Chronic hyperglycemia aggravates lung function in a -Tg murine model.

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model using Tg mice made diabetic by injection of streptozotocin (STZ). In Ussing chamber recordings of the trachea, Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in adenosine triphosphate (ATP)-activated currents compared with wild-type (WT) littermates. Both diabetic WT (WT-D) and diabetic Tg (-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 wk; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF). Bulk lung RNA-seq data showed significant differences between WT-D and -Tg-D mice. Neutrophil counts in BALF were substantially increased in Tg-D lungs compared with controls (-Tg-con) and compared with WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Tg-D mice compared with WT-D mice, consistent with the development of a spontaneous lung infection. We intranasally administered to induce lung infection in these mice for 24 h, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the -Tg mice. The model can be used for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics. We established a chronic CFRD-like mouse model using the -Tg transgenic mice overexpressing the epithelial sodium channel β subunit made diabetic by injection of streptozotocin. The results underscore the urgent need to develop novel therapeutics for CF lung disease.