![]() On the basis of diverse evidence, it has been shown that a matrix-degrading phenotype develops in TB in which MMP activity is relatively unopposed by the specific tissue inhibitors of metalloproteinases (TIMPs). Zinc-containing matrix metalloproteinases (MMPs) have key roles in the inflammatory immunopathology in a wide range of diseases including cancer and arthritis. Excessive neutrophil recruitment associates with pathology in animal models and in man but the mechanism of how neutrophils drive pathology in human TB is not defined. Polymorphonuclear leukocytes or neutrophils are abundant in areas of TB lung cavities. The cavity has high bacillary burden and is associated with spread of infection. The lung cavity is a hallmark of pulmonary tuberculosis, a globally important disease of man. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. JCP received support from Breathing Matters. JSF and PE acknowledge support of the Biomedical Research Centre at Imperial College. RCM is a Wellcome Trust Clinical Research Fellow and TS an MRC Clinical Research Fellow. ![]() CUG was supported by the Wellcome Trust Master Fellowship of Tropical Medicine and Public Health (Grant 085777/Z/08/Z). This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: CWMO is funded by the Singapore National Medical Research Council on an NRF-MOH Healthcare Research Scholarship. Received: DecemAccepted: ApPublished: May 21, 2015Ĭopyright: © 2015 Ong et al. Sassetti, University of Massachusetts, UNITED STATES (2015) Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.Ĭitation: Ong CWM, Elkington PT, Brilha S, Ugarte-Gil C, Tome-Esteban MT, Tezera LB, et al. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. The mechanism of matrix destruction resulting in cavitation is not well defined. HgCl2 does not give white precipitate with aminoacids, so the microorganism which hydrolyses gelatin give no white precipitation with HgCl2.Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. These aminoacids are then utilizes by microorganisms. The microorganism producing an extracellular gelatinase hydrolyses gelatin releasing constituent aminoacids and short peptides. HgCl2 forms white precipitate with gelatin protein. The presence of gelatin protein is detected by adding acidic HgCl2 (mercuric chloride). Gelatin is polymer of aminoacids linked by peptide bonds. Once the gelatin is hydrolysed, even 4☌ temperature cannot restore gel like characteristic. Gelatin dissolves in water at 50☌ and exist in liquid form above 25☌ and solidifies as gel below 25☌. Collagen is the major component of connective tissues and tendon I humans and animals. Gelatin is a globular protein that is produced by hydrolysis of collagen. The main purpose of this test is to detect the ability of organism to produce enzyme gelatinase. ![]() to test whether the organism produces gelatin hydrolyzing enzyme gelatinase or not. ![]()
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