Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells

Onofrio Laselva,Caterina Allegretta,Carlo Avolio,Sante Di Gioia,Massimo Conese

doi:10.3390/cells10082132

Onofrio Laselva, Caterina Allegretta + Show 3 more

Open Access

https://doi.org/10.3390/cells10082132

Copy DOI

Journal: Cells	Publication Date: Aug 19, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: University of Foggia

Abstract

Cystic Fibrosis (CF) is caused by mutations on the CF transmembrane conductance regulator (CFTR) gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early oxidative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stimulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/H2O2 and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Finally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy.

Highlights

Cystic fibrosis (CF) is the most common fatal autosomal recessive disorder amongCaucasians, estimated to affect more than 70,000 people in the world
A 24 h incubation with various concentrations slightly reduced HBE viability, albeit not significantly, whereas CFBE viability did not vary as compared with untreated controls (Figure S1)
Both basal and induced mRNA expression of the pro-inflammatory cytokines IL-1β and TNF-α were assessed by RT-PCR

Summary

Introduction

Cystic fibrosis (CF) is the most common fatal autosomal recessive disorder amongCaucasians, estimated to affect more than 70,000 people in the world. Cystic fibrosis (CF) is the most common fatal autosomal recessive disorder among. Over 2000 sequence variations have been discovered in the CF Transmembrane Conductance Regulator (CFTR). Gene, ~300 of which are pathogenic [1], causing either lack or dysfunction of the mutated protein. The most common mutation is F508del, which accounts for approximately two thirds of all CFTR alleles in patients with CF. Lung disease represents the chief cause of morbidity and mortality of these patients, leading to chronic respiratory failure and lung transplantation. Its pathophysiology is characterized by severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction and bronchiectasis. CF airways lack proper hydration of the mucus overlaying thexd epithelium, with consequent loss of the mucociliary clearance and opportunistic bacterial infections. The innate immunity of CF lungs prompts the secretion of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and chemokines (IL-8)

Objectives

Results

Conclusion