Abstract
Trypanosoma cruzi infection induces an intense inflammatory response in diverse host tissues. The immune response and the microvascular abnormalities associated with infection are crucial aspects in the generation of heart damage in Chagas disease. Upon parasite uptake, macrophages, which are involved in the clearance of infection, increase inflammatory mediators, leading to parasite killing. The exacerbation of the inflammatory response may lead to tissue damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that exerts important anti-inflammatory effects and is involved in improving endothelial functions and proangiogenic capacities. In this study, we evaluated the intermolecular interaction between PPARγ and a new synthetic PPARγ ligand, HP24, using virtual docking. Also, we showed that early treatment with HP24, decreases the expression of NOS2, a pro-inflammatory mediator, and stimulates proangiogenic mediators (vascular endothelial growth factor A, CD31, and Arginase I) both in macrophages and in the heart of T. cruzi-infected mice. Moreover, HP24 reduces the inflammatory response, cardiac fibrosis and the levels of inflammatory cytokines (TNF-α, interleukin 6) released by macrophages of T. cruzi-infected mice. We consider that PPARγ agonists might be useful as coadjuvants of the antiparasitic treatment of Chagas disease, to delay, reverse, or preclude the onset of heart damage.
Highlights
Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi
Selection of the 3,4-pyridinecarboxylic derivative hydroxy-4-pyridinecarboxylic acid derivative 24 (HP24) was based on its properties as PPARγ ligand and on its ability to reduce the pro-inflammatory response in a Dextran-induced colitis mouse model, as previously reported [22]
We demonstrated that HP24 treatment increased the expression of proangiogenic factors, inhibited pro-inflammatory mediators, and reduced fibrosis in the heart of infected mice
Summary
Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. The acute phase of infection is characterized by the presence of parasites in the host bloodstream and diverse tissues. Acute T. cruzi infection is characterized by parasite invasion of the heart and other organs. Macrophages produce proinflammatory mediators in situ, such as nitric oxide (NO), TNFα, and interleukin 6 (IL-6), that inhibit T. cruzi multiplication and differentiation, precluding the spread of the infection within the host [1]. In this regard, some studies have shown that mice administered iNOS inhibitors exhibit higher parasite levels and greater mortality than untreated mice [2, 3]. Other authors have shown the relevant role of TNF-α in protection of mice during the acute T. cruzi infection [4,5,6]
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