title: Pentoxifylline reverses chronic experimental Chagasic cardiomyopathy in association with repositioning of abnormal CD8+ T-cell response.
abstract: BACKGROUND
  Chronic 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.
  
  
  RESULTS
  C57BL/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
  PTX 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.
authors: Laboratório de Biologia das Interações, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Isabela Resende
authors: IR
authors: Pereira
authors: Laboratório de Biologia das Interações, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Glaucia
authors: G
authors: Vilar-Pereira
authors: Laboratório de Biologia Molecular e Doenças Endêmicas, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Otacilio Cruz
authors: OC
authors: Moreira
authors: Laboratório de Cardiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Isalira Peroba
authors: IP
authors: Ramos
authors: Laboratório de Biologia das Interações, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Daniel
authors: D
authors: Gibaldi
authors: Laboratório de Biologia Molecular e Doenças Endêmicas, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Constança
authors: C
authors: Britto
authors: Laboratório de Hanseníase, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Milton Ozório
authors: MO
authors: Moraes
authors: Laboratório de Biologia das Interações, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors: Joseli
authors: J
authors: Lannes-Vieira
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002598:Chagas Cardiomyopathy / Q000188:drug therapy* / Q000276:immunology*; D018031:Connexin 43; D006321:Heart / Q000187:drug effects / Q000469:parasitology; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000276:immunology*
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; D007371:Interferon-gamma; D010431:Pentoxifylline