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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases.

ABSTRACT: RATIONALE: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. OBJECTIVES: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. METHODS: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. MEASUREMENTS AND MAIN RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Walker NF

PROVIDER: S-EPMC3359940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully understood. Therefore, we investigated the role of MMPs in the K/BxN serum-transfer model of RA with the broad-spectrum MMP inhibitor subantimicrobial dose doxycycline (SDD) using complex in vivo and in vitro methodolgy. Methods: Chronic arthritis was induced by repetitive i.p. injections of K/BxN serum in C57BL/6J mice. SDD was administered daily in acidified drinking water (0.5 mg/mL, 80 mg/kg) during the 30 days experimental period. Mechanonociceptive threshold of the paw was evaluated by aesthesiometry, grasping ability by grid test, arthritis severity by scoring, neutrophil myeloperoxidase activity by luminescence, vascular hyperpermeability and MMP activity by fluorescence in vivo imaging and the latter also by gelatin zymography, bone structure by micro-computed tomography (micro-CT). Plasma concentrations of doxycycline were determined by liquid chromatography-mass spectrometry analysis. Results: K/BxN serum induced significant inflammatory signs, mechanical hyperalgesia, joint function impairment, increased myeloperoxidase activity and vascular hyperpermeability. Significant increase of MMP activity was also observed both in vivo and ex vivo with elevation of the 57-60, 75, and 92 kDa gelatinolytic isoforms in the arthritic ankle joints, but neither MMP activity nor any above described functional parameters were influenced by SDD. Most importantly, SDD significantly reduced bone mineral density in the distal tibia and enhanced the Euler number in the ankle. Arthritis-induced microarchitectural alterations demonstrating increased irregularity and cancellous bone remodeling, such as increased Euler number was significantly elevated by SDD in both regions. Conclusion: We showed increase of various MMP activities in the joints by in vivo fluorescence imaging together with ex vivo zymography, and investigated their functional significance using the broad-spectrum MMP inhibitor SDD in the translational RA model. This is the first demonstration that SDD worsens arthritis-induced bone microarchitectural alterations, but it appears to be independent of MMP inhibition.

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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases.

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