Aberrant GSH reductase and NOX activities concur with defective CFTR to pro-oxidative imbalance in cystic fibrosis airways

• Published in: Journal of bioenergetics and biomembranes Vol. 50; no. 2; pp. 117 - 129
• Main Authors: de Bari, L., Favia, M., Bobba, A., Lassandro, R., Guerra, L., Atlante, A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2018; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Biochemistry; Bioorganic Chemistry; Cell Line; Chemistry; Chemistry and Materials Science; Cystic fibrosis; Cystic Fibrosis - enzymology; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Glutathione; Glutathione - metabolism; Glutathione reductase; Glutathione Reductase - metabolism; Histology; Humans; Morphology; NAD(P)H oxidase; NADP - metabolism; NADPH Oxidases - metabolism; Organic Chemistry; Oxidative Stress; Pathogenesis; Reactive Oxygen Species - metabolism; Respiratory System - physiopathology; Respiratory tract; Secretion; Cystic fibrosis; Mitochondria; Cysteine; Glutathione reductase; NADPH oxidase
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-018-9748-x

Cystic fibrosis (CF) is associated to impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel also causing decreased glutathione (GSH) secretion, defective airway bacterial clearance and inflammation. Here we checked the main ROS-producing and ROS-scavenging enzymes as potential additional factors involved in CF pathogenesis. We found that CFBE41o-cells, expressing F508del CFTR, have increased NADPH oxidase (NOX) activity and expression level, mainly responsible of the increased ROS production, and decreased glutathione reductase (GR) activity, not dependent on GR protein level decrease. Furthermore, defective CFTR proved to cause both extracellular and intracellular GSH level decrease, probably by reducing the amount of extracellular GSH-derived cysteine required for cytosolic GSH synthesis. Importantly, we provide evidence that defective CFTR and NOX/GR activity imbalance both contribute to NADPH and GSH level decrease and ROS overproduction in CF cells.