Hyperglycemia (high glucose/sugar levels) and infection with Pseudomonas aeruginosa bacteria can acidify the airway surface liquid in patients with cystic fibrosis (CF), especially in those with diabetes as well, contributing to disease pathogenesis, researchers report.
Their study, “Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+ secretion,” was published in the journal Nature.
CF patients are known to have defective microbiocidal activity (ability to destroy microbes) in the airway surface liquid, due to abnormally acidic pH and poor transport of bicarbonate ions (HCO3-). The mucus of CF patients is also rich in several elements, including glucose, that make it a nutrient-rich environment for bacterial growth.
Both factors, an acidic and nutrient-rich environment, promote the growth of P. aeruginosa, an opportunistic pathogen notoriously associated with CF. The bacteria utilizes lactate (a product that can be converted to glucose) as a food source, and the acidic pH protects the bacteria from being destroyed by defense mechanisms.
It is estimated that about half of adults with CF also have CF-related diabetes (CFRD), a condition linked to respiratory decline and an increased risk of P. aeruginosa infection. CFRD patients are known to have more pulmonary exacerbations and be poorer responders to intravenous antibiotics than CF patients without diabetes.
Researchers assessed lactate production and its concentration in human airway epithelial cells (HBE) from CF and non-CF patients, and also in specific cell lines. They also investigated the impact of P. aeruginosa infection on lactate production and pH on airway surface liquid.
They found that airway fluid from CF patients’ HBEs, which is hyperglycemic, had higher concentrations of lactate compared to normal cells. In CF, HBEs secrete lactate into the airway fluid, leading to an acidification of the environment (lower pH).
The transport of lactate in mammalian cells is, in part, performed through monocarboxylate transporters (MCT), which co-transport lactate with hydrogen ions (H+). It is these H+ ions that make the fluid acidic.
The team found that the changes in lactate concentration and in pH induced in the airways’ fluid by hyperglycemia were exacerbated in the presence of P. aeruginosa bacteria, as the pathogen induces cells to secrete even larger amounts of lactate. An aggravating factor is the deficiency of bicarbonate ions (HCO3–) in the secretions of CF patients. The researchers point out that in normal cell airways, these bicarbonate ions compensate for the generation of hydrogen ions.
Inhibiting MCTs, so as to block the transport of hydrogen ions, can attenuate changes in lactate concentration and pH.
“We conclude that hyperglycaemia and P. aeruginosa induce a metabolic shift which increases lactate generation and efflux into ASL [airway surface liquid] 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 … processes [that] may contribute to worsening respiratory disease in CFRD,” the researchers concluded. “Our data provide the first evidence that lactate is present in the ASL of human bronchial epithelial cells.”
They believe their findings are important to further unraveling the pathologic processes underlying CF.