Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiationReportar como inadecuado




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Particle and Fibre Toxicology

, 14:18

First Online: 08 June 2017Received: 29 December 2016Accepted: 29 May 2017DOI: 10.1186-s12989-017-0198-0

Cite this article as: Dong, J. & Ma, Q. Part Fibre Toxicol 2017 14: 18. doi:10.1186-s12989-017-0198-0

Abstract

BackgroundCarbon nanotubes CNTs have been used in a variety of applications because of their unique properties and functions. However, many CNTs have been shown to induce lung fibrosis in experimental animals with some at a potency greater than that of silica, raising concern over possible toxic effects of CNT exposure in humans. Research into the mechanisms by which CNTs induce pulmonary fibrosis is warranted in order to facilitate the understanding, monitoring, and treatment of CNT-induced lung lesions that might occur in exposed populations. The current study focuses on investigating the role of osteopontin OPN in the development of lung fibrosis upon exposure to multi-walled carbon nanotubes MWCNTs.

MethodsC57BL-6J WT and Opn knockout KO mice were exposed to MWCNTs by pharyngeal aspiration to examine the acute and chronic effects of MWCNT exposure. The role of OPN and its mode of action in lung fibrosis development were analyzed at the cellular and molecular levels in vivo and in vitro.

ResultsOPN was highly and persistently induced in both the acute and chronic phases of the response to MWCNT exposure in mouse lungs. Comparison between WT and Opn KO mice revealed that OPN critically regulated MWCNT-induced lung fibrosis as indicated by reduced fibrotic focus formation and myofibroblast accumulation in Opn KO lungs. At the molecular level, OPN promotes the expression and activation of TGF-β1, stimulates the differentiation of myofibroblasts from fibroblasts, and increases the production of fibrous matrix proteins in lungs and cultured lung cells exposed to MWCNTs.

ConclusionOPN is highly induced in CNT-exposed lungs and plays critical roles in TGF-β1 signaling activation and myofibroblast differentiation to promote fibrosis development from MWCNT exposure. This study reveals an OPN-dependent mechanism to promote MWCNT-induced lung fibrosis. The findings raise the possibility of using OPN as a biomarker to monitor CNT exposure and as a drug target to halt fibrosis development.

KeywordsOsteopontin Multi-walled carbon nanotube Fibrosis TGF-β1 signaling Myofibroblast Fibroblast AbbreviationsAKTv-akt murine thymoma viral oncogene homolog

BALBronchoalveolar lavage

CNTCarbon nanotube

DMDispersion medium

ECMExtracellular matrix

EMTEpithelial to mesenchymal transition

FN1Fibronectin

FSP1Fibroblast specific protein 1

GapdhGlyceraldehyde 3-phosphate dehydrogenase

Hsp47Heat shock protein 47

IPFIdiopathic pulmonary fibrosis

KOKnockout

MWCNTMulti-walled carbon nanotube

OPNOsteopontin

PDGFR-βPlatelet-derived growth factor receptor-β

PI3KPhosphoinositide 3-kinase

SmadSma and Mad related family

SPP1Secreted phosphoprotein 1

SWCNTSingle-walled carbon nanotube

TGF-β1Transforming growth factor-β1

WTWild-type

α-SMAα-smooth muscle actin





Autor: Jie Dong - Qiang Ma

Fuente: https://link.springer.com/







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