Matrix metalloproteinase inhibition in a murine model of cavitary tuberculosis paradoxically worsens pathology

Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis (TB) pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis-infected C3HeB/FeJ mice. We demonstrate that compared to untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% versus 7%; P = 0.029), immunopathology andmortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary TB.