endothelin-1 and Parasitemia

Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10

Topics: Animals; Blood-Brain Barrier; Brain; Cell Adhesion; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Female; Leukocytes; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Parasitemia; Plasmodium berghei

To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival.. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia.. Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance.. Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Cerebral Hemorrhage; Drug Synergism; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hydroxyquinolines; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Microvessels; Parasitemia; Plasmodium berghei; Random Allocation; Survival

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 microM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 microM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Topics: Acute Disease; Animals; Bosentan; Chagas Cardiomyopathy; Cytokines; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Male; Mice; Mice, Inbred C57BL; Parasitemia; Sulfonamides; Trypanosoma cruzi

Cerebral malaria (CM) remains a deadly complication of Plasmodium falciparum infection, and children are at high risk of developing encephalopathy as a result of CM. This is probably a consequence of the activation of many of the inflammatory cytokines as well as the glial cells and the vascular endothelium in the brain. We have previously demonstrated that there is a striking reduction in cerebral blood flow by magnetic resonance imaging when mice are infected with Plasmodium berghei ANKA (PbA), and we now demonstrate a possible role for endothelin (ET-1) in the pathogenesis of CM. The brains of female C57BL/6 mice with PbA infection were examined at Day 5 for the expression of ET-1, endothelin converting enzyme (ECE), and the endothelin receptors A and B (ET(A) and ET(B)) by both reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time PCR. ET-1 and ECE mRNA expression was markedly increased by RT-PCR in PbA-infected mice. Real-time quantitative PCR demonstrated a 3-fold increase in ET-1 (P < 0.05) and a significant increase in ET(A) and ET(B) expression (P < 0.05) in PbA-infected mice. Histopathology bof PbA-infected mice demonstrated a transformation in the morphology of microglial cells and clustering of these cells consistent with activation. Though the full impact of ET-1 on CM remains to be elucidated, these findings demonstrate that in the murine model, there is a significant increase in ET-1 and its components, which is associated with the vasculopathy and immunopathology of CM.

Topics: Animals; Aspartic Acid Endopeptidases; Brain; Cohort Studies; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Female; Injections, Intraperitoneal; Malaria, Cerebral; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Neuroglia; Parasitemia; Plasmodium berghei; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.

Topics: Animals; Chagas Cardiomyopathy; Chronic Disease; Echocardiography; Endothelin-1; Magnetic Resonance Imaging; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Parasitemia

Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi. Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ET(A) receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ET(A) receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.

Topics: Acute Disease; Animals; Bradykinin; Chagas Cardiomyopathy; Endothelin Receptor Antagonists; Endothelin-1; Heart; Male; Models, Animal; Parasitemia; Perfusion; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Vasodilator Agents