title: Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+secretion.
abstract: The cystic fibrosis (CF) airway surface liquid (ASL) provides a nutrient rich environment for bacterial growth including elevated glucose, which together with defective bacterial killing due to aberrant HCO3-transport and acidic ASL, make the CF airways susceptible to colonisation by respiratory pathogens such as Pseudomonas aeruginosa. Approximately half of adults with CF have CF related diabetes (CFRD) and this is associated with increased respiratory decline. CF ASL contains elevated lactate concentrations and hyperglycaemia can also increase ASL lactate. We show that primary human bronchial epithelial (HBE) cells secrete lactate into ASL, which is elevated in hyperglycaemia. This leads to ASL acidification in CFHBE, which could only be mimicked in non-CF HBE following HCO3-removal. Hyperglycaemia-induced changes in ASL lactate and pH were exacerbated by the presence of P. aeruginosa and were attenuated by inhibition of monocarboxylate lactate-H+co-transporters (MCTs) with AR-C155858. We conclude that hyperglycaemia and P. aeruginosa induce a metabolic shift which increases lactate generation and efflux into ASL via epithelial MCT2 transporters. Normal airways compensate for MCT-driven H+secretion by secreting HCO3-, a process which is dysfunctional in CF airway epithelium leading to ASL acidification and that these processes may contribute to worsening respiratory disease in CFRD.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.|Immunology &Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH &Co. KG, Biberach an der Riss, Germany.
authors.forename: James Peter
authors.initials: JP
authors.lastname: Garnett
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, Tooting, London, UK.
authors.forename: Kameljit K
authors.initials: KK
authors.lastname: Kalsi
authors.affiliation: Immunology &Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH &Co. KG, Biberach an der Riss, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Sobotta
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, Tooting, London, UK.
authors.forename: Jade
authors.initials: J
authors.lastname: Bearham
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Carr
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Powell
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Brodlie
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ward
authors.affiliation: Cystic Fibrosis Centre/Marisco Lung Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tarran
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, Tooting, London, UK.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Baines
mesh_terms: D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000503:physiopathology*; D007773:Lactates / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*
chemical_list: D007773:Lactates; D027501:Monocarboxylic Acid Transporters; C490427:SLC16A7 protein, human