Molecular mechanisms of silica-induced caspase activation and apoptosis
Date of Completion
Health Sciences, Toxicology
Silicosis is a chronic lung disease caused by the inhalation of crystalline silica particles. The pathogenicity of silica is due, in part, to its cytotoxicity which can be attributed to either necrosis and/or apoptosis. The cellular and biochemical mechanisms underlying silica-induced apoptosis remain unclear. Apoptosis is an active (physiologic) form of cell death initiated by intrinsic (intracellular) or extrinsic (extracellular) pathways that may contribute to pulmonary inflammation and fibrosis or resolution. Given the central role of alveolar macrophages in the clearance of inhaled particles as well as injured cells, macrophages were chosen as target cells to study pathways leading to apoptosis which could ultimately influence outcome of lung injury. Using an in vitro model of silica-induced apoptosis in a mouse alveolar macrophage cell line, we have identified the mitochondrial intrinsic pathway as a major contributor to silica-induced apoptosis. This was evidenced by disruption of mitochondrial integrity and the activation of specific caspase proteases (i.e., caspase 3 and caspase 9) that influence the onset of apoptosis. Furthermore, the endolysosomal compartment was found to contribute to this intrinsic pathway of silica-induced apoptosis. Silica perturbs endolysosomal permeability and with that the apparent influence of the endolysosomal acidic compartment and specific endolysosomal enzymes (i.e., acidic sphingomyelinase and cathepsin D) on apoptosis. In addition, it appears the endolysosomal enzymatic activity can influence the intrinsic pathway. These findings provide a better understanding of the mechanisms contributing to particle-induced cell injury, suggesting possible targets for therapeutic intervention. ^
Thibodeau, Michael Scott, "Molecular mechanisms of silica-induced caspase activation and apoptosis" (2004). Doctoral Dissertations. AAI3127597.