Artículo
Impairment of CFTR activity in cultured epithelial cells upregulates the expression and activity of LDH resulting in lactic acid hypersecretion
Valdivieso, Ángel Gabriel
; Clauzure, Mariangeles
; Massip Copiz, María Macarena
; Cancio, Carla Estefania; Asensio, Cristian Jorge Alejandro
; Mori, Consuelo
; Santa Coloma, Tomás Antonio
Fecha de publicación:
03/04/2019
Editorial:
Birkhauser Verlag Ag
Revista:
Cellular and Molecular Life Sciences
ISSN:
1420-682X
e-ISSN:
1420-9071
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Mutations in the gene encoding the CFTR chloride channel produce cystic fbrosis (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 HCO3 − 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 efect) 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 efects 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 diferences 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 signifcant efect 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.
Palabras clave:
CFTR
,
CYSTIC FIBROSIS
,
EXTRACELLULAR PH
,
IL-1Β
,
INFLAMMATION
,
LACTATE
,
OXAMATE
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(BIOMED)
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos de INSTITUTO DE INVESTIGACIONES BIOMEDICAS
Articulos(CCT - PATAGONIA CONFLUENCIA)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - PATAGONIA CONFLUENCIA
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - PATAGONIA CONFLUENCIA
Citación
Valdivieso, Ángel Gabriel; Clauzure, Mariangeles; Massip Copiz, María Macarena; Cancio, Carla Estefania; Asensio, Cristian Jorge Alejandro; et al.; Impairment of CFTR activity in cultured epithelial cells upregulates the expression and activity of LDH resulting in lactic acid hypersecretion; Birkhauser Verlag Ag; Cellular and Molecular Life Sciences; 76; 8; 3-4-2019; 1579-1593
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