A matrix metalloproteinase inhibitor promotes granuloma formation during the early phase of Mycobacterium tuberculosis pulmonary infection.
OBJECTIVE
The host response to pulmonary Mycobacterium tuberculosis (Mtb) infection results in granuloma formation in an effort to limit infection, but the host immune cells also provide an environment in which Mtb persists. Granuloma formation requires immune cell infiltration and concurrent extensive remodeling of pulmonary tissue which we hypothesize to be the result of increased matrix metalloproteinases (MMP) activity.


METHODS
C57BL/6 mice infected with virulent Mtb (H37Rv) via intratracheal inoculation were treated with a synthetic inhibitor of MMP activity (BB-94). Mice were assessed for colony forming units, granuloma morphology, leukocyte recruitment and cytokine levels over 90 days of infection.


RESULTS
BB-94 treated mice had significantly decreased numbers of pulmonary and blood-borne Mtb early during disease, increased collagen deposition within early granulomas and significantly decreased pulmonary leukocyte recruitment when compared to vehicle-treated, Mtb-infected mice. Cytokine expression did not differ significantly between groups.


CONCLUSIONS
Events of early granuloma formation can be modified by inhibiting MMP activity, by decreasing leukocyte recruitment, a major source of MMPs during infection, enhancing the establishment of granulomas and decreasing blood-borne dissemination of Mtb.
Izzo
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Department of Microbiology, Midwestern University, Downers Grove, IL 60515, USA. Angelo.Izzo@colostate.edu
Izzo
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Kasimos
J
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Majka
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D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D004334:Drug Administration Schedule; D005260:Female; D006099:Granuloma / Q000473:pathology*; D007958:Leukocyte Count; D008168:Lung / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D010649:Phenylalanine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D013876:Thiophenes / Q000008:administration & dosage*; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000473:pathology*
D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat