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Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice
Author(s) -
Åstrand Annika,
Wingren Cecilia,
Benjamin Audra,
Tregoning John S,
Garnett James P,
Groves Helen,
Gill Simren,
OrogoWenn Maria,
Lundqvist Anders J,
Walters Dafydd,
Smith David M,
Taylor John D,
Baker Emma H,
Baines Deborah L
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13741
Subject(s) - bronchoalveolar lavage , dapagliflozin , pseudomonas aeruginosa , lung , medicine , endocrinology , nasal administration , pharmacology , diabetes mellitus , biology , type 2 diabetes , bacteria , genetics
Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusion and Implications 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.