Pulmonary Aging: Impact of cell senescence on lung inflammation and repair in endotoxin and Klebsiella pneumoniae induced lung injury

在老年人中，发生社区获得性肺炎和急性肺损伤（ALI）的风险增加，并与较高的发病率和死亡率相关。因此，研究确定肺老化的机制及其对肺部对病原体免疫的影响具有相当大的医学和社会经济重要性，特别是在像德国这样的过度老龄化社会。在拟议的研究将破译机制的肺细胞和免疫衰老及其对革兰氏阴性细菌肺部感染的影响在老年小鼠和年轻小鼠。细胞衰老被认为是一种细胞生长停滞的状态，它限制了损伤后的修复，并且与促炎信号和细胞功能受损有关。我们假设肺泡巨噬细胞（AM）和肺泡上皮II型（ATII）细胞的细胞衰老机制是导致肺损伤免疫反应改变的原因，并可能影响老年人的肺再生。AM和ATII细胞在ALI的肺保护和炎症信号传导中发挥重要作用。我们的初步数据表明，AM随着年龄的增长向促炎性M1表型发展，并导致肺部炎症，而老年小鼠的ATII细胞更容易受到炎症损伤，这可能会限制损伤后的再生。然而，目前尚不清楚这些细胞的衰老在多大程度上以及通过何种方式导致了老年肺部疾病的病理。在目前的提案中，我们的目标是破译ATII细胞和AM的细胞老化和细胞衰老对内毒素和肺炎克雷伯菌驱动的年轻和年老小鼠ALI的发展和再生的贡献。因此，我们将确定i)与年轻小鼠相比，老年小鼠的感染、损伤和消退/修复过程；ii) AM细胞衰老对小鼠模型ALI发展的贡献，以及人类血液单核细胞和来自年轻和老年供体的人类AM的细胞衰老和炎症信号传导；iii) ATII细胞衰老对肺部炎症的严重程度、表面活性物质代谢和ALI后的消退/修复的影响。了解AM和ATII细胞老化的机制，以及它们如何导致ALI肺部感染和损伤的严重程度增加，将有助于对衰老过程中肺防御和再生的新见解，这可能是开发老年肺炎和ALI患者新治疗方法的基本要素。

In the elderly, the risk for developing community-acquired pneumonia and acute lung injury (ALI) increases and is associated with higher morbidity and mortality rates. Therefore, investigations determining the mechanisms of pulmonary aging and its impact on lung immunity against pathogens are of considerable medical as well as socio-economic importance, particularly in an over-aging society like in Germany. In the proposed study will decipher mechanisms of pulmonary cell- and immunosenescence and its impact on Gram-negative bacterial pulmonary infection in old versus young mice.Cell senescence is recognized as state of cell growth arrest that limits repair after injury and which is furthermore associated with pro-inflammatory signaling and impaired cell function. We hypothesize that mechanisms of cell senescence in alveolar macrophages (AM) and alveolar epithelial type II (ATII) cells are responsible for alterations in the immune response to lung injury with potential impact on regeneration in the elderly. AM and ATII cells play an important role in the protection of the lung and inflammatory signaling in ALI. Our preliminary data suggest that AM develop towards a pro-inflammatory M1 phenotype with age and contribute to pulmonary inflammation, while ATII cells become more susceptible to inflammatory injury in old mice which potentially limits regeneration after injury. However, it is not clear to what extend and by which means senescence in these cells contributes to the pathology of the disease in old lungs.In the current proposal, we aim to decipher the contribution of cell aging and cell senescence in ATII cells and AM to the development and regeneration of endotoxin and K. pneumoniae driven ALI in young and old mice. Thereby we will determine i) the course of infection, injury and resolution/repair in old as compared to young mice, ii) the contribution of AM cell aging to the development of ALI in murine models, as well as cell senescence and inflammatory signaling in human blood monocytes and human AM from young and old donors and iii) effects of ATII cell senescence on severity of lung inflammation, surfactant metabolism and the resolution/repair after ALI.Understanding the mechanisms of AM and ATII cell aging and how they contribute to an enhanced severity in pulmonary infection and injury in ALI will lead to new insights on pulmonary defense and regeneration in aging that could be elemental for the development of new therapeutic approaches for elderly patients with pneumonia and ALI.