B109-23 Lithium Treatment Activates WNT/β-catenin Signaling and Decreased Polymer Z-AAT Burden in Type 2 Alveolar Epithelial Cells in Alpha-1 Antitrypsin Deficiency (AATD)-related Emphysema

Rationale

Emphysema is the main driver of morbidity in Alpha-1 Antitrypsin Deficiency (AATD), and current therapies slow progression but do not promote lung repair. Lithium, a GSK3β inhibitor that activates WNT/βcatenin signaling, promoted alveolar repair in an elastase-induced emphysema model, restoring WNT activity and reducing airspace enlargement. In addition, in protein aggregation disorders such as Alzheimer disease, lithium has been shown to reduce β-amyloid aggregates, suggesting a secondary mechanism, besides WNT/βcatenin signaling, by which lithium could reduce Z-AAT polymer burden and mitigate emphysema in AATD. We hypothesize that low dose lithium treatment could increase WNT/βcatenin signaling and reduce Z-AAT polymers in alveolar type-2 epithelial cells (AT2) in an AATD mouse model.

Methods

Lungs and AT2 cells from lithium-treated (100mg/kg body weight, daily, 30 days) Z-AAT gain-of-function on SerpinA1 null background (AATD) and wild-type mice were examined via western blot, qRT-PCR, and immunofluorescence. AT2 organoid proliferation measured by colony-forming efficiency (CFE), and AT2 differentiation in AT1-like monolayers were assessed before and after LiCl treatment (10mM, with each media change past day 11 for organoids and past day 3 for monolayers).

Results

At baseline, lungs and Epcam+AT2 cells from AATD mice showed higher GSK3β and lower β-catenin, and Axin2 expression, indicative of impaired canonical WNT signalling compared to wild-type (p < 0.001, 1-way ANOVA). AT2 organoids from AATD mice showed diminished proliferation and differentiation, as measured by CFE and organoid’ size (p < 0.001, 1-way ANOVA). LiCl treatment decreased GSK3β activity and increased Axin2 expression in lungs from wild-type and AATD mice (p < 0.05, 2-way ANOVA). Moreover, AT2 organoids and AT1-like monolayers treated with LiCl increased the WNT targets: CyclinD1 and Axin2 expression (p < 0.05, 2-way ANOVA) and decreased Z-AAT polymer levels as measured by 2C1 staining (p < 0.05, t-test).

Conclusions

Impaired WNT signaling in AATD mice is associated with reduced AT2 proliferation and differentiation, and spontaneous emphysema-like airspace enlargement. Our studies indicate that lithium treatment can activate WNT/β-catenin signaling, leading to AT2 proliferation, lung repair and lower intracellular Z-AAT polymer accumulation. Therefore, lithium could be a novel therapy that may mitigate both polymer-mediated toxicity and emphysema progression in AATD patients.

This abstract is funded by: Alpha-1 Foundation