Mechanisms of dysregulated immunity with aging

衰老过程中免疫失调的机制

• 批准号: 10385857
• 负责人: Jane C Deng
• 金额: $ 58.59万
• 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/10385857
• 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; Persons; 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 infection; influenza virus vaccine; insight; lipid mediator; lung injury; mortality; neutrophil; novel; novel therapeutics; pathogenic virus; recruit; respiratory; respiratory pathogen; 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 老年人在流感病毒肺部感染后表现出较高的发病率和死亡率。遗憾的是，选项 老年人流感的预防和治疗有限，流感疫苗效果较差 老年人比年轻人多。减少流感感染对老年人的影响，尤其是老年人 需要能够有效降低衰老死亡率的新疗法。流感感染会导致大量 炎症，必须解决炎症才能使肺部恢复正常的稳态。不幸的是，很少有 了解衰老如何在炎症消退中发挥作用。我们在小鼠身上的初步数据提供了证据 急性炎症，表现为肺损伤增加和肺内中性粒细胞积聚， 随着衰老而持续存在，表明衰老会导致炎症消退失调。我们假设在 流感病毒感染导致老化，衰老的肺泡上皮细胞分泌中性粒细胞吸引趋化因子 诱导中性粒细胞募集至肺部以及 PGE2（一种多效性脂质介质，可抑制 肺泡巨噬细胞的增殖和功能。由于肺泡巨噬细胞是清除碎片和 解决炎症，我们假设肺泡巨噬细胞随衰老而受损会抑制炎症 流感感染期间的解决。在目标 1 中，我们将研究衰老肺泡的机制 流感病毒感染期间，上皮细胞增强中性粒细胞的募集和保留到肺部 老化。在目标 2 中，我们将研究与年龄相关的 PGE2 增加损害肺泡的机制 巨噬细胞群体的大小和功能。重要的是，我们还将评估肺泡上皮的主要发现 细胞衰老、中性粒细胞趋化剂增加、PGE2 水平增加以及肺泡减少 年轻和老年人肺部的巨噬细胞数量和功能。这项工作有可能阐明 衰老如何诱导肺泡上皮细胞和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。这项研究最终可能会带来新的疗法 恢复这种由衰老引起的异常相互作用，从而提高感染病毒的老年人的生存率 流感病毒和潜在的其他呼吸道病毒病原体。