗效果的临床前评估。在初步实验中，我们注意到膳食缺锌(锌-D)不会影响完整小鼠对H1N1或MRSA的敏感性，但同时暴露于两者(H1N1/MSRA)会导致更严重的急性肺损伤(ALI)。进一步的初步数据显示，人肺泡巨噬细胞(AM)与人肺泡II型细胞(ATII)共培养模型体系中，远端呼吸道上皮细胞死亡(凋亡)和肺泡巨噬细胞(AM)吞噬凋亡细胞(泡泡吞噬)的能力不强，提示人肺泡II型细胞(ATII)与肺泡巨噬细胞(AM)共培养模型体系可能具有机械性意义。额外的初步数据显示，老龄小鼠是锌-D，对H1N1敏感，这表明这是一个考虑锌的药物治疗潜力的有用模型。因此，具体目标是：1.确定锌在甲型H1N1/MRSA所致ALI中的代谢紊乱作用。远端肺对复合感染的敏感性将在制造锌-D的小鼠中进行评估，并与补锌(锌-R)对照组进行对比。补充锌对甲型H1N1流感/耐甲氧西林金黄色葡萄球菌(H1N1/MRSA)的损伤和恢复的能力将通过在(减轻)暴露之前(预防性)或之后纠正锌缺乏来评估。2.确定锌改善肺远端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)缺锌是否影响人ATII细胞和AM对H1N1/MRSA的反应；b)GM-CSF和转化生长因子ü影响人AM的锌稳态和细胞功能的机制；c)补充锌和NO是否影响人类ATII和AM对H1N1、MRSA或H1N1/MRSA的反应。3.测定锌对增龄性低锌血症的治疗效果及对病毒和细菌感染的敏感性。给18-22月龄小鼠补锌，观察甲型H1N1流感/耐甲氧西林金黄色葡萄球菌的效果。另一组老年小鼠将感染H1N1/MRSA，吸入亚硝酸盐将提高肺内不稳定锌的水平。综上所述，这些研究将为锌通过调节肺泡上皮细胞凋亡和巨噬细胞吞噬作用来调节H1N1/MRSA诱导的肺损伤的消退提供新的见解。这种机械性的洞察力可能有助于指导锌在以下方面的使用：(A)针对与病毒性和细菌性肺炎敏感人群有关的全球健康问题的预防性方式；以及(B)建议锌和亚硝酸盐的联合疗法以减轻老年人群的肺炎。