Expression kinetics of metalloproteinases and their tissue inhibitors in experimental murine pulmonary tuberculosis.

Aim: Explore the temporal expression of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during experimental tuberculosis induced by virulent Mycobacterium tuberculosis strain H37Rv. Methods: BALB/c mice were infected via endotracheal instillation with H37Rv. Groups of mice were euthanized at different time points during infection. RNA was isolated from the lungs, and the expression of MMP-3, 8, 9, 10, 12, 13 and TIMP-1-4 was determined by quantitative PCR. Immunohistochemical detection of MMP-3, MMP-9, and MMP-10 was done to determine the cell source. Results: The infection with H37Rv-induced inflammation resulted in maximal up-regulation of MMP-3, 8, 9, 10, 12 and 13 at day 21 postinfection. Additionally, MMP-13 showed another expression peak during late disease at day 60. Airway epithelium and macrophages were the most common MMP-3 and MMP-9 immunopositive cells, while for MMP-10, macrophages and endothelial cells were the most common, particularly at days 14 and 21 in well-formed granulomas. During late disease, vacuolated macrophages in pneumonic areas and bronchial epithelium showed mild MMP immunostaining. Conclusions: MMP-3, 8, 9, 10, 12, and 13 are maximally expressed at the peak of granuloma formation in the mouse tuberculosis model, with no compensation in levels or timing of TIMP expression. This data opens the possibility of participation of these molecules in the granuloma process.