On the variability of silica toxicity: role of surface reactivity in membranolysis and in the activation of inflammatory pathways

Occupational exposure to crystalline silica dusts in respirable size has long been recognized as a cause of debilitating lung diseases (e.g. silicosis, cancer and obstructive diseases). However, not all the silica sources were found equally pathogenic. Differences in crystallinity, size, morphology, and surface functionalities can modify the silica surface and account for the huge variability of silica toxicity. Despite the wealth of studies in the field, the physico-chemical properties and molecular mechanisms underlying the biological responses induced by silica are still partially unknown mostly because of the variable chemical nature of the dusts and the complexity of the cellular responses involved. In this research the complexity of the silica surface-biological matter interactions was simplified by using model of cell membranes (i.e. red blood cells) and the physico-chemical determinants of membranolysis were investigated by testing a large set of silica particles. From the understanding of the determinants of membranolysis, some silica-induced inflammatory pathways that might be correlated to membranolysis were further probed and elucidated, with the final goal to shed light on the silica properties responsible of the toxic effects. At the end of this thesis a new adverse outcome pathway based on surface silanol disorganization as the molecular initiating event is proposed to explain the biological reactivity and its fundamental role in the mechanism of silica pathogenicity.