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. 2020 Dec 18;21(24):9658.
doi: 10.3390/ijms21249658.

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

Isabella Cattani-Cavalieri  1   2   3 , Helber da Maia Valença  1 , João Alfredo Moraes  1 , Lycia Brito-Gitirana  1 , Bruna Romana-Souza  4 , Martina Schmidt  3 , Samuel Santos Valença  4
Affiliations

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

Isabella Cattani-Cavalieri et al. Int J Mol Sci. .

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.

Keywords: air pollution; diesel exhaust particles; dimethyl fumarate; inflammation; lung; mice; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Experimental model and total inflammatory cell number in bronchoalveolar lavage (BAL). (A) Schematic representation of the experimental model used in our studies. Mice were either exposed to vehicle (saline/DMSO) or diesel exhaust particles (DEPs) for 60 consecutive days, with or without dimethyl fumarate (DMF) treatment for the last 30 days. (B) Total cell number in the bronchoalveolar lavage (BAL) of control and DEP-exposed mice, with or without DMF treatment. Data (n = 8) are expressed as the mean ± SEM. * p < 0.05 vs. control group, # p < 0.05 vs. DEP group.
Figure 2
Figure 2
Histological analysis of the inflammatory response (macrophages) and lung injury in control and DEP-exposed mice treated with or without DMF. Representative images of macrophage distribution in mouse lungs in the control (A), DEP (B), and DEP + DMF groups (C). Data on the number of macrophages per mm2 were summarized for all 3 groups (D). Representative images of murine lungs in the control (E), DEP (F), and DEP + DMF (G) groups. Based on these images, the severity of lung injury was assessed using a 5-point scoring system (H). Sections were stained with hematoxylin–eosin and the bar is equal to 50 μm. Red arrows indicate macrophages in the lung sections. Data (n = 8) are expressed as the mean ± SEM. * p < 0.05 vs. control group, # p < 0.05 vs. DEP group.
Figure 3
Figure 3
Densitometric comparison of nuclear factor erythroid 2-related factor 2 (Nrf2, (A)), kelch-like ECH-associated protein 1 (Keap-1, (B)), total nuclear factor kappa B p65 (NF-κB, (C)), phospho-nuclear factor kappa B p65 (p-NF-κB p65, (D)) protein expression in mouse lungs after exposure to DEP for 60 consecutive days, with or without DMF treatment for the last 30 days. Representative immunoblots are shown in panel (E). The densitometry is expressed as arbitrary units (a.u.) and β-actin was used as a loading control for all immunoblots. Except for Keap-1 (n = 6), data (n = 3) are expressed as the mean ± SEM. * p < 0.05 vs. control group, # p < 0.05 vs. DEP group.
Figure 4
Figure 4
Densitometric comparison of Western blots for nitrotyrosine (A), glutathione peroxidase-1/2 (Gpx-1/2, (B)), catalase (C), and superoxide dismutase-1 (SOD-1, (D)) in mouse lungs after 60 consecutive days of exposure to DEP, with or without DMF treatment for the last 30 days. Representative immunoblots are shown in panel (E). The densitometry is expressed as arbitrary units (a.u.) and β-actin was used as a loading control for all immunoblots. Except for nitrotyrosine (n = 6), data (n = 3) are expressed as the mean ± SEM. * p < 0.05 vs. control group, # p < 0.05 vs. DEP group.
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