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.

摘要 老年人在流感病毒肺部感染后表现出高发病率和死亡率。遗憾的是， 老年人流感的预防和治疗是有限的，流感疫苗的有效性较低 比年轻人更有影响力减少流感感染对老年人的影响 需要能有效降低衰老死亡率的新疗法。流感感染导致大量 炎症，这必须解决肺恢复正常的稳态。不幸的是， 了解衰老如何在炎症消退中发挥作用。我们在老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， 随着年龄的增长而持续存在，并表明衰老失调炎症的解决。我们假设， 流感病毒感染伴衰老，衰老肺泡上皮细胞分泌嗜中性粒细胞趋化因子 以及PGE2，一种多效脂质介质，其抑制 肺泡巨噬细胞增殖和功能。由于肺泡巨噬细胞是清除碎片和 解决炎症，我们假设，在肺泡巨噬细胞的损伤与老化抑制炎症 在流感感染期间消退。在目标1中，我们将研究衰老肺泡上皮细胞的机制， 在流感病毒感染期间，上皮细胞增强中性粒细胞募集和滞留到肺中， 衰老在目标2中，我们将研究与年龄相关的PGE2增加损害肺泡上皮细胞的机制。 巨噬细胞群体大小和功能。重要的是，我们还将评估肺泡上皮细胞的关键发现， 细胞衰老，中性粒细胞趋化因子增加，PGE2水平升高，肺泡 巨噬细胞的数量和功能在年轻人和老年人的肺。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， 增加流感病毒肺部感染后的死亡率。这项研究可能最终导致新的疗法， 恢复这种由衰老引起的异常相互作用，从而提高感染了 流感病毒和潜在的其它呼吸道病毒病原体。