Developing Lithium as a Disease-Modifying Therapy for Emphysema Using a Precision Medicine Approach

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death among adults in the United States; nonetheless, we lack disease-modifying therapies. Herein, we hypothesize that lithium may be a novel disease-modifying agent for emphysema in smokers. Lithium is an abundant naturally occurring element that is ubiquitous in soil and groundwater from where it enters our food chain and drinking water supply. Once ingested, lithium is distributed across total body water as it diffuses freely across cell membranes. Lithium can be quite toxic when used in the high doses needed to treat mood disorders. In contrast, natural low-level lithium intake from food and water is associated with multiple beneficial effects, including a lower risk of suicide, depression, Parkinson’s and Alzheimer’s diseases, and improved longevity in independent studies. Therefore, low-dose lithium supplements are available over the counter in the US. Lithium exerts biological effects by activating WNT/β-catenin signaling, which is essential for lung development and to repair damaged alveoli, such as those observed in smokers with emphysema. Our preliminary work suggests that lithium may be a novel protective agent against emphysema. These preliminary findings are based on data from animal models, human patient-derived precision-cut lung slices, users of lithium medication in independent cohorts, assessment of circulating lithium levels in nonusers of lithium medication, and analysis of environmental lithium exposure using independent environmental datasets. During this award, we will assess circulating lithium levels in smokers enrolled in two COPD research cohorts and determine if they are associated with emphysema progression, use extensive proteomic and genomic data from both cohorts to identify the subset of smokers most likely to experience less emphysema progression by augmenting circulating lithium levels, and assess the dose-response relationship between lithium and WNT/β-catenin activity in explanted COPD lung tissues. Our overall objective is to advance lithium from ex vivo and observational human studies to clinical trials as a novel disease-modifying agent for emphysema by substantiating efficacy, implementing precision medicine, and defining a dosing strategy.