Saturday, September 7, 2024
9/7/2024
Abstract The delicate gas-exchange surface of the lung is the site of many burdensome diseases, including COVID-19- induced acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILDs). Old age is a well-established predictor of the incidence and severity of these diseases. Alveolar type 2 (AT2) cells, which acts as the guardian of the gas exchange surface against injury and natural turnover via their progenitor cell activity, are detrimentally impacted by aging. AT2 cell self-renewal and differentiation to produce new alveolar type 1 (AT1) cells, the cells that exchange gas with the capillaries, is compromised in old age. In contrast, other progenitor cell populations in the airways of the lung show little evidence of age-related stem cell exhaustion. Why AT2 cell regenerative capacity is reduced in old age is still an open question. Our preliminary studies in mice supported by a single nuclear RNA and ATAC sequencing dataset demonstrated that old AT2 cells have an IFNγ-inducible transcriptional signature, a cytokine critical for many functions in innate and adaptive immunity. IFNγ is elevated in the aged mouse lung, and evidence exists that IFNγ represses AT2 cell growth in human alveolar organoids and mouse disease models. Resident and infiltrating lymphocytes, which act to surveil the lung epithelium for infectious cells, are often the main source of IFNγ during an immune response. Additional preliminary studies demonstrate that there is an enrichment of resident lymphocytes and resident natural killer cells in aged mouse lungs, indicative of more interactions and/or paracrine signaling within the aged lung parenchyma. It is not known whether elevated IFNγ and/or the changes in lymphocyte populations observed in the healthy aging lung influence AT2 cell regenerative decline. We hypothesize that resident natural killer cells contribute to elevated IFNγ in the aging lung which induces AT2 cell- specific regenerative decline. A variety of approaches will be taken to determine if elevated IFNγ or aging lymphocyte populations are 1) necessary for aging AT2 cell regenerative decline and 2) whether they are sufficient to block AT2 cell regeneration. In vivo alveolar injury from bleomycin, alveolar organoid forming assays, and BH3 profiling will be used to assess AT2 cell regenerative capacity and apoptotic potential. Additionally, flow cytometry and multiple imaging techniques, such as RNA in situ hybridization and immunofluorescent staining, will be used to quantitate and localize lymphocytes or cells releasing IFNγ in the aging lung. Using these strategies, this proposal will answer pertinent questions about shifts in aged AT2 cell-immune interactions, the origins of aging AT2 cell exhaustion, and the role of the aging microenvironment in the causation of age-related disease. This knowledge could prove crucial for proper preventative care and targeted therapies in individuals with age-related lung disease in the future.
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