title: Antimycobacterial drugs modulate immunopathogenic matrix metalloproteinases in a cellular model of pulmonary tuberculosis.
abstract: Tuberculosis is characterized by extensive destruction and remodelling of the pulmonary extracellular matrix. Stromal cell-derived matrix metalloproteinases (MMPs) are implicated in this process and may be a target for adjunctive immunotherapy. We hypothesized that MMPs are elevated in bronchoalveolar lavage fluid of tuberculosis patients and that antimycobacterial agents may have a modulatory effect on MMP secretion. Concentrations of MMP-1, -2, -3, -7, -8, and -9 were elevated in the bronchoalveolar lavage fluid from tuberculosis patients compared to those in bronchoalveolar lavage fluid from patients with other pulmonary conditions. There was a positive correlation between MMP-3, MMP-7, and MMP-8 and a chest radiological score of cavitation and parenchymal damage. Respiratory epithelial cell-derived MMP-3 was suppressed by moxifloxacin, rifampicin, and azithromycin in a dose-dependent manner. Respiratory epithelial cell-derived MMP-1 was suppressed by moxifloxacin and azithromycin, whereas MMP-9 secretion was only decreased by moxifloxacin. In contrast, moxifloxacin and azithromycin both increased MMP-1 and -3 secretion from MRC-5 fibroblasts, demonstrating that the effects of these drugs are cell specific. Isoniazid did not affect MMP secretion. In conclusion, MMPs are elevated in bronchoalveolar lavage fluid from tuberculosis patients and correlate with parameters of tissue destruction. Antimycobacterial agents have a hitherto-undescribed immunomodulatory effect on MMP release by stromal cells.
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.
authors.forename: Shivani
authors.initials: S
authors.lastname: Singh
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.
authors.forename: Andre
authors.initials: A
authors.lastname: Kubler
authors.affiliation: Tuberculosis Unit, Department of Medicine and Paediatrics, Nalanda University Hospitals, Agam Kuan, Patna, India.
authors.forename: Utpal K
authors.initials: UK
authors.lastname: Singh
authors.affiliation: Tuberculosis Unit, Department of Medicine and Paediatrics, Nalanda University Hospitals, Agam Kuan, Patna, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.
authors.forename: Harriet
authors.initials: H
authors.lastname: Gardiner
authors.affiliation: Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Rajniti
authors.initials: R
authors.lastname: Prasad
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, United Kingdom Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, United Kingdom j.friedland@imperial.ac.uk.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000382:microbiology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000382:microbiology; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008954:Models, Biological; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D061251:Primary Cell Culture; D012293:Rifampin / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D007527:Isoenzymes; D017963:Azithromycin; D020782:Matrix Metalloproteinases; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin