Furin inhibition protects against acute lung injury in a mouse model of Pseudomonas aeruginosa infection.

Abstract

Pseudomonas aeruginosa (PA) is responsible for significant morbidity and mortality, particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, as well as hospital-acquired pneumonia and ventilator-associated pneumonia. The rise of antibiotic-resistant PA strains necessitates alternative treatment strategies. Among the different toxins secreted by PA, Exotoxin-A (Exo-A) becomes cytotoxic when cleaved by furin. This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection. Furin inhibition significantly improved survival rates and reduced lung injury in mouse pneumonia models using Exo-A and PA103. Additionally, BOS-318 accelerated bacterial clearance in vivo, and increased phagocytosis by alveolar macrophages. Bulk RNA-sequencing done on whole lung homogenate at 6 hours revealed an immune profile with decreased natural killer cell signaling in the BOS-318-treated group, possibly because of a decrease in natural killer recruitment observed at 24 hours, suggesting a role of furin in shaping the immune response. Moreover, administration of BOS-318 as a therapeutic strategy results in a protection of the lung epithelium. Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections.