(431) Lung infection in a chronic cystic fibrosis-related diabetes murine model

Background: Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF) patients and leads to increased mortality by accelerating the decline in lung function. Scnn1b -Tg mice are known to exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic airway inflammation.

Methods: Here, we established a chronic CFRD-like mouse model utilizing the Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit made diabetic by injection of streptozotocin (STZ).

Results: We compared the ion channels in trachea from both adult Scnn1b -Tg and wildtype (WT) littermates of matched genetic background with Ussing chamber recordings. We found that Scnn1b -Tg mice trachea expressed significantly larger amiloride-sensitive currents (I_ENaC), and similar forskolin-activated currents (I_FSK) as well as ATP-activated currents (I_ATP) compared to WT mice. Furthermore, Scnn1b -Tg mice exhibited significantly higher neutrophil counts in bronchoalveolar lavage (BAL) fluid than that of WT mice. Upon establishment of diabetes by STZ injection, both WT (WT/STZ) and Scnn1b -Tg (Scnn1b -Tg/STZ) mice exhibited substantially elevated tail blood glucose and a mild decrease in body weight. We monitored both WT/STZ and Scnn1b -Tg/STZ mice for a total of 8 weeks after STZ injection. The neutrophil counts in the BAL fluid were substantially increased in the Scnn1b -Tg/STZ mouse lung compared to control mice (Scnn1b -Tg, without STZ injection). Lung histology data showed magnified mucus plugging in small airways and neutrophil infiltration in Scnn1b -Tg/STZ mice compared to WT/STZ mice. Although bacterial culture mouse lung homogenates did not show spontaneous bacterial infection in the Scnn1b -Tg/STZ mouse lung thus far, the above data suggest that the mice developed a spontaneous lung infection. Ongoing studies will identify the pathogen(s) involved in the spontaneous lung infection in Scnn1b -Tg/STZ mice. We further intranasally administered Pseudomonas aeruginosa PAO1 ( > 1.0 x 10⁶ CFU/mouse) to induce lung infection in these mice for 24 hours. We found by analysis of tail blood that all non-STZ-treated mice (WT and Scnn1b -Tg) exhibited hypoglycemia after infection, while both WT/STZ and Scnn1b -Tg/STZ mice exhibited profound hyperglycemia.

Conclusions: In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b -Tg mice. The model exhibited both spontaneous lung infection as well as changes upon induced lung infection. The model can be utilized for future studies toward understanding the mechanism(s) underlying CFRD and developing novel therapeutics for CFRD lung disease.

Acknowledgements: (Support: CFF MCCART21P0, Marcus Professorship in CF)

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