Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells

Our plain-English summary of Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells, by T.N. Perkins, P.M. Peeters, A. Shukla, et al (Human Molecular Genetics, 2015).

The study

• Authors: T.N. Perkins, P.M. Peeters, A. Shukla, I. Arijs, J. Dragon, E.F. Wouters, N.L. Reynaert, B.T. Mossman
• Journal: Human Molecular Genetics
• Published: 2015;24(5):1374-89
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials.

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In plain English

This was a laboratory study on human airway lining cells grown in dishes, not on people. It compared early changes in gene activity caused by crocidolite asbestos and cristobalite silica. The authors exposed normal human bronchial epithelial cells for 24 hours to asbestos at 15 × 10^6 square micrometres of particle surface per square centimetre of dish, or to silica at that same dose and at a dose five times higher, with three samples per group. They then measured gene activity with microarrays and rechecked selected findings in an immortalized airway cell line, BEAS-2B. Compared with unexposed cells, asbestos altered 321 probe-sets (262 genes). Silica altered 3 probe-sets at the same dose and 1247 probe-sets (1033 genes) at the higher dose. Both minerals raised IL-8 secretion in BEAS-2B cells. Asbestos, but not silica, cut transferrin receptor protein by 50% at 48 hours. Silica alone increased secretion of the growth factor FGF2. The authors concluded that asbestos was most specifically associated with abnormal cell proliferation and carcinogenesis. They linked silica with additional inflammatory responses, pattern recognition and fibrogenesis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture experiment using microarray gene expression profiling and pathway analysis, with selected findings confirmed by QRT-PCR and protein assays
• Who was studied: One purchased isolate of normal primary human bronchial epithelial cells (NHBE), with 3 samples per group: unexposed control, asbestos, low-dose silica and high-dose silica (12 samples). Selected findings were confirmed in the immortalized bronchial epithelial cell line BEAS-2B.
• Exposure: Respirable crocidolite asbestos fibers (NIEHS reference sample) and cristobalite silica particles for 24 hours, with doses expressed by surface area. In NHBE cells, asbestos was given at 15 × 10^6 µm²/cm² (1.0 µg/cm²). Silica was given at 15 × 10^6 µm²/cm² (2.94 µg/cm²) and at 75 × 10^6 µm²/cm² (14.7 µg/cm²). The comparison of shared and mineral-specific changes used asbestos at 15 and silica at 75 × 10^6 µm²/cm², which the authors described as equitoxic doses. BEAS-2B cells received 75 and 150 × 10^6 µm²/cm². Controls received saline solution alone.
• Main results:
  • In NHBE cells, asbestos (15 × 10^6 µm²/cm²) significantly altered 321 probe-sets (262 genes) compared with unexposed controls. The threshold was more than 1.5-fold with adjusted P less than 0.05.
  • In NHBE cells, silica altered only 3 probe-sets (3 genes) at 15 × 10^6 µm²/cm². At 75 × 10^6 µm²/cm² it altered 1247 probe-sets (1033 genes).
  • Of 1316 probe-sets altered across the exposures, 252 were altered by both asbestos and high-dose silica. A further 69 were altered only by asbestos and 995 only by high-dose silica.
  • Changes shared by both minerals involved genes for inflammation, cell adhesion/migration and cellular stress (for example IL8, MMP1 and BIRC3, confirmed by QRT-PCR). In BEAS-2B cells, both minerals increased IL-8 secretion, caspase-1 activity and CLDN1 protein.
  • In BEAS-2B cells, asbestos, but not silica, caused a 50% decrease in transferrin receptor (TFRC) protein at 48 hours. Asbestos also specifically increased SEMA3A expression, while silica decreased it.
  • In BEAS-2B cells at the highest concentration (150 × 10^6 µm²/cm²), silica alone increased FGF2, PTX3 and CREB5 and decreased SFRP1. Silica also selectively induced FGF2 secretion.
• The authors' conclusion: The authors concluded that both minerals strongly affected genes governing cell adhesion/migration, inflammation and cellular stress. In their view, asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, while silica was associated with additional inflammatory responses, pattern recognition and fibrogenesis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite.

Medical terms in this study, explained in our Lexicon: Environmental Exposure, Fibrosis, Silicosis, Epithelium, Crocidolite, Inflammation, Asbestos Exposure, Carcinogenesis.

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