Inhaled Stressors and Lung Aging

PROJECT SUMMARY Air pollution and inhaled particulate matter have been recognized as major global health risks which contribute to overall disease burden and mortality. Majority of the global population lives in areas that do not meet air quality standards, therefore placing humans in elevated health risk. The impact of inhaled environmental stressors (PM2.5 and cigarette smoke) on two key component of aging, mitochondrial dysfunction and cellular senescence, remains unknown and an area of high scientific interest and impact. The major goal of this work is to define how PM2.5, DEP and smoke influences mitochondrial dysfunction and senescence using translational human organoid and precision cut lung slice models. We will define tractable human-based models to then test tissue resiliency versus pathogenesis in response to inhaled stressors to identify new therapeutic targets for adult lung aging. Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with no current therapies that significantly alter disease progression and is considered to be a disease of accelerated lung aging. Cigarette smoke (CS) and air pollution are important major causative factors in COPD that results in mitochondrial dysfunction and reactive oxygen species (ROS). Alveolar epithelial type 2 cells (AT2s) are essential progenitor cells for normal lung homeostasis (cell renewal) and epithelial repair after lung injury and in COPD. Mitochondrial dysfunction and cell senescence, a state of cell cycle arrest, have been implicated in lung aging and COPD and may reduce AT2 cell progenitor function and epithelial repair. This proposal will determine how inhaled environmental stressors (PM2.5 and smoke) alter mitochondrial function and senescence as key aging outputs using translational human organoid and precision cut lung slice models. Our study will determine the following: 1) To test the hypothesis that PM2.5 and CS will result in mitochondrial dysfunction and senescence readouts in adult human lung models, 2) To establish tractable and robust models for testing the effects of inhaled stressors in the adult lung, 3) To determine the effects of co- exposure of PM2.5 with CS on mitochondrial dysfunction and senescence in smoker and COPD lungs using our established models to test health span and susceptibility, 4) To utilize a deep learning platform to identify drugs or compounds to reverse the transcriptional profile of mitochondrial dysfunction or senescence in aged adult lung models. The outcome of this proposal will develop and define translatable models for the analysis of mitochondrial dysfunction and senescence due to PM2.5 and CS and how these inhaled insults shift from healthy lung aging to accelerated, pathogenic lung aging or COPD. This work will provide critical knowledge connecting these processes and will inform the discovery of new respiratory therapies.