RESUMO
OBJECTIVES: Antifungal triazole derivatives have been studied as possible alternatives for the treatment of Chagas' disease. Voriconazole has demonstrated in vitro activity against Trypanosoma cruzi, but its efficacy in vivo has not yet been tested. We aimed to determine the effect of voriconazole in a murine model of acute T. cruzi infection. METHODS: Treatment efficacy was evaluated by comparing parasitaemia, mortality and organ involvement (by histological examination) of infected mice. RESULTS: Treatment with voriconazole significantly lowered parasitaemia and mortality compared with controls, reduced the percentage of mice with amastigote nests in heart and skeletal muscle and moderately decreased myocardial inflammation. CONCLUSIONS: Our findings support the potential of voriconazole for the treatment of acute Chagas' disease and motivate future animal studies using varying doses and treatment schemes. Further evaluation of voriconazole for clinical use in human Chagas' patients is warranted.
Assuntos
Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Estruturas Animais/parasitologia , Animais , Doença de Chagas/mortalidade , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Histocitoquímica , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico , Análise de Sobrevida , VoriconazolRESUMO
Infection with a myotropic Trypanosoma cruzi clone induces maternal fertility failure. In the current work, we evaluated whether reduction of maternal parasitaemia before mating has beneficial effects on pregnancy outcome. Female mice were subjected to benznidazole (Bz) treatment after infection. On day 30 of therapy, mating was assessed and pregnancy outcome was determined on day 14 of gestation. Fetal resorptions diminished in T. cruzi-infected Bz-treated mice compared with T. cruzi-infected untreated mice. This was in agreement with the reduction in the blood/solid tissue parasite load and with the percentage of necrotic foci in placental samples from T. cruzi-infected Bz-treated females. To study eventual changes in the immune homeostasis of T. cruzi-infected Bz-treated mice, activation of the immune system was evaluated at the end of Bz therapy and before mating. We found specific IgG1 reduction resulting in a predominance of specific IgG2a, reduced numbers of CD69+ CD4+ cells and diminished frequency and numbers of CD44+ T cells. Concanavalin A-stimulated splenocytes from T. cruzi-infected Bz-treated mice produced higher amounts of IFN-gamma than T. cruzi-infected untreated mice. These results indicate that reduction of maternal parasite load improves pregnancy outcome. These findings correlate with a favourable modulation of the immune response.
Assuntos
Doença de Chagas/parasitologia , Parasitemia/parasitologia , Complicações Parasitárias na Gravidez/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Anticorpos Antiprotozoários/sangue , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/imunologia , Doença de Chagas/tratamento farmacológico , Feminino , Regulação da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Imunoglobulina G/sangue , Interferon gama/metabolismo , Lectinas Tipo C , Camundongos , Nitroimidazóis/uso terapêutico , Parasitemia/tratamento farmacológico , Placenta/parasitologia , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Resultado da Gravidez , Baço/citologia , Baço/metabolismo , Fatores de TempoRESUMO
Enhanced atrial natriuretic factor (ANF) production by the heart is related to hemodynamic overload, cardiac growth, and hypertrophy. The heart is one of the most affected organs during Trypanosoma cruzi infection. We tested the hypothesis that myocarditis produced by parasite infection alters the natriuretic peptide system by investigating the behavior of plasma ANF during the acute and chronic stages of T. cruzi infection in rats. Sprague-Dawley rats were infected with T. cruzi clone Sylvio-X10/7. Cardiac morphology showed damage to myocardial cells and lymphocyte infiltration in the acute phase; and fibrosis and cell atrophy in the chronic period. Plasma ANF levels (radioimmunoassay) were significantly higher in acute (348 +/- 40 vs. 195 +/- 36 pg/ml, P < 0.05, n = 17) and chronic T. cruzi myocarditis (545 +/- 81 vs. 229 +/- 38 pg/ml, P < 0.001, n = 11) than in their respective controls (n = 10 and 14). Rats in the chronic phase also showed higher levels than rats in the acute phase (P < 0.01). The damage of myocardial cells produced by the parasite and the subsequent inflammatory response could be responsible for the elevation of plasma ANF during the acute period of T. cruzi infection. The highest plasma ANF levels found in chronically infected rats could be derived from the progressive failure of cardiac function.
