Navitoclax inhibits senescence in human alveolar type 2 cells from COPD patients

<bold>Background:</bold> Elevated cellular senescence is a key driver of COPD progression. It may be associated with the loss of alveolar type 2 (AT2) cells during the development of emphysema as senescent AT2 cells may lose their capacity to act as stem cells to repair damage. It may be possible to eliminate senescent AT2 cells using such as navitoclax, which induces apoptosis. Therefore, this study investigates the effects of the senolytic drug navitoclax on senescent AT2 cells. <bold>Hypothesis:</bold> AT2 cells from COPD patients show increased senescence that is reduced by navitoclax. <bold>Methods:</bold> AT2 cells were isolated from human lung tissue from age-matched controls and COPD subjects and confirmed by expression of surfactant protein C (SPC). Cells were cultured in the absence or presence of navitoclax (0.1-3µM) for 48h. Senescence markers, p16^INK4a and p21^CIP1, were assessed via RT-qPCR and Western blot. Cell viability was measured by MTT assay. <bold>Results:</bold> mRNA expression of <italic>CDKN1A</italic> (p21^CIP1) was increased by 2-fold in COPD-derived AT2 cells compared to cells from controls (n=4, *p<0.05). Navitoclax significantly reduced <italic>CDKN1A</italic> expression by 2-fold at 0.1 and 1μM (n=3) and 5-fold at 3μM (n=3), with no significant effect on p16^INK4a or SPC expression (*p<0.05, **p<0.01, one-way ANOVA). This was confirmed by Western blot, where a 3-fold decrease in p21^CIP1 protein expression at a concentration of 1μM was observed. Navitoclax did not affect cell viability. <bold>Conclusion:</bold> AT2 cells from COPD patients exhibit increased senescence compared with cells from controls, and this can be reduced by navitoclax. This suggests that senolytic therapies may be a novel approach for COPD.