Effect of the putative senotherapy, Fisetin on small airway epithelial cells in COPD

<bold>Background:</bold> COPD is associated with accelerated lung ageing and increased cellular senescence. Senescent cells cannot replicate but are metabolically active and secrete proinflammatory factors that may drive disease progression. Fisetin is a flavonoid found in fruits and can act as a senolytic. We aimed to investigate the effects of fisetin on cellular senescence and proliferation of small airway epithelial cells (SAEC) derived from COPD patients. <bold>Methods:</bold> SAEC from COPD patients or healthy donors were cultured for up to 5 days with 1-100μM of fisetin. Cell viability was measured by MTT and CXCL8, measured by ELISA. Proliferation was measured by X-CELLigence ®. <bold>Results:</bold> Cell viability of COPD SAEC decreased when cultured with 30μM of fisetin for 72h (n=3, 53.3% ± 20.1%) compared to untreated cells. Fisetin does not affect healthy SAEC (n=5). The treatment with 30μM of fisetin induced COPD SAEC proliferation during the first 24h of culture (n=3) but not in healthy SAEC. COPD SAEC showed decreased production of CXCL8 after 24h (n=3, 3.4 ± 0.4ng/ml in untreated SAEC vs 1.9 ± 0.3ng/ml in cells cultured with fisetin). <bold>Conclusion:</bold> The data suggest that treating COPD SAEC with fisetin reduces proinflammatory factors and seems to induce cell proliferation within the first 24h of culture whereas the cell viability decreased after 72h. Thus, fisetin may act as a senolytic and further exploration is needed to confirm it can be used as a new approach for COPD therapies.