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Particle and Fibre Toxicology

, 8:31

First Online: 13 October 2011Received: 21 December 2010Accepted: 13 October 2011


Inhalation of nanoparticles may lead to pulmonary inflammation. However, the precise mechanisms of particle uptake and generation of inflammatory mediators by alveolar macrophages AM are still poorly understood. The aim of this study was to investigate the interactions between particles and AM and their associated pro-inflammatory effects in relation to particle size and physico-chemical properties.

NR8383 rat lung AM were treated with ultrafine uf, fine f TiO2 or fine crystalline silica DQ12 quartz. Physico-chemical particle properties were investigated by transmission electron microscopy, elemental analysis and thermogravimetry. Aggregation and agglomeration tendency of the particles were determined in assay-specific suspensions by means of dynamic light scattering.

All three particle types were rapidly taken up by AM. DQ12 and ufTiO2 , but not fTiO2 , caused increased extracellular reactive oxygen species ROS, heme oxygenase 1 HO-1 mRNA expression and tumor necrosis factor TNF-α release. Inducible nitric oxide synthase iNOS mRNA expression was increased most strongly by ufTiO2 , while DQ12 exclusively triggered interleukin IL 1β release. However, oscillations of intracellular calcium concentration and increased intracellular ROS were observed with all three samples. Uptake inhibition experiments with cytochalasin D, chlorpromazine and a Fcγ receptor II FcγRII antibody revealed that the endocytosis of fTiO2 by the macrophages involves actin-dependent phagocytosis and macropinocytosis as well as clathrin-coated pit formation, whereas the uptake of ufTiO2 was dominated by FcγIIR. The uptake of DQ12 was found to be significantly reduced by all three inhibitors. Our findings suggest that the contrasting AM responses to fTiO2 , ufTiO2 and DQ12 relate to differences in the involvement of specific uptake mechanisms.

KeywordsNR8383 cells titanium dioxide particle internalization size distribution agglomeration List of abbreviations usedAMalveolar macrophages

ANOVAanalysis of variance

AP-1activator protein 1

Caiintracellular calcium concentration

CBcarbon black

CCPclathrin coated pits


CytDcytochalasin D

DCFH-DAdichlorodihydrofluorescein diacetate

DF-LSMdark field light scattering microscopy

DLSdynamic light scattering

DMPO5; 5-dimethyl-1-pyrroline-N-oxide

DMSOdimethyl sulphoxide

DQ12 quartzDörentruper quartz

EAElemental analysis

EPRElectron Paramagnetic Resonance

FCSfetal calf serum

FcγRIIFcγ receptor II

FSCforward scatter

fTiO2fine titanium dioxide


HBSSHank-s buffered saline solution

HO-1heme oxygenase 1

IgG1κImmunoglobulin G1; kappa chain

IL-1βinterleukin 1β

iNOSinducible nitric oxide synthase


MARCOMacrophage receptor with collagenous structure

NADPHnicotinamide adenine dinucleotide phosphate

NALP3NACHT; LRR and PYD domains-containing protein 3

NF-κBnuclear factor kappa B

NLRPNOD-like receptor family


PBSphosphate buffered saline

PKCprotein kinase C

PLCPhospholipase C

PMAphorbol 12-myristate 13-acetate

ROIsregions of interest

ROSreactive oxygen species

SSAspecific surface area

SSCsideward scatter

TEMtransmission electron microscopy

TGAthermogravimetric analysis

TNF-αtumor necrosis factor alpha

ufTiO2ultrafine titanium dioxide

WST-1water-soluble tetrazolium.

Electronic supplementary materialThe online version of this article doi:10.1186-1743-8977-8-31 contains supplementary material, which is available to authorized users.

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Autor: Agnes M Scherbart - Julia Langer - Alexey Bushmelev - Damiёn van Berlo - Petra Haberzettl - Frederik-Jan van Schooten - An


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