2015 Uppergate Dr., Suite 350, Atlanta, GA 30322.
Am J Physiol Lung Cell Mol Physiol. 2014 Jan 1;306(1):L43-9. doi: 10.1152/ajplung.00224.2013. Epub 2013 Oct 4.
Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1-5 × 10(6) cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD.
囊性纤维化相关糖尿病（CFRD）是与囊性纤维化（CF）相关的最常见合并症，影响超过 30 岁的一半以上患者。CFRD 具有临床意义，预示着肺功能加速下降、更频繁的肺部恶化和死亡率增加。尽管 CFRD 相关的发病率很高，但对其潜在的 CFRD 相关肺部病理学知之甚少。我们的目的是开发一种 CFRD 小鼠模型，以探讨以下假设：CFRD 中的高血糖与肺部细菌清除减少有关。利用链脲佐菌素在纠正肠道 CF 跨膜电导调节剂（CFTR）敲除（CFKO）小鼠及其 CFTR 表达野生型同窝仔鼠（WT）中诱导糖尿病表型。随后，用铜绿假单胞菌（PAO1）（75 μl 1-5×10(6)cfu/ml）经气管内接种对小鼠进行挑战 18 小时。收集支气管肺泡灌洗液以测定葡萄糖浓度和细胞计数。一部分肺组织匀浆并培养，以衡量剩余存活 PAO1 接种物。与非糖尿病小鼠相比，糖尿病小鼠的气道葡萄糖增加。糖尿病 WT 小鼠和对照 CFKO 小鼠清除肺部细菌的能力显著降低。重要的是，与非糖尿病 CFKO 小鼠相比，糖尿病 CFKO 小鼠清除细菌的能力明显降低，尽管气道中中性粒细胞的募集更为明显。这一发现表明，CFRD 小鼠对气管内 PAO1 挑战具有夸大但效果较差的炎症细胞反应，为鉴定促进 CFRD 中细菌清除的治疗策略提供了一种新的有用的小鼠模型。
