Background <p>This study was to investigate the role of exosomes derived from distal airway stem cells (DASC) in apoptosis of pulmonary vascular endothelial cells (PVEC) in chronic obstructive pulmonary disease (COPD) and to explore the potential mechanisms.</p> Methods <p>Cigarette smoke extract (CSE) plus cigarette smoke (CS)-induced COPD mice were treated with DASC and exosomes. The microRNA (miR) sequencing of exosomes was performed to explore the underlying mechanisms. We determined the expression of miR-181d-5p and PDAP1 in patients with COPD.</p> Results <p>Compared with control mice, DASC and exosomes derived from DASC could alleviate emphysema changes, decrease the mean linear intercept and alveolar destructive index, reduce apoptosis of PVEC in COPD mice. Furthermore, miR-181d-5p was significantly decreased in exosomes derived from COPD mice DASC when compared with exosomes derived from normal mice DASC. The knockdown of miR-181d-5p in exosomes derived from DASC could weaken its effects in alleviating emphysema and apoptosis of PVEC, increase the expression of PDAP1, and decrease the expression of miR-181d-5p. The overexpression of miR-181d-5p and knockdown of PDAP1 could significantly reduce apoptosis in CSE-induced PVEC. Furthermore, the overexpression of PDAP1 could reverse the anti-apoptotic effect of miR-181d-5p on CSE-induced PVEC. Finally, the expression of miR-181d-5p was decreased in patients with COPD and positively related to pulmonary function, while the expression of PDAP1 was increased and negatively related to pulmonary function.</p> Conclusions <p>Exosomes derived from DASC could alleviate lung injury in COPD. The mechanism may be to reduce the apoptosis of PVEC by delivering miR-181d-5p by targeting PDAP1.</p> Graphic Abstract <p></p>