Insights into mineral fibre-induced lung epithelial cell toxicity and pulmonary fibrosis
Renea P. Jablonski, Seok-Jo Kim, Paul Cheresh, Gang Liu, David W. Kamp, 2017. "Insights into mineral fibre-induced lung epithelial cell toxicity and pulmonary fibrosis", Mineral Fibres: Crystal Chemistry, Chemical-Physical Properties, Biological Interaction and Toxicity, A. F. Gualtieri
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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 early molecular 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 AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1), a base excision repair enzyme, and mitochondrial 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.
Acronyms: Alveolar epithelial cell (AEC); alveolar epithelial type I cell (AT1); alveolar epithelial type II cell (AT2); Alveolar macrophage (AM); autophagy protein 5 (ATG5); base excision repair (BER); bronchoalveolar duct (BAD); cigarette smoke (CS); c-Jun N-terminal kinase (JNK); endoplasmic reticulum (ER); epidermal growth factor receptor (EGFR); extracellular matrix (ECM); extracellular superoxide dismutase (EC-SOD); electron transport chain (ETC); extracellular signal-related kinase (ERK); genome-wide association studies (GWAS); idiopathic pulmonary fibrosis (IPF); inositol requiring kinase 1 alpha (IRE1α); mammalian target of rapamycin (mTOR); mitochondria-associated ER membrane (MAM); mitochondrial aconitase (ACO-2); mitochondrial DNA (mtDNA); mitochondrial membrane potential (∆ψm); mitogen-activated protein kinase (MAPK); multi-walled carbon nanotubes (MWCN); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox-4); non-small cell lung cancer (NSCLC); 8-oxoguanine-DNA glycosylase 1 (OGG1); particulate matter (PM); protein kinase-like ER kinase (PERK); PTEN-induced putative kinase 1 (PINK1); reactive nitrogen species (RNS); reactive oxygen species (ROS); sirtuin (SIRT); sirtuin 3 (SIRT3); surfactant protein C (SPC); transforming growth factor beta (TGF-β); thioredoxin interacting protein (TXNIP); tricarboxylic acid (TCA) cycle; unfolded protein response (UPR).