Infection by Leishmania amazonensis in mice: a potential model for chronic hypoxia.

Hypoxia is a common feature of injured and infected tissues. Hypoxia inducible factors 1α and 2α (HIF-1α, HIF-2α) are heterodimeric transcription factors mediating the cellular responses to hypoxia and also the vascular endothelial growth factor (VEGF). VEGF is a cytokine which can be induced by hypoxia, whose pathogenic mechanisms are still unclear and which is the subject of debate. Murine cutaneous lesions during Leishmania amazonensis parasite infection are chronic, although they are small and self-controlled in C57BL/6 mice and severe in BALB/c mice. In the present study we examined the presence of hypoxia, HIF-1α, HIF-2α and VEGF during the course of infection in both mouse strains. Hypoxia was detected in lesions from BALB/c mice by pimonidazole marking, which occurred earlier than in lesions from C57Bl/6 mice. The lesions in the BALB/c mice showed HIF-1α and HIF-2α expression in the cytoplasm of macrophages and failed to promote any VEGF expression, while lesions in the C57BL/6 mice showed HIF-2α nuclear accumulation and subsequent VEGF expression. In conclusion, the animal models of leishmaniasis demonstrated a diversity of patterns of expression, cell localization and activity of the main transducers of hypoxia and may be useful models for studying the pathogenic mechanisms of HIF-1α and HIF-2α during chronic hypoxic diseases.