Pulmonary toxicity of nanoparticles, influence on the barrier of the pulmonary epithelium

mso-ansi-language:EN-US" lang="EN-US">Nanotechnology is already being used in severalindustries for a very diverse range of products: personal care products,cosmetics, sunscreens, clothing, sporting goods, electronics, food and beverages,paints and coatings. The production of nanoparticles and their marketing willincrease even more in the coming years.mso-ansi-language:EN-US" lang="EN-US">It is generally assumed that the physical and chemicalcharacteristics that define nanoparticles (NPs) unique properties are alsoresponsible for the possible adverse effects. Due to their small size, which isin the range of biological molecules (proteins, lipids, DNA), NPs mightdistribute to the smallest biological structures, access and interact with finecellular and molecular structures. mso-ansi-language:EN-US" lang="EN-US">Inhalation is considered to be the most importantroute of exposure, but the deleterious effects induced by inhalation of NPs arenot limited to the lungs, since the cardiovascular system may also be affected.Moreover, some human subpopulations may be more susceptible to the deleteriouseffects induced by nanoparticle inhalation, e.g. people withpre-existingcardiovascular disease and the elderly.mso-ansi-language:EN-US" lang="EN-US">The objectives of this project were to:line-height:150%;mso-list:l0 level1 lfo1">font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-family:Symbol;mso-ansi-language:EN-US" lang="EN-US">· mso-bidi-font-size:11.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">Optimize acoculture model of the lung-blood barrier to study the adverse pulmonary andextra-pulmonary effects after NP administration (to the pulmonary / apical compartment) line-height:150%;mso-list:l0 level1 lfo1">font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-family:Symbol;mso-ansi-language:EN-US" lang="EN-US">· mso-bidi-font-size:11.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">Study theadverse effects after pulmonary nanoparticle administration in two differentanimal models that reflect susceptible human subpopulations.mso-ansi-language:EN-US" lang="EN-US">The most important physical and chemicalcharacteristics of NPs were reviewed in detail (Chapter 1) and links betweenthese characteristics and the observed toxic effects were made where possible.It is generally assumed that the smaller a particle, the more toxic it is. Forother characteristics, a clear relation is less evident. Currently, we also lackclarity as to which characteristics are most important for determiningpotential hazards.mso-ansi-language:EN-US" lang="EN-US">A coculture model of the lung-blood barrier wasdeveloped where human bronchial epithelial cells (16HBE14o-) with monocytes(THP-1) and human microvascular endothelial cells (HLMVEC) were seeded onopposite sides of a permeable membrane, representing the lungs and pulmonarycirculation respectively. The roleof chemically-activated macrophage-likecells in the co-culture was investigated and it was observed that these cellsdisturbed the barrier integrity by disrupting the epithelial tight junctions(Chapter 2). Non-activated monocytes were shown to be activated by SiO2NPs and lipopolysaccharide (LPS), taken as a positive control, withoutdisturbing the barrier integrity. The toxicity of SiO2 and TiO2NPs at non-cytotoxic concentrations was assessed, with LPS and TBHP as positivecontrols for inflammation and oxidative stress (Chapter 3). Both NPs decreasedthe barrier integrity and total glutathione concentrations in the pulmonarycompartment. In a time-course experiment, oxLDL was decreased 24 hours afterexposure to the two types of nanoparticles. SiO2 NPs induced themost pronounced inflammatory response, which resembled that caused by LPS.mso-ansi-language:EN-US" lang="EN-US">Bmal1 (brain and muscle ARNT-like protein-1) knockout mice(Bmal1-/-) have a disturbed circadian rhythm, causing them toprematurely age, 13.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">and have a mso-ansi-language:EN-US" lang="EN-US">procoagulant 12.0pt;mso-bidi-font-size:13.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">phenotype(Chapter 4). These mice (Bmal1+/+and Bmal1-/-), togetherwith 18 month old mice (Chapter 5) were usedas animal models reflecting peoplewith pre-existing cardiovascular disease and the elderly, respectively and weresubacutely exposed to MWCNT or ZnO NPs and additionally TiO2 NPswere studied in the old mice. In the Bmal1 mice, tEN-US" lang="EN-US">he MWCNTs and ZnO NPs showed opposite pulmonary toxicity butsimilarprocoagulant effects. Moreover, the observed pulmonary effects correlated withthe hemostatic effects and these correlations were more apparent in the Bmal1-/-mice suggesting it is a sensitive model to study the pulmonary andextra-pulmonary toxicity after pulmonary administration ofNPs. In the oldmice, the MWCNTs and ZnO NPs induced pulmonary inflammation together with acuteprocoagulant effects. Moreover, histological analysis showed the presence ofMWCNTs in the heart and the induction of fibrosis induced by ZnO NPs.mso-ansi-language:EN-US" lang="EN-US"> mso-ansi-language:EN-US" lang="EN-US">In conclusion, we observed that inflammation andoxidative stress were the driving mechanisms in both normal">in vitro and in vivostudies causing the observed toxic effects. Moreover, we demonstrated thatpulmonary NP exposure evoked hemostatic toxicity, providing further evidencethat the lungs and the cardiovascular system are linked. 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Publication year:2014

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