Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide

The phosphotyrosine phosphatase inhibitor bpV(phen) has the ability to mark edly decrease the progression of leishmaniasis in vivo. Here, we have ident ified the mechanisms that are responsible for this protective effect. We re port that two potent peroxovanadium (pV) compounds, bpV(phen) and bpV(pic), control progression of leishmaniasis in a similar manner by modulating NO- dependent microbicidal action. We observed that their injection can rapidly and transiently induce the expression of inducible NO synthase (iNOS) in l ivers of mice and enhance circulating nitrate levels. Treatment of mice wit h bpV(phen) or bpV(pic) completely controlled progression of leishmaniasis in an NO-dependent manner,since inhibition of iNOS with aminoguanidine comp letely reversed this pV-mediated protection. This NO-dependent pV-mediated protection was further demonstrated by the incapacity of bpV(phen)-treated Nramp(-/-), iNOS(-/-) mutant mice to control Leishmania major infection. Us ing an air pouch model, we showed that bpV(phen) can strongly modulate secr etion of L. major-induced pro-inflammatory molecules and neutrophil recruit ment. In addition, we observed that bpV(phen) per se can strongly induce th e expression of Th1 type cytokines over Th2 in spleens of animals. Overall, this study has allowed us to establish the in vivo functional and immunolo gical events involved in pV-mediated protective mechanism against leishmani asis and that NO plays a pivotal role in this process.