title: Macrophage-derived peroxynitrite diffusion and toxicity to Trypanosoma cruzi.
abstract: We studied the capacity of macrophage-derived peroxynitrite to diffuse into and exert cytotoxicity against Trypanosoma cruzi, the causative agent of Chagas' disease. In two types of macrophage-T. cruzi co-cultures, one with a fixed separation distance between source and target cells, and another involving cell-to-cell interactions, peroxynitrite resulted in significant oxidation of intracellular dihydrorhodamine and inhibition of [(3)H]thymidine incorporation in T. cruzi, which were not observed by superoxide or nitric oxide alone. The effects were attenuated in the presence of bicarbonate, in agreement with the extracellular consumption of peroxynitrite by its fast reaction with CO(2). However, studies using different T. cruzi densities, which allow to modify average diffusion distances of exogenously added peroxynitrite to target cells, indicate that at distances <5 microm, the diffusion process outcompetes the reaction with CO(2) and that the levels of peroxynitrite formed by macrophages would be sufficient to cause toxicity to T. cruzi during cell-to-cell contact and/or inside the phagosome.
authors.affiliation: Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: María Noel
authors.initials: MN
authors.lastname: Alvarez
authors.forename: Lucía
authors.initials: L
authors.lastname: Piacenza
authors.forename: Florencia
authors.initials: F
authors.lastname: Irigoín
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Peluffo
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques / Q000379:methods; D004058:Diffusion; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology*
chemical_list: D016877:Oxidants; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D010100:Oxygen