Abstract
Background and PurposeHyperglycaemia 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 ApproachThe 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 ResultsFasting 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 ImplicationsPharmacological 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.
Highlights
People with diabetes mellitus are at increased risk of, and have worse outcomes from, lower respiratory tract infections compared to those without diabetes mellitus
Fasting blood glucose concentrations were higher in db/db than C57BL/6J wild type (WT) mice (20.36 ± 2.6, n = 10 compared to 7.20 ± 0.0.18 mM, P < 0.05, n = 10, Figure 1A) as were Bronchoalveolar lavage fluid (BALF)
Fasting lactate concentration was significantly higher in the BALF from db/db mice than from WT (0.18 ± 0.02 compared to 0.05 ± 0.01 mM, P < 0.05, n = 10 respectively, Figure 1C)
Summary
People with diabetes mellitus are at increased risk of, and have worse outcomes from, lower respiratory tract infections compared to those without diabetes mellitus. In people with chronic obstructive pulmonary disease (COPD), diabetes is associated with an increased likelihood and frequency of exacerbations (Kinney et al, 2014), and increased duration of hospital stay and mortality from exacerbations (Gudmundsson et al, 2006; Parappil et al, 2010) In those with cystic fibrosis (CF), diabetes is an independent risk factor for pulmonary exacerbations (Jarad and Giles, 2008; Sawicki et al, 2013) and for failure of intravenous or oral antibiotic treatment (Briggs et al, 2012; Parkins et al, 2012). Increased ASL glucose concentrations predispose to respiratory infection, both by promoting the growth of pathogenic organisms that use glucose as a carbon source, P. aeruginosa and S. aureus, and by suppressing host immunity. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique
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