Impact of Environmental Exposures on Lung Immunity over Age

PROJECT SUMMARY/ABSTRACT Dr. Ural is a Postdoctoral Scientist in Dr. Donna Farber’s lab working on identifying alterations in the immune system of aging lung and lung-associated lymph nodes. As demographics are changing across many parts of the world, age related lung diseases are expected to become a major healthcare burden. Recent studies have shown that lung function starts to decline after third decade of life, and this leads to increased mortality rate in elderly people due to infectious and non-infectious lung diseases. Human aging is shaped with prolonged exposure to the environment; however, due to limited availability of healthy pulmonary tissues, the impact of environmental exposures (e.g., air pollution) to the aging immune system is not well studied. Macrophages are a diverse population of cells that perform specialized tissue functions. Environmental exposures such as air pollution can have direct effect on the local immune system and pulmonary macrophages are among the first cell types to respond to all the environmental exposures for tissue homeostasis and surveillance. However, macrophage studies in human tissues are very limited due to limited availability of such tissues. It is important to elucidate how aging pulmonary macrophage immunity changes with environmental exposures in order to develop effective immune therapies to recently encountered pathogens. Dr. Donna Farber’s lab has a unique collaboration with a local procurement organization to obtain multiple tissue sites from healthy brain-dead organ donors. Our studies showed that carbon particulates accumulate in human lung draining lymph nodes (LLN) with age while the corresponding mesenteric lymph nodes (MLNs) show no particulate matter. Carbon particulates are contained within a subset of lymph node macrophages, and this leads to reduced activation and phagocytosis with impaired production of cytokines in this macrophage subset. Moreover, these alterations in aging LLNs disrupt B cell follicle integrity with reduction in lymphatics, which is not observed in MLNs. Our central hypothesis is that the environmental particulates are contained within a specific pulmonary macrophage subset because of its distinct localization and due to these particulates, aging pulmonary macrophages have altered transcriptional profile, with compromised respiratory immune response. The aims of this proposal are 1) Evaluate functional properties of human pulmonary macrophage population that takes up environmental particulates over age. 2) Evaluate the phagocytosis and migration potential of aging pulmonary macrophages and how macrophages with atmospheric particulate matter respond to recently encountered pathogens over age. This career award will give Dr. Ural the opportunity to advance her training and experience on macrophage aging, using innovative approaches such as two-photon imaging, CODEX imaging, and computational analysis of high dimensional transcriptomics data. This award will comprehensively prepare Dr. Ural for her future career as an independent pulmonary researcher studying the role of aging in tissue specific immune regulation.