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The effect of crystalline silica on the activation and function of human peripheral blood mononuclear cells (MNCs) : an in vitro investigation of the mechanisms leading to reduced resistance to mycobacterial infection in miners

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dc.contributor.advisor Gulumian M en
dc.contributor.advisor Bianchi PC en
dc.contributor.author Makhubela S en
dc.date.accessioned 2016-09-22T11:14:07Z
dc.date.available 2016-09-22T11:14:07Z
dc.date.created 1998 en
dc.date.submitted 2004 en
dc.identifier.uri http://hdl.handle.net/20.500.11892/106309
dc.description.abstract Epidemiological, as well as in vitro, and in vivo animal studies have demonstrated that individuals exposed to silica or who have silicosis are more susceptible to infection to Mycobacterium tuberculosis. Furthermore, even after discontinuation of exposure to silica, those individuals were found to be at higher risk of contracting pulmonary tuberculosis. The mechanism by which exposure to silica increases susceptibility to M. tuberculosis infection has not yet been fully elucidated. Therefore, this study was undertaken in order to investigate the effect of crystalline silica on the activation and function of Mycobacterium bovis (Bacillus Calmette Gu�rin: BCG)-infected mononuclear cells (MNC) in vitro. Materials and methods: An in vitro model was used, whereby human peripheral whole blood or isolated MNC from healthy donors, were treated with crystalline silica (Min-U-Sil 5), BCG, or the combination of silica and BCG. Thereafter, the following measurements were performed: Cell activation (expression of CD69), function (phagocytosis), oxidative status (intracellular glutathione, lipid peroxidation, intracellular generation of ROS) and the production of cytokines, TNF-α and IFN-γ. The expression of CD69, intracellular glutathione, intracellular generation of ROS, phagocytosis, and intracellular TNF-α and IFN-γ were evaluated by flow cytometry. The generation of lipid hydroperoxides was assessed using fluorescence spectrometry. IFN-γ and TNF-α in the culture supematants of treated MNC were determined using the ELISA method. Results (summarized in Figure 6.1 and Table 6.1) have demonstrated that in the presence of crystalline silica, BCG-infected monocytes exhibited reduced ability to phagocytose bacteria, reduced ability to express early activation marker, CD69, and reduced ability to produce TNF-α, all of which might contribute to the reduced ability of silica-loaded phagocytic cells to resist mycobacterial infection. On the other hand, results have shown that in the presence of crystalline silica, BCG-infected MNC exhibited increased CD69 expression and IFN-γ production by lymphocytes, but reduced GSH concentration, increased lipid peroxidation and ROS levels by monocytes and lymphocytes, all of which are shown to contribute to increased killing of mycobacteria. These responses have further substantiated those shown in the literature, but failed to explain the paradoxical increased susceptibility of silica-induced predisposition to mycobacterial infection. In conclusion, this in vitro investigation has demonstrated that three of the several parameters evaluated, namely, the expression of CD69 by monocytes, TNF-α production and the phagocytic ability of MNC, may contribute to the mechanism by which exposure to crystalline silica leads to increased susceptibility to infection with M. tuberculosis. Therefore, future studies should pursue in vivo investigation of the effect of crystalline silica on the activation and function of the virulent strain of M. tuberculosis-infected cells. en
dc.language English en
dc.subject Medical sciences: Diseases en
dc.subject Other diseases en
dc.title The effect of crystalline silica on the activation and function of human peripheral blood mononuclear cells (MNCs) : an in vitro investigation of the mechanisms leading to reduced resistance to mycobacterial infection in miners en
dc.type Doctoral degree en
dc.description.degree PhD (Science) en


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