Exploring Lithium as a Potential Disease-Modifying Therapy for Emphysema

Chronic obstructive pulmonary disease (COPD) remains the fourth leading cause of death among adults in the United States.1,2 Despite its prevalence and significant burden on healthcare, no disease-modifying therapies exist. While tobacco smoking is a primary risk factor, it accounts for only ~50% of attributable risk, highlighting the need for further research into environmental and biological contributors.2 Lithium, a naturally occurring element, has recently emerged as a potential therapeutic candidate for emphysema due to its ability to activate WNT/β-catenin signaling—a pathway critical for lung development and repair.3,4

Lithium and WNT/β-Catenin Signaling in COPD

WNT/β-catenin signaling is indispensable for alveolar repair after injury.5,6 Our preliminary work indicates that lithium may enhance this reparative mechanism. Intra-peritoneal lithium administration in mice activated WNT/β-catenin signaling and reduced experimental emphysema.7 Individuals using lithium for mood stabilization exhibited lower emphysema severity in independent cohorts. Ex vivo studies of human lung tissue demonstrated that lithium-induced reparative processes were proportional to the degree of airflow obstruction.8

Research Aims and Methodology

Given these promising preliminary findings, our study aims to assess whether higher circulating lithium levels are associated with emphysema in a new study. Using data from 200 COPDGene participants, we will measure lithium levels via inductively coupled plasma mass spectrometry (ICP-MS) and correlate them with radiographic emphysema. Additionally, we seek to determine the relationship between circulating and lung tissue lithium levels. By utilizing plasma and lung tissue samples from 35 organ donors and transplant recipients, we will compare lithium levels to establish whether systemic lithium levels reflect pulmonary lithium concentrations.

Potential Clinical Implications

Our findings could pave the way for a paradigm shift in COPD treatment. Unlike conventional therapies that primarily target symptoms, lithium offers a potential disease-modifying approach. Lithium at levels found in the environment or available as over-the-counter supplements has demonstrated neuroprotective and anti-inflammatory benefits with minimal toxicity. Given lithium’s established pharmacokinetics and widespread availability, transitioning from observational studies to interventional trials is highly feasible.

Lithium's ability to activate WNT/β-catenin signaling and promote alveolar repair presents a compelling case for its role as a novel COPD therapy. Our ongoing studies seek to provide robust evidence supporting lithium’s protective effects, ultimately laying the groundwork for clinical trials. If successful, lithium supplementation could offer a cost-effective, widely accessible intervention for emphysema—challenging the current paradigm that COPD is an irreversible disease.

Chandra has no relevant disclosures to report.

REFERENCES

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7.Kneidinger N, Yildirim AO, Callegari J, et al. Activation of the WNT/beta-catenin pathway attenuates experimental emphysema. Am J Respir Crit Care Med 2011;183(6):723-33. DOI: 10.1164/rccm.200910-1560OC.

8.Uhl FE, Vierkotten S, Wagner DE, et al. Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. Eur Respir J 2015;46(4):1150-66. DOI: 10.1183/09031936.00183214.