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.
Highlights
Concentrations and promoted the growth of respiratory pathogens such as P. aeruginosa over and above the effects of other hallmarks of the cystic fibrosis (CF) airway surface liquid (ASL) including acidic pH and mucus hyperviscosity[8,9]
This resulted in a significant rise in ASL glucose concentration in non-CF human bronchial epithelial (HBE) and CFBE consistent with previous results in H441 and Calu[3] cells[9,20] (Fig. 1A)
ASL lactate concentrations were elevated in all cell types (Fig. 1B–D) (2.1 ± 0.7 mM to 5.7 ± 1.5 mM in non-CF HBE monolayers; 3.7 ± 0.3 mM to 8.3 ± 1.0 mM in H441; 2.2 ± 0.7 mM to 7.1 ± 1.2 mM in Calu-3; P < 0.05, n = 7–13)
Summary
Concentrations and promoted the growth of respiratory pathogens such as P. aeruginosa over and above the effects of other hallmarks of the CF ASL including acidic pH and mucus hyperviscosity[8,9]. Cellular lactate production by cancer cells in aerobic conditions (the Warburg effect) is well documented[11]. Glycolysis progression to lactate production under aerobic conditions is a normal feature of mammalian cell metabolism, even in tissues that take up lactate from the circulation, such as the heart[12]. It is conceivable that airway epithelial cells contribute to the elevated ASL lactate concentrations seen in CF and CFRD. We determined whether epithelial lactate production contributed to the acidic ASL observed in CF by secretion via MCTs. In addition, due to the prevalence of P. aeruginosa infections in CFRD, we investigated the influence of the bacterium on epithelial lactate production and ASL pH
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