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1.
Environ Res ; 230: 115607, 2023 08 01.
Article in English | MEDLINE | ID: mdl-36965793

ABSTRACT

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.


Subject(s)
Asbestos , Lung Neoplasms , Mesothelioma , Humans , Asbestos/toxicity , Mesothelioma/chemically induced , Mesothelioma/epidemiology , Lung Neoplasms/chemically induced , Lung Neoplasms/epidemiology , Lung/pathology , Asbestos, Amphibole/toxicity , Inflammation/metabolism
2.
Part Fibre Toxicol ; 10: 3, 2013 Feb 12.
Article in English | MEDLINE | ID: mdl-23402370

ABSTRACT

BACKGROUND: In myeloid cells the inflammasome plays a crucial role in innate immune defenses against pathogen- and danger-associated patterns such as crystalline silica. Respirable mineral particles impinge upon the lung epithelium causing irreversible damage, sustained inflammation and silicosis. In this study we investigated lung epithelial cells as a target for silica-induced inflammasome activation. METHODS: A human bronchial epithelial cell line (BEAS-2B) and primary normal human bronchial epithelial cells (NHBE) were exposed to toxic but nonlethal doses of crystalline silica over time to perform functional characterization of NLRP3, caspase-1, IL-1ß, bFGF and HMGB1. Quantitative RT-PCR, caspase-1 enzyme activity assay, Western blot techniques, cytokine-specific ELISA and fibroblast (MRC-5 cells) proliferation assays were performed. RESULTS: We were able to show transcriptional and translational upregulation of the components of the NLRP3 intracellular platform, as well as activation of caspase-1. NLRP3 activation led to maturation of pro-IL-1ß to secreted IL-1ß, and a significant increase in the unconventional release of the alarmins bFGF and HMGB1. Moreover, release of bFGF and HMGB1 was shown to be dependent on particle uptake. Small interfering RNA experiments using siNLRP3 revealed the pivotal role of the inflammasome in diminished release of pro-inflammatory cytokines, danger molecules and growth factors, and fibroblast proliferation. CONCLUSION: Our novel data indicate the presence and functional activation of the NLRP3 inflammasome by crystalline silica in human lung epithelial cells, which prolongs an inflammatory signal and affects fibroblast proliferation, mediating a cadre of lung diseases.


Subject(s)
Carrier Proteins/immunology , Epithelial Cells/drug effects , Inflammasomes/immunology , Lung/drug effects , Silicon Dioxide/toxicity , Blotting, Western , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Cell Culture Techniques , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/immunology , Epithelial Cells/pathology , Fibroblasts/drug effects , Fibroblasts/immunology , Fibroblasts/pathology , Humans , Inflammasomes/biosynthesis , Inflammasomes/genetics , Lung/immunology , Lung/pathology , NLR Family, Pyrin Domain-Containing 3 Protein , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
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