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

Matrix metalloproteinase inhibition in a murine model of cavitary tuberculosis paradoxically worsens pathology
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.
0022-1899
633-636
Ordonez, Alvaro
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Pokkali, Supriya
0d7ba70c-c364-4dd4-8dcf-eff087179a60
Sanchez-Bautista, Julian
c499d524-a860-4a74-9256-58de12b2f515
Klunk, Maria
eae94f15-c637-430e-8f56-ee4d2f03c968
Urbanowski, Michael
76ff3258-a007-4aac-9223-91735fa5f9ab
Kubler, Andre
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Bishai, William R.
d12021cd-50f9-4ac7-b89b-ecb8a73f735b
Elkington, Paul
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Jain, Sanjay
f93f1adf-a4a9-4f37-abd5-a5dcb5bb77cb
Ordonez, Alvaro
6ab637e7-fbe4-4d2d-b8b9-6bb468c88f18
Pokkali, Supriya
0d7ba70c-c364-4dd4-8dcf-eff087179a60
Sanchez-Bautista, Julian
c499d524-a860-4a74-9256-58de12b2f515
Klunk, Maria
eae94f15-c637-430e-8f56-ee4d2f03c968
Urbanowski, Michael
76ff3258-a007-4aac-9223-91735fa5f9ab
Kubler, Andre
65cd3ed7-9e90-41ef-87b2-0ade53ab8094
Bishai, William R.
d12021cd-50f9-4ac7-b89b-ecb8a73f735b
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Jain, Sanjay
f93f1adf-a4a9-4f37-abd5-a5dcb5bb77cb

Ordonez, Alvaro, Pokkali, Supriya, Sanchez-Bautista, Julian, Klunk, Maria, Urbanowski, Michael, Kubler, Andre, Bishai, William R., Elkington, Paul and Jain, Sanjay (2019) Matrix metalloproteinase inhibition in a murine model of cavitary tuberculosis paradoxically worsens pathology. The Journal of Infectious Diseases, 219 (4), 633-636. (doi:10.1093/infdis/jiy373).

Record type: Article

Abstract

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.

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Ordonez_author_accepted - Accepted Manuscript
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Accepted/In Press date: 15 June 2018
e-pub ahead of print date: 16 June 2018
Published date: 15 February 2019

Identifiers

Local EPrints ID: 421505
URI: https://eprints.soton.ac.uk/id/eprint/421505
ISSN: 0022-1899
PURE UUID: 4f3d0e18-274f-4074-a059-ae8906b7bbcd
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 14 Jun 2018 16:30
Last modified: 03 Dec 2019 05:21

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Contributors

Author: Alvaro Ordonez
Author: Supriya Pokkali
Author: Julian Sanchez-Bautista
Author: Maria Klunk
Author: Michael Urbanowski
Author: Andre Kubler
Author: William R. Bishai
Author: Paul Elkington ORCID iD
Author: Sanjay Jain

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