Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

Abstract

Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease. Methodology/Principal findings C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Conclusions/Significance AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

The roles of COX-2 in protozoan infection

“…The curcumin mechanism of action may include inhibition of the Ca 2 +/NFAT-dependent pathological COX-2/mPGES-1/PGE2 pathway in trypanosome-infected cardiomyocytes, potentially conferring cardioprotection in infected mice ( 62 ). Moreover, inhibition of PGE2 synthesis with aspirin synergistically enhanced the activity of nitrofurantoin and benznidazole in infected RAW 264.7 cells ( 70 , 71 ).…”

“…Multiple drugs are currently available for the treatment of Chagas disease, including aspirin, benznidazole, and nifurtimox ( 4 , 70 ). Among these drugs, aspirin triggers resolvin D1 production during the early chronic phase of T. cruzi infection, which modulates systemic infection levels and inflammatory responses in cardiac tissue and reduces immune cell infiltration, cardiomyocyte hypertrophy, fibrosis and the parasite load in heart tissue ( 70 ). Moreover, curcumin treatment in mice with acute Chagas disease improved mouse survival and prevented the activation of associated inflammatory processes in the heart ( 28 ).…”

Evidence for the presence and diagnostic utility of SPM in human peripheral blood

“…Firstly, because as detailed above, there is extensive documentation from many groups (including some of the co-authors of O’Donnell et al 1, 2, 3, 4, 5, 6, 7, 8 ) which identify and quantitate SPM in an array of biological systems. Indeed, as discussed above, a PubMed search term of “resolvins” gives 1,420 reports (as of today) from groups around the world using commercially available resolvins and other SPMs confirming their potent stereoselective actions in a wide range of models and presence in human tissue samples 3, 9, 10, 11, 12, 13, 14, 15, 16 . Secondly, while it is the case that the different entities mentioned by the authors have recommended the used of s/n ratios as an analytical criterion, the suggestion made by O’Donnell et al ,that this is the only criterion recommended by these entities is not fact.…”

Roles of Resolvins in Chronic Inflammatory Response

“…Patients with Chagas disease always develop chronic myocarditis when the infection is untreated. 17R-RvD1 modulates a local and systemic inflammation in mouse cardiac tissue chronically infected with parasites, reduces cellular infiltration, and reduces cardiac hypertrophy and fibrosis in the early chronic phase of the disease, providing a strategy for improving drug therapy [ 121 ].…”