Åstrand Annika, Wingren Cecilia, Benjamin Audra, Tregoning John S, Garnett James P, Groves Helen, Gill Simren, Orogo-Wenn Maria, Lundqvist Anders J, Walters Dafydd, Smith David M, Taylor John D, Baker Emma H, Baines Deborah L
Respiratory, Inflammation and Autoimmunity Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
Institute for Infection and Immunity, St George's, University of London, London, UK.
Br J Pharmacol. 2017 May;174(9):836-847. doi: 10.1111/bph.13741. Epub 2017 Mar 9.
Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice.
The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique.
Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung.
Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection.
高血糖会增加气道表面液体中的葡萄糖浓度，并增加肺部铜绿假单胞菌感染的风险。我们研究了抗糖尿病药物达格列净降低血糖和气道葡萄糖浓度是否能减少糖尿病小鼠肺部铜绿假单胞菌的生长/存活。
在C57BL/6J（野生型，WT）或瘦素受体缺陷（db/db）小鼠中，于鼻内给予脂多糖（LPS）或接种铜绿假单胞菌之前口服达格列净，研究达格列净对血糖和气道葡萄糖浓度、炎症反应及感染的影响。使用灌注充液肺技术在Wistar大鼠中研究肺部葡萄糖转运和液体吸收。
db/db小鼠肺中的空腹血糖、气道葡萄糖和乳酸浓度升高。LPS刺激增加了WT和db/db小鼠支气管肺泡灌洗液中的炎症细胞，无论是否接受达格列净治疗。db/db小鼠肺部的铜绿假单胞菌菌落形成单位（CFU）增加。达格列净预处理可使db/db小鼠的血糖和支气管肺泡灌洗葡萄糖浓度以及铜绿假单胞菌CFU降至WT小鼠的水平。达格列净对小鼠的炎症反应或大鼠肺中的肺部葡萄糖转运及液体吸收没有不良影响。
达格列净通过药理作用降低血糖可有效减少糖尿病小鼠肺部的铜绿假单胞菌感染，且对大鼠肺部无不良影响。达格列净在预防或治疗肺部感染方面有减少抗菌药物使用或增强其效果的潜力。
