PDE4B selective inhibitor unveils novel therapeutic avenue by targeting inflammation and cellular senescence in chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD), a respiratory disorder characterized by airway remodeling within a chronic inflammatory microenvironment, affects millions worldwide. Cigarette smoke, the primary etiological factor, triggers chronic pulmonary inflammation and respiratory epithelial cell senescence, rendering anti-inflammatory strategies pivotal for alleviating COPD progression and pulmonary aging. This study demonstrates that A33, a highly selective phosphodiesterase 4B inhibitor, potently attenuates chronic inflammation by suppressing nuclear factor kappa-B (NF-κB) activation in damaged epithelial cells and reducing the secretion of pro-inflammatory cytokines. Additionally, A33 exhibits senolytic potential by regulating the senescence-associated secretory phenotype (SASP) in senescent cells. A33 encapsulated liposomes decorated with mPEG (incorporating 5% DSPE-mPEG in the formulations) exhibited satisfactory stability and enhanced respiratory mucus penetration ability, successfully improving the effective pulmonary epithelial delivery of A33. Both in vitro and in vivo experiments show that mPEG-decorated A33-encapsulated liposomes enhance pulmonary mucus penetration and enable efficient intracellular delivery. In a cigarette smoke extract-induced mouse model, A33 treatment significantly inhibited COPD progression and improved pulmonary senescence, validating its therapeutic efficacy. Collectively, these findings introduce a promising local treatment strategy for COPD.