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Free Radic Biol Med ; 30(11): 1234-42, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-11368921

RESUMO

The cytotoxins produced by phagocytic cells lacking peroxidases such as macrophages remain elusive. To elucidate macrophage microbicidal mechanisms in vivo, we compared the lesion tissue responses of resistant (C57Bl/6) and susceptible (BALB/c) mice to Leishmania amazonensis infection. This comparison demonstrated that parasite control relied on lesion macrophage activation with inducible nitric oxide synthase expression (iNOS), nitric oxide synthesis, and extensive nitration of parasites inside macrophage phagolysosomes at an early infection stage. Nitration and iNOS expression were monitored by confocal microscopy; nitric oxide synthesis was monitored by EPR. The main macrophage nitrating agent was shown to be peroxynitrite derived because parasite nitration occurred in the virtual absence of polymorphonuclear cells (monitored as peroxidase activity) and was accompanied by protein hydroxylation (monitored as 3-hydroxytyrosine levels). In vitro studies confirmed that peroxynitrite is cytotoxic to parasites whereas nitric oxide is cytostatic. The results indicate that peroxynitrite is likely to be produced close to the parasites and most of it reacts with carbon dioxide to produce carbonate radical anion and nitrogen dioxide whose concerted action leads to parasite nitration. In parallel, some peroxynitrite decomposition to the hydroxyl radical should occur due to the detection of hydroxylated proteins in the healing tissues. Consequently, peroxynitrite and derived radicals are likely to be important macrophage-derived cytotoxins.


Assuntos
Carbonatos/metabolismo , Radicais Livres/metabolismo , Leishmania infantum/patogenicidade , Leishmaniose/metabolismo , Macrófagos/parasitologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/biossíntese , Ácido Peroxinitroso/metabolismo , Tirosina/análogos & derivados , Animais , Dióxido de Carbono/metabolismo , Cromatografia Líquida de Alta Pressão , Di-Hidroxifenilalanina/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Hidroxilação , Leishmaniose/patologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia de Fluorescência , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II , Peroxidase/metabolismo , Tirosina/metabolismo
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