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

Isabella Cattani-Cavalieri,João Alfredo Moraes,Helber Da Maia Valença,Samuel Santos Valença,Lycia Brito-Gitirana,Martina Schmidt,Bruna Romana-Souza

doi:10.3390/ijms21249658

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.

Highlights

Air pollution is a global problem that can cause several health issues, mainly affecting the respiratory system [1,2,3,4]
We aimed to explore the therapeutic potential of Dimethyl fumarate (DMF) against pulmonary damage caused by chronic diesel exhaust particles (DEPs) exposure in mice
superoxide dismutase 1 (SOD-1) protein expression was reduced in the DEP + DMF group when compared to the control and DEP groups, whereas DEP exposure alone had no effect on SOD-1 levels (Figure 4D,E)

Summary

Introduction

Air pollution is a global problem that can cause several health issues, mainly affecting the respiratory system [1,2,3,4]. Chronic exposure of rats to DEP with 3 mg/m3 from diesel engine exhaust elevated the pro-inflammatory cytokines interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)-α in BAL, serum and lung homogenates, and elevated total number of inflammatory cells, neutrophils, eosinophils and lymphocytes [16]. Exposure of mice to DEP (SRM 2975; NIST) by intratracheal installation increased the protein level of the nuclear factor kappa B (NF-κB) p65 measured 24 h after exposure to DEP [19]. Exposure of mice to DEP from the vent of a workshop in a diesel engine manufacturing factory by intratracheal instillation increased the expression of both Nrf gene and Nrf protein in the lung measured up to 48 h after exposure to DEP [24]. Our group demonstrated that mice exposed to biodiesel particulate matter elevated Nrf protein expression in the lung after 5-day exposure to the pollutant [25]

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