Copper-Associated Oxidative Stress Contributes to Cellular Inflammatory Responses in Cystic Fibrosis.

Johanna Cormenier,Nadia Alfaidy,Mohamed Benharouga,Kevin Gemy,Isabelle Michaud-Soret,Pierre Richaud,Amal Kouadri,Laurence Macari,Peggy Charbonnier

doi:10.3390/biomedicines9040329

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF Transmembrane Conductance Regulator (CFTR), an apical chloride channel. An early inflammation (EI) in the lung of CF patients occurring in the absence of any bacterial infection has been reported. This EI has been proposed to be associated with oxidative stress (OX-S), generated by deregulations of the oxidant/antioxidant status. Recently, we demonstrated that copper (Cu), an essential trace element, mediates OX-S in bronchial cells. However, the role of this element in the development of CF-EI, in association with OX-S, has never been investigated. Using healthy (16HBE14o-; HBE), CF (CFBE14o-; CFBE), and corrected-wild type CFTR CF (CFBE-wt) bronchial cells, we characterized the inflammation and OX-S profiles in relation to the copper status and CFTR expression and function. We demonstrated that CFBE cells exhibited a CFTR-independent intrinsic inflammation. These cells also exhibited an alteration in mitochondria, UPR (Unfolded Protein Response), catalase, Cu/Zn- and Mn-SOD activities, and an increase in the intracellular content of iron, zinc, and Cu. The increase in Cu concentration was associated with OX-S and inflammatory responses. These data identify cellular Cu as a key factor in the generation of CF-associated OX-S and opens new areas of investigation to better understand CF-associated EI.

Highlights

Cystic fibrosis (CF) is an autosomal recessive disease characterized by viscous mucus [1] and abnormal ion transport across the apical plasma membrane (PM) of the gastrointestinal and the pulmonary epithelia [1]
Using the wellcharacterized transformed healthy (HBE) and CF (CFBE) bronchial epithelial cells, we determined the role of CFTR in reactive oxygen species (ROS) production
The above results demonstrated that numerous processes that are linked to copper First, we showed that copper treatment increased intracellular copper concentration

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive disease characterized by viscous mucus [1] and abnormal ion transport across the apical plasma membrane (PM) of the gastrointestinal and the pulmonary epithelia [1]. The absence of a functional CFTR at the plasma membrane deregulates ions and water flux, leading to dehydrated secretion, thick mucus, reduced clearance of inhaled particles, including bacteria. This leads to persistent infection and chronic inflammation, two major causes of the severe morbidity and mortality in CF population [1,5]. The CF airway contains large concentrations of several pro-inflammatory mediators, including tumor necrosis-α (TNFα), interleukin (IL)-1β, IL-6, IL-8, and IL-17 [5,6] Secretion of these inflammatory mediators has been reported to be influenced by alterations in CFTR function [7]. The origin of this inflammation has been a matter of debate and appeared to be the consequence of a hyperactivation of the NF-κB transcription factor and an ER retention of the CFTR-F508del [15]

Methods

Results

Conclusion