OBJECTIVE AND DESIGN: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.MATERIALS AND METHODS: CFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-êB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.RESULTS: Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-êB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-á (TNF-á) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.CONCLUSIONS: Lack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury.
Animals Bronchoalveolar Lavage Fluid