Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology. (16th June 2018)

• Record Type: Journal Article
• Authors: Ordonez, Alvaro A; Pokkali, Supriya; Sanchez-Bautista, Julian; Klunk, Mariah H; Urbanowski, Michael E; Kübler, André; Bishai, William R; Elkington, Paul T; Jain, Sanjay K
• Is Part Of: Journal of infectious diseases. Volume 219:Number 4(2019)
• Page Start: 633
• Page End: 636
• Publication Date: 2018-06-16
• Subjects: Tuberculosis -- matrix metalloproteinases -- cavities -- cipemastat -- mouse; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiy373
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract : Treatment with cipemastat, a selective matrix metalloproteinase inhibitor, paradoxically worsens disease in a mouse model of tuberculosis. Our investigation demonstrates that host-directed therapies for tuberculosis could have unpredicted deleterious effects. Cipemastat will require careful preclinical evaluation before undergoing clinical trials. Abstract: Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis 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 with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.