title: Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.
abstract: 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.
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Åstrand
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wingren
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Audra
authors.initials: A
authors.lastname: Benjamin
authors.affiliation: Mucosal Infection & Immunity Group, Section of Virology, Imperial College London, St Mary's Campus, London, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Tregoning
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Garnett
authors.affiliation: Mucosal Infection & Immunity Group, Section of Virology, Imperial College London, St Mary's Campus, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Groves
authors.affiliation: Mucosal Infection & Immunity Group, Section of Virology, Imperial College London, St Mary's Campus, London, UK.
authors.forename: Simren
authors.initials: S
authors.lastname: Gill
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Orogo-Wenn
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Anders J
authors.initials: AJ
authors.lastname: Lundqvist
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Dafydd
authors.initials: D
authors.lastname: Walters
authors.affiliation: Cardiovascular & Metabolic Diseases Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines Research Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: John D
authors.initials: JD
authors.lastname: Taylor
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Baker
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Baines
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011552:Pseudomonas Infections / Q000097:blood* / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D051247:Sodium-Glucose Transport Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D051247:Sodium-Glucose Transport Proteins; C529054:dapagliflozin