Impairment of CFTR activity in cultured epithelial cells upregulates the expression and activity of LDH resulting in lactic acid hypersecretion

• Published in: Cellular and molecular life sciences : CMLS 2019-04, Vol.76 (8), p.1579-1593
• Main Authors: Valdivieso, Ángel G., Clauzure, Mariángeles, Massip-Copiz, María M., Cancio, Carla E., Asensio, Cristian J. A., Mori, Consuelo, Santa-Coloma, Tomás A.
• Format: Article
• Language: English
• Subjects: Acid production; Animals; Anthracenes - pharmacology; Bacterial diseases; Bacterial infections; Biochemistry; Biomedical and Life Sciences; Biomedicine; Caco-2 Cells; Cell Biology; Children; Chloride ions; Colonization; Cystic fibrosis; Cystic Fibrosis - microbiology; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Electron transport chain; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Hydrogen-Ion Concentration; IL-1β; Intestine; Intestines - cytology; Ion channels; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - antagonists & inhibitors; L-Lactate Dehydrogenase - genetics; Lactate dehydrogenase; Lactic acid; Lactic Acid - metabolism; Life Sciences; Lung - cytology; Lungs; Mitochondria; Mutation; NADH-ubiquinone oxidoreductase; Organic Chemicals - pharmacology; Original; Original Article; Oxamic Acid; pH effects; Pyrimidines - pharmacology; Respiratory tract; Src protein
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-018-3001-y

Mutations in the gene encoding the CFTR chloride channel produce cystic fibrosis (CF). CF patients are more susceptible to bacterial infections in lungs. The most accepted hypothesis sustains that a reduction in the airway surface liquid (ASL) volume favor infections. Alternatively, it was postulated that a reduced HCO 3 − transport through CFTR leads to a decreased ASL pH, favoring bacterial colonization. The issue is controversial, since recent data from cultured primary cells and CF children showed normal pH values in the ASL. We have reported previously a decreased mitochondrial Complex I (mCx-I) activity in cultured cells with impaired CFTR activity. Thus, we hypothesized that the reduced mCx-I activity could lead to increased lactic acid production (Warburg-like effect) and reduced extracellular pH (pHe). In agreement with this idea, we report here that cells with impaired CFTR function (intestinal Caco-2/pRS26, transfected with an shRNA-CFTR, and lung IB3-1 CF cells) have a decreased pHe. These cells showed increased lactate dehydrogenase (LDH) activity, LDH-A expression, and lactate secretion. Similar effects were reproduced in control cells stimulated with recombinant IL-1β. The c-Src and JNK inhibitors PP2 and SP600125 were able to increase the pHe, although the differences between control and CFTR-impaired cells were not fully compensated. Noteworthy, the LDH inhibitor oxamate completely restored the pHe of the intestinal Caco-2/pRS26 cells and have a significant effect in lung IB3-1 cells; therefore, an increased lactic acid secretion seems to be the key factor that determine a reduced pHe in these epithelial cells.