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Abstract
Cystic Fibrosis (CF) lung disease is responsible for most of the morbidity and mortality in these patients. CF airway disease is characterized by decreased mucociliary clearance, chronic, polymicrobial infections and robust, neutrophil-dominated inflammation. Progression of lung disease is attributed to chronic inflammation by neutrophils and persistence of bacterial infections. Staphylococcus aureus (S. aureus) is the most prevalent infectious agents in the respiratory tract of CF patients and neutrophils represent the most important immune cell type to fight this pathogen. Furthermore, the CF lung is abundant with inflammatory markers released from increased activation of neutrophils, including neutrophil elastase (NE) that can further damage the lung tissue in these patients. NE contributes to worsened lung damage and inhibition of NE is an important target to combat further lung damage in these patients. We hypothesized that the CF airway environment impairs S. aureus killing by neutrophils and the NE inhibitor, ecotin inhibits NE to prevent CF lung pathology without compromising neutrophil-mediated bacterial clearance. Our results show that PMNs exposed to the CF lung environment are impaired in S. aureus killing and this impairment is caused by the deficiency of phagolysosome fusion of neutrophils. Our results also show that ecotin is an effective NE inhibitor in CF airway samples. Altogether, we have discovered a novel pathway in which CF neutrophils in the airways are defective in killing S. aureus. We have also uncovered a new potential therapeutic to improve lung damage by NE, as ecotin shows promising effects of NE inhibition.