Abstract
Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease.
Highlights
American Trypanosomiasis (Chagas’ disease) is a parasitic illness caused by the flagellate protozoan Trypanosoma cruzi [1]
This phenomenon correlates with the presence of 15-epi-LXA4, a molecule known as an ‘‘aspirin-triggered lipoxin,’’ which increases at low doses of aspirin, and decreases when aspirin dose is increased. 15-epi-LXA4 has been related with the anti-inflammatory effect of aspirin; in this setting, we found that 15-epi-LXA4 is able to decrease the cardiac inflammation and others parameters related with Chagas’ disease
Outcome of infected mice treated with acetylsalicylic acid (ASA) does not correlate with administered dose We evaluated the effect of ASA on BALB/c mice infected with trypomastigotes of T. cruzi (Dm28c strain), at doses ranging from 5 to 100 mg/Kg
Summary
American Trypanosomiasis (Chagas’ disease) is a parasitic illness caused by the flagellate protozoan Trypanosoma cruzi [1]. The area covered by this disease starts in the south of the United States and continues to the central area of Chile and Argentina. It has been present in America for 9,000 years [2]. There is an annual productivity loss of US$1.2 billion due to Chagas’ disease in the 7 endemic countries [4]. The migration of people from endemic regions to developed countries has expanded the risk of infection, especially through blood transfusions and organ transplants. There are currently immigrant infected populations in Japan, Australia, Spain, and in the United States, transforming this disease into an emerging global problem [5]. The impact of Chagas’ disease in U.S has been recently compared to the first years of the beginning of the VIH/ AIDS epidemic [6]
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