Protective Role of Acetylsalicylic Acid in Experimental Trypanosoma cruzi Infection: Evidence of a 15-epi-Lipoxin A ₄-Mediated Effect

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. PGE ₂ 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 LTB ₄ production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA ₄ (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA ₄ in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA ₄ levels. Importantly, 15-epi-LXA ₄ 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.

Author Summary

Chagas' disease is an infection produced by the parasite Trypanosoma cruzi. This pathology is endemic in Latin America and has become a public health issue in some non-endemic countries like the USA, Spain and Australia. There is no curative treatment against Chagas' disease. NSAIDs, like aspirin, have been assayed as drugs with therapeutic potential in Chagas' disease, but the studies about this issue show contradictory results; also, the mechanism involved in aspirin effect is not yet clear. In this study, we explore a broad range of doses the protective role of aspirin. We found that aspirin has a therapeutic effect at low doses, an effect that disappears when doses are increased. This phenomenon correlates with the presence of 15-epi-LXA ₄, a molecule known as an “aspirin-triggered lipoxin,” which increases at low doses of aspirin, and decreases when aspirin dose is increased. 15-epi-LXA ₄ has been related with the anti-inflammatory effect of aspirin; in this setting, we found that 15-epi-LXA ₄ is able to decrease the cardiac inflammation and others parameters related with Chagas' disease. Finally, we present the first study that shows that the protective effect of aspirin on Chagas' disease could be mediated by the synthesis of 15-epi-LXA ₄.