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

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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.