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Thorax. Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose
[Source: Thorax, full page: (LINK). Abstract, edited.]
<CITE><ABBR>Thorax</ABBR> 2013;68:835-845 doi:10.1136/thoraxjnl-2012-203178 </CITE>
<CITE></CITE>
<CITE></CITE>Respiratory infection / Original article
Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose
James P Garnett 1, Emma H Baker 1, Sonam Naik 1, Jodi A Lindsay 2, Gwenan M Knight 2, Simren Gill 3, John S Tregoning 2,3, Deborah L Baines 1
Author Affiliations: <SUP>1</SUP>Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK <SUP>2</SUP>Division of Clinical Sciences, Centre for Infection and Immunity, St George's, University of London, London, UK <SUP>3</SUP>Mucosal Infection and Immunity, Section of Infectious Diseases, Imperial College London, London, UK
Correspondence to Dr Deborah L Baines, Division of Biomedical Sciences, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK; d.baines@sgul.ac.uk
Received 4 January 2013 - Revised 18 April 2013 - Accepted 28 April 2013 - Published Online First 24 May 2013
Abstract
Background
Diabetes is a risk factor for respiratory infection, and hyperglycaemia is associated with increased glucose in airway surface liquid and risk of Staphylococcus aureus infection.
Objectives
To investigate whether elevation of basolateral/blood glucose concentration promotes airway Staphylococcus aureus growth and whether pretreatment with the antidiabetic drug metformin affects this relationship.
Methods
Human airway epithelial cells grown at air?liquid interface (?18 h pre-treatment, 30 μM?1 mM metformin) were inoculated with 5?10<SUP>5</SUP> colony-forming units (CFU)/cm<SUP>2</SUP> S aureus 8325-4 or JE2 or Pseudomonas aeruginosa PA01 on the apical surface and incubated for 7 h. Wild-type C57BL/6 or db/db (leptin receptor-deficient) mice, 6?10 weeks old, were treated with intraperitoneal phosphate-buffered saline or 40 mg/kg metformin for 2 days before intranasal inoculation with 1?10<SUP>7</SUP> CFU S aureus. Mice were culled 24 h after infection and bronchoalveolar lavage fluid collected.
Results
Apical S aureus growth increased with basolateral glucose concentration in an in vitro airway epithelia?bacteria co-culture model. S aureus reduced transepithelial electrical resistance (R<SUB>T</SUB>) and increased paracellular glucose flux. Metformin inhibited the glucose-induced growth of S aureus, increased R<SUB>T</SUB> and decreased glucose flux. Diabetic (db/db) mice infected with S aureus exhibited a higher bacterial load in their airways than control mice after 2 days and metformin treatment reversed this effect. Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.
Conclusions
Hyperglycaemia promotes respiratory S aureus infection, and metformin modifies glucose flux across the airway epithelium to limit hyperglycaemia-induced bacterial growth. Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.
Airway Epithelium - Bacterial Infection - COPD Exacerbations - Respiratory Infection
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
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<CITE><ABBR>Thorax</ABBR> 2013;68:835-845 doi:10.1136/thoraxjnl-2012-203178 </CITE>
<CITE></CITE>
<CITE></CITE>Respiratory infection / Original article
Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose
James P Garnett 1, Emma H Baker 1, Sonam Naik 1, Jodi A Lindsay 2, Gwenan M Knight 2, Simren Gill 3, John S Tregoning 2,3, Deborah L Baines 1
Author Affiliations: <SUP>1</SUP>Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK <SUP>2</SUP>Division of Clinical Sciences, Centre for Infection and Immunity, St George's, University of London, London, UK <SUP>3</SUP>Mucosal Infection and Immunity, Section of Infectious Diseases, Imperial College London, London, UK
Correspondence to Dr Deborah L Baines, Division of Biomedical Sciences, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK; d.baines@sgul.ac.uk
Received 4 January 2013 - Revised 18 April 2013 - Accepted 28 April 2013 - Published Online First 24 May 2013
Abstract
Background
Diabetes is a risk factor for respiratory infection, and hyperglycaemia is associated with increased glucose in airway surface liquid and risk of Staphylococcus aureus infection.
Objectives
To investigate whether elevation of basolateral/blood glucose concentration promotes airway Staphylococcus aureus growth and whether pretreatment with the antidiabetic drug metformin affects this relationship.
Methods
Human airway epithelial cells grown at air?liquid interface (?18 h pre-treatment, 30 μM?1 mM metformin) were inoculated with 5?10<SUP>5</SUP> colony-forming units (CFU)/cm<SUP>2</SUP> S aureus 8325-4 or JE2 or Pseudomonas aeruginosa PA01 on the apical surface and incubated for 7 h. Wild-type C57BL/6 or db/db (leptin receptor-deficient) mice, 6?10 weeks old, were treated with intraperitoneal phosphate-buffered saline or 40 mg/kg metformin for 2 days before intranasal inoculation with 1?10<SUP>7</SUP> CFU S aureus. Mice were culled 24 h after infection and bronchoalveolar lavage fluid collected.
Results
Apical S aureus growth increased with basolateral glucose concentration in an in vitro airway epithelia?bacteria co-culture model. S aureus reduced transepithelial electrical resistance (R<SUB>T</SUB>) and increased paracellular glucose flux. Metformin inhibited the glucose-induced growth of S aureus, increased R<SUB>T</SUB> and decreased glucose flux. Diabetic (db/db) mice infected with S aureus exhibited a higher bacterial load in their airways than control mice after 2 days and metformin treatment reversed this effect. Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.
Conclusions
Hyperglycaemia promotes respiratory S aureus infection, and metformin modifies glucose flux across the airway epithelium to limit hyperglycaemia-induced bacterial growth. Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.
Airway Epithelium - Bacterial Infection - COPD Exacerbations - Respiratory Infection
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
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