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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases
Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases
- Source :
- American journal of respiratory and critical care medicine. 185(9)
- Publication Year :
- 2012
-
Abstract
- Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage.To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology.Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs.HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation.HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB.
- Subjects :
- Pulmonary and Respiratory Medicine
Adult
Tuberculosis
Guinea Pigs
HIV Infections
Matrix metalloproteinase
Critical Care and Intensive Care Medicine
Mycobacterium tuberculosis
Young Adult
Immunopathology
medicine
Animals
Humans
Tuberculosis, Pulmonary
Doxycycline
Lung
biology
business.industry
Standard treatment
Macrophages
Sputum
Articles
Middle Aged
medicine.disease
biology.organism_classification
Matrix Metalloproteinases
Anti-Bacterial Agents
CD4 Lymphocyte Count
medicine.anatomical_structure
Matrix Metalloproteinase 8
Immunology
Cytokines
Matrix Metalloproteinase 2
Matrix Metalloproteinase 3
medicine.symptom
Matrix Metalloproteinase 1
business
medicine.drug
Subjects
Details
- ISSN :
- 15354970
- Volume :
- 185
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- American journal of respiratory and critical care medicine
- Accession number :
- edsair.doi.dedup.....b86251b99058a48dac26b01a7d181e0a