Bronchial epithelial cell-derived extracellular vesicles in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by progressive and persistent inflammatory disease of the airway and/or alveoli, affecting approximately 300 million people globally. Extracellular vesicles (EVs) are lipid-membrane bound vesicles that are released from all cell types, which can be both beneficial and detrimental depending on the content they carry. As airway epithelial cells are the first line of defence against harmful particles, this work explored the role of COPD bronchial epithelial cell-derived EVs in the pathogenesis and progression of COPD.

Bronchial epithelial EVs were co-incubated with healthy epithelial cells; known senescence markers were assessed, which showed no significant change, suggesting EVs are not involved in the propagation of senescence locally (epithelial-epithelial). Common NLRP3 inflammasome markers were also assessed, which also showed no significant change. In a subsequent study, the effect of COPD EVs in healthy macrophages was assessed. RNA sequencing of macrophages stimulated with COPD EVs revealed the upregulation of various inflammasome-related genes, including NLRP3 and IL-1β. EV stimulation also promoted significant IL-1β and IL-18 release, which could be attenuated with caspase- 1 inhibitor (VX-765) or NLRP3 inhibitor (MCC950) treatment. This study shows for the first time that COPD epithelial cell-derived EVs are able to both prime and activate the inflammasome in healthy macrophages.

Alongside this data, the proteome of COPD EVs was also assessed. This analysis highlighted a loss of antibacterial proteins in COPD EVs, which was then functionally assessed in macrophage NTHi infection. Incubation with healthy EVs promoted NTHi clearance and reduced pro-inflammatory cytokine release, while this mechanism was absent in cells co-incubated with COPD EVs. This highlights that COPD epithelial EVs lack multiple antibacterial proteins that are essential in mounting an immune response against NTHi in macrophages. LL-37 and LTF were highlighted as key proteins in this analysis. Moreover, the role of EVs in viral COPD infections were also assessed. Treatment with valaciclovir for EBV infection provided some significant changes in the protein content of airway EVs from BAL. Two proteins that were highlighted as particularly interesting targets were LGALS9 and SLURP1. Overall, COPD EV co-incubation with healthy macrophages resulted in a persistent state of inflammation and bacterial burden. Both sets of findings contribute to the overall knowledge of COPD pathogenesis and highlight epithelial EVs as key players in the propagation of inflammation and infection.

Date of Award	Dec 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Cliff Taggart (Supervisor), Anna Krasnodembskaya (Supervisor) & Hong Guo Parke (Assistant Supervisor)