Project 2: Environmental exposures in pre-clinical FPF

PROJECT SUMMARY Pulmonary fibrosis (PF) is a progressive lung disease that typically presents in older adults who have moderately advanced disease and a limited life expectancy of 3-5-years after diagnosis. The current paradigm of disease pathogenesis is one of recurrent, low-grade injury to the lung epithelium (e.g., by cigarette smoke)

with an abnormal repair process in a susceptible individual. The exposome is defined as the totality of exposures experienced over a lifespan. Key stakeholders have called for integration across other ‘omics platforms to understand how exposures impact health. A key gap in our current understanding of PF

pathobiology is a limited understanding of how environmental exposures contribute to disease development, as few (if any) studies have integrated an assessment of environmental exposures with disease pathobiology. Our group and others have demonstrated that clinical (symptomatic) PF develops after years when a more subtle

abnormality is present on lung imaging and/or tissue examination. Because family history is a major risk factor for PF (up to 100-fold increased risk), we established the At-Risk for Familial PF Cohort to study the natural history of pre-clinical PF among asymptomatic relatives of PF patients. This cohort of middle-aged adults is

enriched with individuals with pre-clinical PF; 22% had abnormal interstitial changes of the lung parenchyma, termed interstitial lung abnormalities (ILA), on the enrollment screening chest CT scan, and 30% experienced pre-symptomatic progression of ILA or developed symptomatic PF during a longitudinal observation period of

~5-years. At-Risk Cohort participants self-report environmental exposures at cohort enrollment, and several of these exposures (e.g., coal dust, welding, mold) were associated with ILA and its progression. In addition, At- Risk Cohort participants with ILA have alterations in peripheral blood gene expression in pathways also

associated with environmental exposures. The objectives of this Project are to identify specific environmental exposures and potential biological intermediaries that are associated with pre-clinical PF. The central hypothesis is that environmental exposures contribute to the development of PF by causing direct injury and/or

altering the repair response, with exposure-associated biological alterations detectible before the onset of clinical disease. The Specific Aims are: 1) Determine the chemical, metal, and respirable environmental exposures associated with pre-clinical PF; and 2) Identify putative metabolic or transcriptomic intermediaries

between environmental exposures and pre-clinical PF. In a sub-study nested in the At-Risk Cohort, exposures are measured via complementary modalities, including wearable devices, and biological intermediaries via serum metabolomics and single-cell RNA sequencing of peripheral blood mononuclear cells. Pre-clinical PF-

associated features will be identified among age- and sex-matched pairs with or without ILA. The combined result will be to gain understanding of the mechanisms through which environmental exposures lead to the development of PF, and identify novel ways to intervene prior to the onset of symptomatic disease.