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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerosols / adverse effects*
  • Animals
  • Disease Models, Animal
  • Environmental Exposure*
  • Female
  • Lung / microbiology
  • Lung / pathology*
  • Matrix Metalloproteinase 1 / metabolism*
  • Mycobacterium tuberculosis / growth & development*
  • Protease Inhibitors / administration & dosage
  • Rabbits
  • Tuberculosis, Pulmonary / epidemiology*
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / pathology*


  • Aerosols
  • Protease Inhibitors
  • Matrix Metalloproteinase 1