Inflammatory Macrophages Associate With Tissue Injury and Fibrosis in a Mouse Model of Tuberculosis.

Abstract

Post-tuberculosis lung disease causes a significant burden of global disease. While a consensus definition of post-tuberculosis lung disease is still in development, parenchymal cavitation, bronchiectasis, and fibrosis are recognized pathologic features. The molecular mechanisms driving development of each feature are largely unknown. To facilitate the mechanistic study of tuberculosis-associated pathologic tissue remodeling and fibrosis, we adapted a mouse model of infection. The morphologies of fibrosis observed in mice were similar to those observed in human tissue samples, and fibrillar collagen deposition did not resolve with antituberculosis antibiotics. Inflammatory transcriptional signatures were persistently upregulated during chronic infection and did not fully resolve after weeks of antibiotics. Inflammatory and fibrosis-associated macrophages similarly persisted during treatment. Immunofluorescence microscopy revealed persistent macrophage populations and shifts in abundance and distribution of type 2 alveolar cells at sites of fibrogenesis. A mouse model recapitulates key aspects of tuberculosis-assocaiated fibrosis. Transcriptional and cellular markers of inflammation persist through weeks of antibiotic treatment.