Pentoxifylline Reverses Chronic Experimental Chagasic Cardiomyopathy in Association with Repositioning of Abnormal CD8+ T-Cell Response

Abstract

BackgroundChronic chagasic cardiomyopathy (CCC), the main clinical sign of Chagas disease, is associated with systemic CD8+ T-cell abnormalities and CD8-enriched myocarditis occurring in an inflammatory milieu. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has immunoregulatory and cardioprotective properties. Here, we tested PTX effects on CD8+ T-cell abnormalities and cardiac alterations using a model of experimental Chagas’ heart disease.Methodology/Principal FindingsC57BL/6 mice chronically infected by the Colombian Trypanosoma cruzi strain and presenting signs of CCC were treated with PTX. The downmodulation of T-cell receptors on CD8+ cells induced by T. cruzi infection was rescued by PTX therapy. Also, PTX reduced the frequency of CD8+ T-cells expressing activation and migration markers in the spleen and the activation of blood vessel endothelial cells and the intensity of inflammation in the heart tissue. Although preserved interferon-gamma production systemically and in the cardiac tissue, PTX therapy reduced the number of perforin+ cells invading this tissue. PTX did not alter parasite load, but hampered the progression of heart injury, improving connexin 43 expression and decreasing fibronectin overdeposition. Further, PTX reversed electrical abnormalities as bradycardia and prolonged PR, QTc and QRS intervals in chronically infected mice. Moreover, PTX therapy improved heart remodeling since reduced left ventricular (LV) hypertrophy and restored the decreased LV ejection fraction.Conclusions/SignificancePTX therapy ameliorates critical aspects of CCC and repositioned CD8+ T-cell response towards homeostasis, reinforcing that immunological abnormalities are crucially linked, as cause or effect, to CCC. Therefore, PTX emerges as a candidate to treat the non-beneficial immune deregulation associated with chronic Chagas' heart disease and to improve prognosis.

CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi-Induced Chronic Cardiomyopathy

“…However, these levels were significantly reduced in T. cruzi-infected ccl3 −/− mice in parallel to the reduction in concentrations of inflammatory cytokines in heart tissue and occurred in the presence of a more regulatory milieu, with reduced TNF concentrations and preserved IL-10 levels. Altogether, these data corroborated the idea that a dysregulated inflammatory profile is associated with heart injury and functional and electrical abnormalities (26,(30)(31)(32) in chronically infected mice.…”

“…Further, in the acute phase of C57BL/6 infection by the Colombian strain prolonged QTc has been associated with severe and specific miRNA alterations (50), as well as increased TNF and IFNγ gene expression (51). Blockage of TNF by neutralizing antibody (30), disruption of TNF/TNFR1 signaling by pentoxifylline administration (31) and reduction of TNF expression in the heart tissue by benznidazole therapy (26) reduced the prolonged QTc, reinforcing the participation of TNF-signaling in this abnormality. Our study was limited as we did not approach the CCL3-driven molecular mechanisms promoting heart tissue parasitism in chronic T. cruzi infection.…”

“…The activity of the creatine kinase myocardial band (CK-MB) is a marker of myocardial injury associated with CCC severity in experimental models (29)(30)(31)(32). CK-MB activity was measured with commercial kits (cat.…”

Resveratrol Reverses Functional Chagas Heart Disease in Mice

“…We have chosen a model of infection with the Colombian strain of T . cruzi , which has been isolated from a patient in Colombia [27] and has been used in many functional heart studies in the last 25 years [16, 28, 29]. At 60 dpi, BALB/c infected with Colombian T .…”

Análise do papel modulador da interação PD-1/PD-L1 na fase crônica da infecção murina pelo <i>Trypanosoma cruzi</i>.

“…Colombiana com Pentoxifilina (PTX), um inibidor de fosfodiesterases utilizado no tratamento de doenças vasculares periféricas que age também sobre o receptor de TNFα, normaliza a resposta de células T CD8 + exaustas, melhorando a cardiomiopatia chagásica crônica (PEREIRA et al 2015). Neste mesmo contexto, a interação das moléculas inibitórias PD-1 e PD-L1 poderia ser responsável pela inibição da resposta imune na fase crônica da infecção de forma análoga ao descrito em outros modelos crônicos, fazendo desta interação um importante objeto de estudo.…”