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J Infect Dis. 2018 Jun 5;218(1):53-63. doi: 10.1093/infdis/jiy127.

Repetitive Aerosol Exposure Promotes Cavitary Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction.

Author information

1
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Queen's Hospital, Barking, Havering and Redbridge University Hospital National Health Service Trust, Romford, Essex.
4
National Institute for Health Research Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, United Kingdom.
5
Institute for Life Sciences, University of Southampton, United Kingdom.

Abstract

Background:

Cavitation is a serious consequence of tuberculosis. We tested the hypothesis that repetitive exposure to the same total bacterial burden of Mycobacterium tuberculosis drives greater lung destruction than a single exposure. We also tested whether inhibition of endogenous matrix metalloproteinase-1 (MMP-1) may inhibit cavitation during tuberculosis.

Methods:

Over a 3-week interval, we infected rabbits with either 5 aerosols of 500 colony-forming units (CFU) of M. tuberculosis or a single aerosol of 2500 CFU plus 4 sham aerosols. We administered the MMP-1 inhibitor cipemastat (100 mg/kg daily) during weeks 5-10 to a subset of the animals.

Results:

Repetitive aerosol infection produced greater lung inflammation and more cavities than a single aerosol infection of the same bacterial burden (75% of animals vs 25%). Necropsies confirmed greater lung pathology in repetitively exposed animals. For cipemastat-treated animals, there was no significant difference in cavity counts, cavity volume, or disease severity compared to controls.

Conclusions:

Our data show that repetitive aerosol exposure with M. tuberculosis drives greater lung damage and cavitation than a single exposure. This suggests that human lung destruction due to tuberculosis may be exacerbated in settings where individuals are repeatedly exposed. MMP-1 inhibition with cipemastat did not prevent the development of cavitation in our model.

PMID:
29554286
PMCID:
PMC5989619
[Available on 2019-06-05]
DOI:
10.1093/infdis/jiy127

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