Abstract
Asthma is a chronic inflammatory lung syndrome with an increasing prevalence and a rare but significant risk of death. Its pathophysiology is complex, and therefore we investigated at the systemic level a potential implication of oxidative stress and of peripheral blood mononuclear cells’ (PBMC) mitochondrial function. Twenty severe asthmatic patients with severe exacerbation (GINA 4–5) and 20 healthy volunteers participated at the study. Mitochondrial respiratory chain complexes activities using different substrates and reactive oxygen species (ROS) production were determined in both groups by high-resolution respirometry and electronic paramagnetic resonance, respectively. Healthy PBMC were also incubated with a pool of plasma of severe asthmatics or healthy controls. Mitochondrial respiratory chain complexes activity (+52.45%, p = 0.015 for VADP) and ROS production (+34.3%, p = 0.02) were increased in asthmatic patients. Increased ROS did not originate mainly from mitochondria. Plasma of severe asthmatics significantly increased healthy PBMC mitochondrial dioxygen consumption (+56.8%, p = 0.031). In conclusion, such asthma endotype, characterized by increased PMBCs mitochondrial oxidative capacity and ROS production likely related to a plasma constituent, may reflect activation of the immune system. Further studies are needed to determine whether increased PBMC mitochondrial respiration might have protective effects, opening thus new therapeutic approaches.
Highlights
Asthma is a common disease that affects 300 million people worldwide (1 in 10 children and 1 in 12 adults) resulting in a substantial morbidity and an important annual healthcare expenditure.The disease is characterized by chronic inflammation of the conducting airway resulting in bronchial obstruction, mucus overproduction, airway remodeling and bronchial hyper-responsiveness [1,2].Different mechanistic pathways are involved in such complex pathology
There was no difference in age, sex and smoking between severe asthmatic patients and the control group
The main result of this study is to demonstrate that mitochondrial respiratory chain complexes’ activities of peripheral blood mononuclear cells (PBMC) are stimulated in severe asthmatic patients with severe exacerbation, and that such enhancement is associated with increased reactive oxygen species
Summary
Asthma is a common disease that affects 300 million people worldwide (1 in 10 children and 1 in 12 adults) resulting in a substantial morbidity and an important annual healthcare expenditure.The disease is characterized by chronic inflammation of the conducting airway resulting in bronchial obstruction, mucus overproduction, airway remodeling and bronchial hyper-responsiveness [1,2].Different mechanistic pathways are involved in such complex pathology. Generation of oxidative stress with increased reactive oxygen species (ROS) production and mitochondrial dysfunction have been observed (bronchus, airway epithelium) in murine models of ovalbumin-induced asthma and in bronchial epithelial cell cultures [3,4,5,6,7,8]. Increased ROS production results in oxidative lipid peroxidation, protein and DNA damages (single-stranded and double-stranded breaks) [9], thought to aggravate the airway inflammation and to play a role in bronchial smooth muscle impairment and mucus secretion. Damaged antioxidant defense mechanisms, altered homeostasis of the airway surface liquid and acute or chronic bacterial airway infections seem to aggravate oxidative stress in asthma [10]. A self-entertaining phenomenon of inflammation and oxidative stress production occurs and damage-associated molecular patterns (so called alarmins), activate immune cells and their specific tissue [16]
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