Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology.

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.

• Authors: Alvaro A Ordonez, Supriya Pokkali, Julian Sanchez-Bautista, Mariah H Klunk, Michael E Urbanowski, André Kübler, William R Bishai, Paul T Elkington, Sanjay K Jain
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 219 Issue 4 Pg. 633-636 (01 29 2019) ISSN: 1537-6613 [Electronic] United States
• PMID: 29920600 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinase 7

Topics

• Animals
• Disease Models, Animal
• Female
• Matrix Metalloproteinase 7 (metabolism)
• Matrix Metalloproteinase Inhibitors (administration & dosage)
• Mice, Inbred C3H
• Mycobacterium tuberculosis (growth & development)
• Survival Analysis
• Tuberculosis, Pulmonary (mortality, pathology)