Repetitive aerosol exposure promotes cavitary tuberculosis and enables screening for targeted inhibitors of extensive lung destruction

Abstract

Background:

Cavitation is a serious consequence of tuberculosis. We tested the hypothesis that repetitive exposure to the same total bacterial burden of Mtb drives greater lung destruction than a single exposure. We also tested whether inhibition of endogenous MMP1 may inhibit cavitation during TB.

Methods:

Over a three weeks interval we infected rabbits with either 5 aerosols of 500 CFU of Mtb or a single aerosol of 2500 CFU plus four sham aerosols. We administered the MMP1 inhibitor cipemastat (100 mg/kg daily) from week 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 versus 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 Mtb drives greater lung damage and cavitation than a single exposure. This suggests that human lung destruction due to TB may be exacerbated in settings where individuals are repeatedly exposed. MMP1-inhibition with cipemastat did not prevent the development of cavitation in our model.

More information

Identifiers

ORCID for Paul Elkington: orcid.org/0000-0003-0390-0613

Catalogue record

Export record

Altmetrics