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Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0.

Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework.

Author information

1
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada.
2
Department of Biological and Chemical Work Environment, National Institute of Occupational Health, Oslo, Norway.
3
National Research Centre for the Working Environment, Lerso Parkallé 105, DK-2100, Copenhagen, Denmark.
4
Department of Micro- and Nanotechnology, Technical University of Denmark, DK-2800, Kgs. Lyngby, Denmark.
5
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, K1A 0K9, Canada. sabina.halappanavar@canada.ca.

Abstract

BACKGROUND:

The accumulation of MWCNTs in the lung environment leads to inflammation and the development of disease similar to pulmonary fibrosis in rodents. Adverse Outcome Pathways (AOPs) are a framework for defining and organizing the key events that comprise the biological changes leading to undesirable events. A putative AOP has been developed describing MWCNT-induced pulmonary fibrosis; inflammation and the subsequent healing response induced by inflammatory mechanisms have been implicated in disease progression. The objective of the present study was to address a key data gap in this AOP: empirical data supporting the essentiality of pulmonary inflammation as a key event prior to fibrosis. Specifically, Interleukin-1 Receptor1 (IL-1R1) and Signal Transducer and Activator of Transcription 6 (STAT6) knock-out (KO) mice were employed to target inflammation and the subsequent healing response using MWCNTs as a model pro-fibrotic stressor to determine whether this altered the development of fibrosis.

RESULTS:

Wild type (WT) C57BL/6, IL-1R1 (KO) or STAT6 KO mice were exposed to a high dose of Mitsui-7 MWCNT by intratracheal administration. Inflammation was assessed 24 h and 28 days post MWCNT administration, and fibrotic lesion development was assessed 28 days post MWCNT administration. MWCNT-induced acute inflammation was suppressed in IL-1R1 KO mice at the 24 h time point relative to WT mice, but this suppression was not observed 28 days post exposure, and IL-1R1 KO did not alter fibrotic disease development. In contrast, STAT6 KO mice exhibited suppressed acute inflammation and attenuated fibrotic disease in response to MWCNT administration compared to STAT6 WT mice. Whole genome analysis of all post-exposure time points identified a subset of differentially expressed genes associated with fibrosis in both KO mice compared to WT mice.

CONCLUSION:

The findings support the essentiality of STAT6-mediated signaling in the development of MWCNT-induced fibrotic disease. The IL-1R1 KO results also highlight the nature of the inflammatory response associated with MWCNT exposure, and indicate a system with multiple redundancies. These data add to the evidence supporting an existing AOP, and will be useful in designing screening strategies that could be used by regulatory agencies to distinguish between MWCNTs of varying toxicity.

KEYWORDS:

Adverse outcome pathway; Fibrosis; Il-1; Inflammation; Lung disease; M2 Macrophage; Multi-walled carbon nanotubes; Nanomaterials; STAT6

PMID:
28903780
PMCID:
PMC5598059
DOI:
10.1186/s12989-017-0218-0
[Indexed for MEDLINE]
Free PMC Article

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