Project 1 for the Air pollution disrupts Inflammasome Regulation in HEart And Lung Total Health (AIRHEALTH) Study

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ABSTRACT: PROJECT 1 Air pollution, particularly particulate matter <2.5µm (PM2.5) comprising a variety of organic molecules produced by combustion, is a significant driver of chronic lung disease (e.g., asthma). PM2.5 enters pulmonary alveoli during chronic and acute PM2.5 exposure, releasing proinflammatory and vasoactive factors that contribute to pulmonary pathology. Recently, the cytokine IL-1β and the inflammasome pathway have been implicated in mechanisms underlying air-pollution-induced immune system activation and inflammation. Our proposal, for the first time, brings together a unifying hypothesis that pollution mediated heart and lung disease occurs through a shared IL-1β inflammasome pathway. This is not to say other factors are not relevant and we will concurrently test oxidative stress and other pathways through high dimensional, rigorous, and validated assays. We have shown that epigenetic modifications such as DNA methylation during air pollution exposure indicate extent of exposure and can be linked to lung diseases. Although such advances have been made in pollution-caused lung diseases, specific mechanisms of action have been elusive, driving an unmet need for new approaches to protect individuals at risk and to reduce the detrimental effects of PM2.5 exposure. We hypothesize that air pollution exposure induces circulating and cellular cytokines such as IL-1β and other pathways through epigenetic mechanisms and immune cell activation, leading to direct and indirect activation of lung epithelial cells, contributing to chronic lung disease. We will perform immune, and epigenetic studies in blood samples derived from highly characterized cohorts with individual estimate exposures to air pollution. We collected samples over time; therefore, we have samples from cohorts in a clean air environment (i.e. health control). Our project on stem-cell-derived lung tissues harmonizes with studies on stem-cell-derived cardiac tissues, along with novel aims specific to mechanisms in immune and lung tissue. We will share data across all Projects and Cores to synergize findings across immune, lung, and heart areas of study to achieve our overarching goal of uncovering the mechanisms of IL-1β and other pathways dysregulation in inflammation- associated cardiopulmonary pathology in response to chronic and acute air pollution exposure. Understanding the contribution of IL-1β and other markers will likely lead to the development and application of new ways to prevent and treat diseases associated with public health issues associated with air pollution, like asthma. Our study includes longitudinal and repeat measures within our cohorts of individuals (same individual over time is tested) with diverse ethnicities, some of which represent underserved populations. Our analyses will control for confounders (age, sex, body mass index, medications, other) and will address heterogeneity by similar matching of characteristics of the cohorts (two test cohorts and validation cohort).