Abstract / Summary
Tuberculosis remains a leading fatal infectious disease globally. Hypoxic microenvironment and vascular abnormalities in tuberculous granulomas severely compromise anti-tuberculosis drug efficacy, yet the underlying mechanisms remain poorly understood. This study investigates the therapeutic effect and molecular mechanisms of local catalase (CAT)-based oxygen therapy for tuberculosis. A murine subcutaneous tuberculous granuloma model was established using Bacillus Calmette-Guérin (BCG). Mice were treated with CAT, cobalt chloride (CoCl₂, hypoxia mimetic), or saline control at day 6 (early stage) and day 12 (late stage) post-infection. Outcomes were assessed via histopathology, immunohistochemistry/immunofluorescence, ELISA, and lipidomics analysis. BCG infection progression correlated with worsening granuloma hypoxia, vascular dysfunction (reduced CD31/α-SMA expression), increased collagen deposition, lipid accumulation, and bacterial load. Early CAT intervention alleviated hypoxia (downregulated HIF-1α and VEGF), improved vascular structure and permeability, reduced collagen and lipid deposition, and specifically modulated lipid metabolism (downregulated PS (18:0/18:0), upregulated PI/PE subtypes). In contrast, late CAT treatment showed limited efficacy, while CoCl₂-induced hypoxia markedly exacerbated all pathological changes. Early CAT-based local oxygen therapy effectively inhibits subcutaneous tuberculous granuloma progression by ameliorating the pathological microenvironment and regulating aberrant lipid metabolism in a BCG-infected murine model. These findings suggest a potential application prospect in animal models more closely recapitulating human tuberculosis.