Impact of macrophage carbon load and epigenetic aging on lung function decline and mortality - combustion-emitted particulate matter (CE-PM) is emitted through incomplete combustion of fossil fuels…

Impact of macrophage carbon load and epigenetic aging on lung function decline and mortality - combustion-emitted particulate matter (CE-PM) is emitted through incomplete combustion of fossil fuels and biomass and is a critical public health and climate change issue in the united states (US) and worldwide. A key feature of CE-PM is the presence of black carbon (BC) cores as universal carriers of a wide variety of combustion-derived chemical constituents. Due to different temporality and spatiality for major CE-PM emissions and a large intra- and inter-individual variation in respiratory physiology, significant knowledge gaps remain regarding the dose of BC particles in human lungs as well as the dose-response relationship of lung deposition dose with lung aging and mortality. Accelerated lung aging is a risk factor for the development of chronic obstructive pulmonary disease (copd) and lung cancer, two leading causes of disability and death in the US and globally. Epigenetic alteration is a hallmark of lung aging and implicates key biological pathways underlying copd development. Our overarching goals are 1) to evaluate the impact of lung deposition dose of BC and sputum methylation change on lung function decline (LFD) and mortality, and 2) to explore the lung dose of BC - epigenetics interactions. This project will be conducted in 1071 members from the lovelace smokers cohort and 500 members from the pittsburgh lung screening study who have ≥4 spirometry and longitudinal sputum collections. Macrophage carbon load assay is a novel sputum cytology-based method that quantifies BC particles in macrophages and reflects lung dose of total CE-PM exposure at an individual level over the past several months. An innovative machine-learning algorithm for engulfed carbon particles has been developed that automates the scoring process with high accuracy. Aim 1 will evaluate the dose-response relationships between lung dose of BC, LFD, and mortality. Our recent studies showed that promoter methylation of a 12-gene panel measured in baseline sputum is capable of quantifying the extent of airway remodeling and predicts LFD and mortality. Aim 2 will characterize the sputum methylation index (MI) trajectory in longitudinal samples in a subset (n=200) and then quantify the change of sputum MI between baseline and 5-year follow-up in all study subjects (n=1571). The endotype (sputum methylation) - phenotype (LFD) correlation will be assessed. Identifying determinants of sputum MI change is a key component for characterizing its full validity as a lung aging biomarker. Aim 3 will assess whether total CE-PM exposure, baseline MI, and established risk factors affecting baseline MI are associated with sputum MI change. Aim 4 will explore the moderation effect of epigenetic lung aging on the associations between total CE-PM exposure, LFD, and mortality. This study represents a novel and significant advance for air pollution epidemiology through characterizing the dose of BC in human lungs as well as its dose-response relationships with lung aging and mortality. Findings from this study will inform future research, facilitating the development of novel air quality metrics based on BC to mitigate health risks and address climate change.