A chronic mouse lung infection modeling the mucus obstruction, lung function, and inflammation of human cystic fibrosis.

Mouse models of cystic fibrosis (CF) have been used to study chronic lung infections; however, these models have lacked the airway mucus that defines human CF pathophysiology and required the use of mucoid . Alternative models have used either transgenic mice overexpressing a lung epithelial sodium channel to mimic the mucus-rich CF lung environment, synthetic CF sputum medium (SCFM2) to induce bacterial phenotypes consistent with human CF, or agar beads to promote chronic infections by non-mucoid . Here, we combined these alternative models and established a chronic lung infection model using SCFM2 agar beads and Tg mice (SCFM2-Tg) to recapitulate nutrient and mucus characteristics of the human CF lung environment and test the effects of chronic infections on bacterial burden, lung function, and the immune response. Using wild-type SCFM2-C57BL/6 mice as controls, SCFM2-Tg mice failed to clear bacterial infections, and lung function measurements showed that infected SCFM2-Tg mice had decreased inspiratory capacity and compliance, elevated airway resistance, and significantly reduced forced expiratory volumes. Flow cytometry and cytokine arrays showed that, like people with CF, SCFM2-Tg mice developed inflammation characterized by neutrophil and eosinophil infiltration and Th2 lymphocytic cytokine responses. Chronically infected SCFM2-Tg mice developed an exacerbated mix of innate and Th1, Th2, and Th17-mediated inflammation, causing higher lung cellular damage and elevated numbers of unusual Siglec F neutrophils. SCFM2-Tg mice will be useful for investigating bacterial pathogenesis by non-mucoid , including treatments and the roles of Siglec F neutrophils in CF inflammation.