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'Images of Clay'
'Images of Clay'
EMU Notes in Mineralogy - volume 18
Mineral fibres: Crystal chemistry, chemical-physical properties, biological interaction and toxicity
(A.F. Gualtieri, editor)
Chapter 14. Insights into mineral fibre-induced lung epithelial cell toxicity and pulmonary fibrosis
R. P. Jablonski, S.-J. Kim, P. Cheresh and D. W. Kamp
Asbestos mineral-fibre exposure is a well established cause of pulmonary fibrosis (asbestosis) and malignancies (bronchogenic carcinoma and mesothelioma). In this chapter, we review the work of numerous groups employing asbestos fibres to investigate the earlymolecular events promoting alveolar epithelial cell (AEC) injury, a key event for inciting and advancing pulmonary fibrosis. First, we summarize the accumulating evidence implicating the crucial role of the AEC in the pathobiology of pulmonary fibrosis, including asbestosis. We summarize briefly the mechanisms by which AEC toxicity from asbestos exposure results from the generation of reactive oxygen species (ROS) from at least three sources: (1) by redox reactions occurring on the fibre surface; (2) by surrounding inflammatory cells, especially macrophages; and (3) by AECs, especially from the mitochondria. Second, we review the emerging evidence showing that asbestos fibre-derived ROS induce AEC mtDNA damage important for promoting mitochondrial dysfunction and mitochondria (intrinsic)- and p53-regulated apoptosis, events important in facilitating lung fibrosis and malignant transformation.We focus on a novel role for AECmtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1), a base excision repair enzyme, andmitochondrial aconitase (ACO-2) in preserving mtDNA integrity important in preventing asbestos-induced AEC apoptosis and lung fibrosis. Third, we examine studies implicating autophagy (lysosomal degradation of cytosolic materials), autophagy of mitochondria (mitophagy), and kinase signalling pathways in modulating lung epithelial cell toxicity following asbestos exposure and in patients with idiopathic pulmonary fibrosis (IPF). Finally, we review the evidence implying that an ‘‘exaggerated’’ aging lung is important in the pathogenesis of IPF and asbestosis. We focus on the role of the sirtuins (SIRT), especially SIRT3, in maintaining mitochondrial integrity important for preventing mtDNA damage and fibrosis. Collectively, the asbestos paradigm is informing our understanding of the cellular and molecular mechanisms underlying AEC mitochondrial dysfunction, autophagy/mitophagy and apoptosis that can promote lung fibrosis. Importantly, these studies are providing the scientific basis for novel therapeutic targets that may prove useful for the management of asbestos pulmonary toxicity with broader implications for other age-related diseases, including
IPF and lung cancer, for which more effective treatments are urgently required.
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