Assuntos
Fator Natriurético Atrial/sangue , Cardiomiopatia Chagásica/sangue , Modelos Animais de Doenças , Doença Aguda , Animais , Peso Corporal , Cardiomiopatia Chagásica/mortalidade , Doença Crônica , Coração/parasitologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Cardiac tissue from chagasic mice was studied to evaluate the expression and biological activity of beta-adrenoceptors in association with circulating beta-adrenoceptor-related autoantibodies. METHODS: BALB/c inbred mice that were either treated or not treated with atenolol (2.5 mg/kg) and infected or not infected with 1 x 10(4) trypomastigotes (CA-1 strain) were sacrificed weekly up to week nine. Morphological, binding and contractility studies were performed on the four different groups of animals. The effect of their serum antibodies was also assayed in binding and contractility studies on normal heart preparations. RESULTS: Hearts from chagasic myocarditis mice showed a beta-adrenoceptor-related dysfunction, with a decrease in heart contractility, impaired response to exogenous beta-adrenoceptor agonist and a significant reduction in beta-adrenergic binding sites. Those effects were maximum at eight-nine weeks post-infection and were improved by treating infected mice with atenolol. In addition, serum or IgG from chagasic myocarditis mice was capable of interacting with cardiac beta-adrenoceptors, reducing the number of binding sites and inhibiting the contractile response to exogenous norepinephrine. IgG effects that were observed in normal myocardium, were highest in sera from mice eight-nine weeks post-infection and correlate with the degree of myocarditis. Moreover, chagasic autoantibodies from infected mice recognized a peptide corresponding to the sequence of the second extracellular loop of the human beta 1-adrenoceptor. CONCLUSIONS: (1) The development of alterations in beta-adrenergic receptors, related to cardiac dysfunction, may be associated with the presence of circulating antibodies against these receptors and (2) it is possible that the chronic deposits of these autoantibodies in cardiac beta-adrenoceptors could lead to a progressive blockade with sympathetic denervation, a phenomenon that has been described in the course of chagasic myocarditis.
Assuntos
Autoanticorpos/sangue , Cardiomiopatia Chagásica/metabolismo , Miocárdio/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Análise de Variância , Animais , Atenolol/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Imunoglobulina G , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Miocárdica , Fatores de TempoRESUMO
The aim of this study is to establish the response of cardiac myocytes to the infection with Trypanosoma cruzi. The role of myocardial cell proliferation on heart remodelation and the ability of these cells to produce nitric oxide and control intracellular parasite growth during T. cruzi infection were evaluated. The presence of proliferating cell nuclear antigen (PCNA) was determined in myocardial cells of Wistar rats infected with T. cruzi, resulting in a significant increase of PCNA+ labelling in all stages of disease. The ability of myocardial cells to control growth of intracellular parasites and the production of nitric oxide were evaluated in cultures of cardiac myocytes obtained from neonatal rats. Different combinations of cytokines were added to culture media. The number of cardiac cells displaying intracellular amastigotes was lower in cultures supplemented with IL-1b, TNF-a and IFN-g than with other cytokine combinations and controls. The addition of cytokines resulted also in an increase of nitric oxide production in both infected and non-infected controls. These results demonstrate that myocardial cells participate actively in the response of the heart to the infection with T. cruzi.
Assuntos
Cardiomiopatia Chagásica/parasitologia , Coração/parasitologia , Trypanosoma cruzi/crescimento & desenvolvimento , Doença Aguda , Animais , Animais Recém-Nascidos , Divisão Celular , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Doença Crônica , Interferon gama/análise , Interferon gama/metabolismo , Interleucina-1/análise , Interleucina-1/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismoRESUMO
T lymphocytes from T. cruzi infected mice susceptible to the development of myocarditis altered the contractility of normal mouse atria in vitro. While lymphocytes obtained from normal mice had no effect, lymphocytes from T. cruzi-infected mice cultured with normal atria induced negative or positive inotropic effects depending upon the post-infection period; negative inotropism was induced by lymphocytes obtained from animals at 1 to 4 weeks post-infection, and positive inotropism was induced by lymphocytes taken at 7 to 14 weeks post-infection. These effects were mediated by soluble factors as evidenced by the ability of lymphocyte culture supernatants to alter contractility. Cell enrichment experiments indicated that T lymphocytes rather than B lymphocytes were responsible for these inotropic effects. Lyt(2+)-enriched T lymphocytes were found to be responsible for triggering the negative inotropic effect at 3 weeks post-infection when myocarditis was less intense, whereas Lyt1(+)-enriched T lymphocytes induced the positive inotropic effect at 8 weeks after T. cruzi infection when myocarditis was severe. Furthermore, inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism blunted the negative inotropic effect while inhibitors of lipoxygenase pathway inhibited the positive inotropic effect. PGE2 was found to be spontaneously released by Lyt(2+)-enriched T cells obtained at 3 weeks post-infection while LTC4 was released by atria cultured in the presence of Lyt 1+ T cells obtained at 8 weeks post-infection. In conclusion, these findings suggest that infiltrating T lymphocytes may contribute to myocardial dysfunction during T. cruzi infection by releasing or inducing the release of harmful arachidonic acid metabolites such as PGE2 and LTC4 which alter normal cardiac function.