Mechanisms of dysregulated immunity with aging

摘要 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。令人遗憾的是， 老年人对流感的预防和治疗是有限的，流感疫苗效果较差 在老年人中比在年轻人中。减少流感感染对老年人的影响 需要新的治疗方法，能够有效地降低随年龄增长的死亡率。流感感染导致大量 炎症，必须解决，才能使肺部恢复正常的动态平衡。不幸的是，几乎没有 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中性粒细胞在肺内聚集， 随着年龄的增长持续存在，并表明衰老对炎症的分解有调节作用。我们假设在 流感病毒感染伴衰老的肺泡上皮细胞分泌中性粒细胞趋化因子 诱导中性粒细胞重新聚集到肺和PGE2，PGE2是一种多效性脂质介质，它抑制 肺泡巨噬细胞的增殖和功能。因为肺泡巨噬细胞是清除碎片和 解决炎症，我们假设随着年龄的增长，肺泡巨噬细胞的损伤抑制了炎症 在流感感染期间的解决办法。在目标1中，我们将研究衰老肺泡的机制 在流感病毒感染期间，上皮细胞促进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增加损害肺泡的机制。 巨噬细胞群的大小和功能。重要的是，我们还将评估肺泡上皮细胞的关键表现。 细胞衰老，中性粒细胞趋化因子增加，前列腺素E_2水平升高，肺泡减少 年轻人和老年人肺中巨噬细胞的数量和功能。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 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治疗方法 恢复这种由衰老引起的异常相互作用，从而提高感染了老年人的存活率 流感病毒和潜在的其他呼吸道病毒病原体。

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.