RESUMO

AIM: Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary tuberculosis (TB). METHODS & RESULTS: A model of progressive pulmonary TB in BALB/c mice, immunohistochemistry and digital pathology were used. High HIF-1α expression was observed during early TB in activated macrophages. During late TB, even higher HIF-1α expression was observed in foamy macrophages, which are resistant to apoptosis. Blocking HIF-1α during early infection with 2-methoxyestradiol worsened the disease, while during late TB, it induced macrophage apoptosis and decreased bacillary loads. CONCLUSION: HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.

Assuntos

Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Tuberculose Pulmonar/metabolismo , 2-Metoxiestradiol/administração & dosagem , Animais , Antituberculosos/administração & dosagem , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/fisiopatologia