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Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

Åstrand, A; Wingren, C; Benjamin, A; Tregoning, JS; Garnett, JP; Groves, H; Gill, S; Orogo-Wenn, M; Lundqvist, AJ; Walters, D; et al. Åstrand, A; Wingren, C; Benjamin, A; Tregoning, JS; Garnett, JP; Groves, H; Gill, S; Orogo-Wenn, M; Lundqvist, AJ; Walters, D; Smith, DM; Taylor, JD; Baker, EH; Baines, DL (2017) Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice. Br J Pharmacol, 174 (9). pp. 836-847. ISSN 1476-5381 https://doi.org/10.1111/bph.13741
SGUL Authors: Baines, Deborah Baker, Emma Harriet

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Abstract

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.

Item Type: Article
Additional Information: © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Pharmacology & Pharmacy, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Br J Pharmacol
ISSN: 1476-5381
Language: eng
Dates:
DateEvent
May 2017Published
13 February 2017Published Online
7 February 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/K012770/1Medical Research CouncilUNSPECIFIED
PubMed ID: 28192604
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108565
Publisher's version: https://doi.org/10.1111/bph.13741

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