Patients with cystic fibrosis (CF) suffer from chronic infections and lung inflammation leading to bronchiectasis and, ultimately, respiratory failure. Although recent advances, including the approval of highly effective CFTR modulator therapy (HEMT), have improved the overall quality of life of people with CF (PwCF), chronic infection and inflammation are the primary cause of morbidity. Although the magnitude of the inflammatory response is known to be increased in the CF lung, the mechanisms underlying persistent inflammation are unknown. We have shown that lung macrophages are critical to the local inflammatory response in CF. Lung macrophages include functionally distinct subpopulations including CD169+ and CD169- lung macrophages. Our preliminary data demonstrate that CF CD169- lung macrophages have decreased expression of Nrf2, a transcription factor known to regulate cellular metabolism, compared to non-CF bronchiectasis and control subjects, and this did not improve with HEMT. We also found that CF CD169- lung macrophages are persistently glycolytic and inflammatory, even in the setting of HEMT, while non-CF bronchiectasis and healthy CD169- lung macrophages can transition to an inflammation resolving phenotype. As immune cell crosstalk can be mediated by extracellular vesicles (EVs), we investigated the impact of CD169+ lung macrophage EVs on the inflammatory response of CD169- lung macrophages and found that CF CD169+ lung macrophage EVs induce persistent inflammation in CD169- lung macrophages. Lastly, we have preliminary data showing altered expression of miRNAs predicted to inhibit Nrf2 and reduced levels of inflammation resolving lipids in EVs from CF CD169+ lung macrophages. Thus, we hypothesize that specific miRNAs and lipids within CF CD169+ LM EVs reduce Nrf2 levels in CD169- LMs, causing persistent glycolysis and failure to transition to an inflammation resolving phenotype. In Aim 1, we will test the hypothesis that there are functionally importan