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Repetitive Aerosol Exposure Promotes Lung Pathology and Cavitation in Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction
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A5541 - Repetitive Aerosol Exposure Promotes Lung Pathology and Cavitation in Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction
Author Block: W. R. Bishai1, M. Urbanowski1, E. Ihms1, K. Bigelow1, A. Kubler2, P. T. Elkington3; 1Johns Hopkins Sch of Medicine, Baltimore, MD, United States, 2Queens Hospital, Barking, United Kingdom, 3University of Southampton, Southampton, United Kingdom.
Introduction. Reduced pulmonary function and lung cavitation are dangerous consequences of tuberculosis. We tested the hypothesis that repetitive exposure to the same total bacterial burden of M. tuberculosis drives greater lung pathology than a single exposure. We also tested the hypothesis that inhibition of endogenous MMP1 may inhibit cavitation during TB.
Methods. We infected rabbits with quantified doses of M. tuberculosis with either 5 aerosols of 500 CFU over three weeks or a single aerosol of 2500 CFU plus four sham aerosols over the same time period. We monitored disease progression over 14 weeks by CT scanning and terminal necropsy. We administered the potent MMP1 inhibitor cipemastat at 100 mg/kg daily from week 5-9 to a subset of the rabbits using a dose shown to achieve MMP1 inhibitory levels for at least 18 hours.
Results. Repetitive aerosol infection produced greater lung pathology and more cavities than a single aerosol infection of the same bacterial burden. With repetitive infection 75% of the rabbits showed cavitation as opposed to single aerosol exposure rabbits which showed a 25% frequency of cavitation. Necropsies confirmed greater granulomatous inflammation and area of lung pathology in repetitively exposed animals. 44% of rabbits receiving cipemastat developed at least one cavity (mean number of cavities 8.8) compared with 62% of control rabbits (mean number of cavities 2.2). There was no statistical difference in cavity counts, cavity volume, or disease severity between the groups.
Conclusions. Our data show that five repetitive aerosol exposures of 500 CFU of M. tuberculosis drive greater lung damage and cavitation than exposure to a single aerosol exposure of 2500 CFU. This suggests that human lung pathology 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.
Author Block: W. R. Bishai1, M. Urbanowski1, E. Ihms1, K. Bigelow1, A. Kubler2, P. T. Elkington3; 1Johns Hopkins Sch of Medicine, Baltimore, MD, United States, 2Queens Hospital, Barking, United Kingdom, 3University of Southampton, Southampton, United Kingdom.
Introduction. Reduced pulmonary function and lung cavitation are dangerous consequences of tuberculosis. We tested the hypothesis that repetitive exposure to the same total bacterial burden of M. tuberculosis drives greater lung pathology than a single exposure. We also tested the hypothesis that inhibition of endogenous MMP1 may inhibit cavitation during TB.
Methods. We infected rabbits with quantified doses of M. tuberculosis with either 5 aerosols of 500 CFU over three weeks or a single aerosol of 2500 CFU plus four sham aerosols over the same time period. We monitored disease progression over 14 weeks by CT scanning and terminal necropsy. We administered the potent MMP1 inhibitor cipemastat at 100 mg/kg daily from week 5-9 to a subset of the rabbits using a dose shown to achieve MMP1 inhibitory levels for at least 18 hours.
Results. Repetitive aerosol infection produced greater lung pathology and more cavities than a single aerosol infection of the same bacterial burden. With repetitive infection 75% of the rabbits showed cavitation as opposed to single aerosol exposure rabbits which showed a 25% frequency of cavitation. Necropsies confirmed greater granulomatous inflammation and area of lung pathology in repetitively exposed animals. 44% of rabbits receiving cipemastat developed at least one cavity (mean number of cavities 8.8) compared with 62% of control rabbits (mean number of cavities 2.2). There was no statistical difference in cavity counts, cavity volume, or disease severity between the groups.
Conclusions. Our data show that five repetitive aerosol exposures of 500 CFU of M. tuberculosis drive greater lung damage and cavitation than exposure to a single aerosol exposure of 2500 CFU. This suggests that human lung pathology 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.
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