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

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

doi:10.1093/infdis/jiy373

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	633-636
Number of pages	4
Journal	Journal of Infectious Diseases
Volume	219
Issue number	4
DOIs	https://doi.org/10.1093/infdis/jiy373
State	Published - Jan 29 2019

Keywords

Tuberculosis
cavities
cipemastat
matrix metalloproteinases
mouse

ASJC Scopus subject areas

General Medicine

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10.1093/infdis/jiy373

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title = "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.",

keywords = "Tuberculosis, cavities, cipemastat, matrix metalloproteinases, mouse",

author = "Ordonez, {Alvaro A.} and Supriya Pokkali and Julian Sanchez-Bautista and Klunk, {Mariah H.} and Urbanowski, {Michael E.} and Andr{\'e} K{\"u}bler and Bishai, {William R.} and Elkington, {Paul T.} and Jain, {Sanjay K.}",

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AU - Ordonez, Alvaro A.

AU - Pokkali, Supriya

AU - Sanchez-Bautista, Julian

AU - Klunk, Mariah H.

AU - Urbanowski, Michael E.

AU - Kübler, André

AU - Bishai, William R.

AU - Elkington, Paul T.

AU - Jain, Sanjay K.

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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.

AB - 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.

KW - Tuberculosis

KW - cavities

KW - cipemastat

KW - matrix metalloproteinases

KW - mouse

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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