Dimethyl Fumarate Attenuates Lung Inflammation and Oxidative Stress Induced by Chronic Exposure to Diesel Exhaust Particles in Mice

Abstract

Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 μg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants.

Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

“…Clinical evidences demonstrated the superiority of DMF in treating multiple sclerosis patients and preclinical studies have shown that DMF could treat several human diseases including lung disease. Cattani-Cavalieri et al found that DMF could attenuate lung injury induced by chronic exposure to diesel exhaust particles in mice [23]. Grzegorzewska et al reported that DMF ameliorates pulmonary arterial hypertension and bleomycin-induced lung brosis [11].…”

Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases

“…Oxidation and nitration of manganese-superoxide dismutase (MnSOD) are present in the asthmatic airways, and these modifications correlate with clinical features of asthma severity. Tyrosine nitration and chlorination from eosinophil and neutrophil activation cause inhibition of MnSOD activity and catalase, impairing antioxidant defenses in asthma [ 72 , 80 , 81 , 82 , 83 , 84 ]. Redox imbalance and redox-dependent mechanisms engage inflammatory mediator release, epithelial damage, reduced lung function and airway hyperresponsiveness in asthma pathogenesis [ 85 , 86 ].…”

Air Pollution and the Airways: Lessons from a Century of Human Urbanization

“…Secondly, DEP is also known for its induction of oxidative stress and DNA damage in the airways via ROS [147][148][149][150][151][152]. H 2 O 2 , a marker for oxidative stress, is increased in BAL fluid of mice exposed to DEP together with serum ceramide levels clearly indicating that oxidative stress is induced after DEP exposure [147,149].…”