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- Title
Repetitive Aerosol Exposure Promotes Cavitary Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction.
- Authors
Urbanowski, Michael E; Ihms, Elizabeth A; Bigelow, Kristina; Kübler, André; Elkington, Paul T; Bishai, William R; Kübler, André
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
LUNG microbiology; TUBERCULOSIS microbiology; TUBERCULOSIS epidemiology; AEROSOLS; ANIMAL experimentation; BIOLOGICAL models; COMPARATIVE studies; LUNGS; RESEARCH methodology; MEDICAL cooperation; MYCOBACTERIUM tuberculosis; PROTEOLYTIC enzymes; RABBITS; RESEARCH; TUBERCULOSIS; ENVIRONMENTAL exposure; PROTEASE inhibitors; EVALUATION research
- Publication
Journal of Infectious Diseases, 2018, Vol 217, Issue 6, pN.PAG
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiy127