Mechanisms of dysregulated immunity with aging

衰老过程中免疫失调的机制

• 批准号: 9975665
• 负责人: Jane C Deng
• 金额: $ 59.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975665
• 关键词: Acute; Age; Age-Years; Aging; Alveolar Macrophages; Back; Bronchoalveolar Lavage; CXCL1 gene; Cell Aging; Cells; Cessation of life; Chemotactic Factors; Data; Dinoprostone; Elderly; Epithelial Cells; Exhibits; Funding; Homeostasis; Human; Immune; Immune system; Immunity; Impairment; In Vitro; Individual; Inflammation; Influenza; Lead; Lung; Lung infections; Measures; Morbidity - disease rate; Mus; Neutrophil Infiltration; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Population Sizes; Prevention; Production; Resolution; Respiratory Failure; Risk; Role; Sampling; Signal Transduction; Source; Testing; Transgenic Mice; Translating; Viral; Virus Diseases; Work; age related; aged; alveolar epithelium; burden of illness; cell age; chemokine; improved; in vivo; influenza virus vaccine; influenzavirus; insight; lipid mediator; lung injury; mortality; neutrophil; novel; novel therapeutics; pathogen; pathogenic virus; recruit; respiratory; senescence

ABSTRACT Older people exhibit high morbidity and mortality after influenza viral lung infection. Regrettably, options for prevention and treatment of influenza in older individuals are limited, and the influenza vaccine is less effective in older people than in younger people. Reducing the impact of influenza infection in the elderly in particular requires novel therapies that can effectively reduce mortality with aging. Influenza infection causes substantial inflammation, which must be resolved for the lungs to return to normal homeostasis. Unfortunately, little is known about how aging plays a role in inflammation resolution. Our preliminary data in mice provide evidence that acute inflammation, manifested as increased lung damage and neutrophil accumulation within the lungs, persists with aging and suggest that aging dysregulates inflammation resolution. We hypothesize that during influenza viral infection with aging, senescent alveolar epithelial cells secrete neutrophil-attracting chemokines to induce neutrophil recruitment into the lung as well as PGE2, a pleiotropic lipid mediator, which suppresses alveolar macrophage proliferation and function. As alveolar macrophages are key in clearing debris and resolving inflammation, we postulate that impairments in alveolar macrophages with aging inhibit inflammation resolution during influenza infection. In Aim 1, we will examine the mechanisms by which senescent alveolar epithelial cells enhance neutrophil recruitment and retention into the lung during influenza viral infection with aging. In Aim 2, we will investigate the mechanisms by which age-related increases in PGE2 impair alveolar macrophages population size and function. Importantly, we will also assess key findings of alveolar epithelial cell senescence, increased neutrophil chemoattractants, increased PGE2 levels, and decreased alveolar macrophage number and function in young and aged human lungs. This work has the potential to elucidate how aging induces an aberrant interaction between alveolar epithelial cells and alveolar macrophages, thereby increasing mortality after influenza viral lung infection. This study could ultimately lead to novel therapies to restore this aberrant interaction induced by aging, resulting in improved survival in older people infected with influenza virus and potentially other respiratory viral pathogens as well.

抽象的 流感病毒肺部感染后，老年人表现出高发病率和死亡率。遗憾的是，选择 老年人的预防和治疗流感受到限制，流感疫苗的效率较低 在老年人中比在年轻人中。尤其是减少流感感染对老年人的影响 需要新的疗法，可以通过衰老有效地降低死亡率。流感感染引起大量 炎症，必须解决肺部恢复正常的体内平衡。不幸的是，几乎没有 知道衰老如何在炎症解决中起作用。我们在小鼠中的初步数据提供了证据 这种急性炎症表现为增加肺部损伤和中性粒细胞在肺部的积累， 持续衰老，并表明衰老失调会解决炎症。我们假设在 衰老，衰老肺泡上皮细胞分泌嗜中性粒细胞趋化因子，流感病毒感染 诱导嗜中性粒细胞募集到肺中以及PGE2（一种多效脂质介体）抑制 肺泡巨噬细胞增殖和功能。因为肺泡巨噬细胞是清除碎屑和 解决炎症，我们假设肺泡巨噬细胞的损害会抑制炎症 流感感染期间的分辨率。在AIM 1中，我们将检查衰老肺泡的机制 上皮细胞在流感病毒感染期间增强中性粒细胞的募集和保留到肺中 老化。在AIM 2中，我们将研究与年龄相关的PGE2损害肺泡的机制 巨噬细胞的种群规模和功能。重要的是，我们还将评估肺泡上皮的关键发现 细胞衰老，中性粒细胞趋化剂增加，PGE2水平升高，肺泡降低 巨噬细胞的数量和功能在人类肺中。这项工作有可能阐明 衰老如何诱导肺泡上皮细胞与肺泡巨噬细胞之间的异常相互作用，从而 流感病毒肺部感染后死亡率增加。这项研究最终可能导致新的疗法 恢复衰老引起的这种异常相互作用，从而改善感染的老年人的生存率 流感病毒以及潜在的其他呼吸道病毒病原体。