Arbejdsmiljøforskningsfonden - Dansk Center for Nanosikkerhed

Projekter: ProjektForskning



When nanoparticles (NP) is inhaled, they are deposited in the outermost branches of the lungs (alveoli), where lung surfactant (LS) is present in the thin water layer covering the lung surface and constitutes the primary barrier function. LS are proteins and phospholipids with detergent-like properties which reduce the surface tension of the water layer and prevent the lung surfaces from collapsing at exhalation. LS and lipids are excreted from the alveoli cells and form a monolayer at the air-LS-liquid interface in the alveoli [1]. Contact between NP and the water layer is liable to result in at least two different effects: 1) the function of the LS is disturbed or inactivated and 2) the LS is bound to NP and thus changes its possible toxic properties [2]. Several studies indicate that in particular NP, unlike microparticles, may partially inactivate the LS function [3-5]. The ability of proteins to bind to NP and form a "corona" depends on the NP's physico-chemical properties, as well as of the protein, that may be denaturated by binding to NP [6-8]. A very recent study indicates that NP with a "corona" consisting of a specific LS (surfactant protein A) are more easily taken up by the macrophages in the alveoli than the NP with a "corona" of other proteins [9].
The project depends on the combination of knowledge from several fields of research: 1) The interaction between NP and LS systems (in vitro and in vivo) [2], 2) protein-NP interactions [8], 3) airway administration of nanomedicine [10], and 4) NP-based mass spectrometry (MS) for the analysis of biomolecules [11, 12]. The aim of this study is to provide: 1.) Better understanding of the relevant toxicological mechanisms and 2.) To predict the toxicological effects of NP based on the physico-chemical characteristics of these materials.

The central part of the study is the development and use of MS methods for studying the interaction between NP and different LS. The focus will be the exploration of how this interaction affects the surface tension of artificial and natural lung fluids. If required for the interpretation of results, more detailed studies of the binding between the NP and LS will be carried out [13]. A strategy for the study of interactions of NP with LS is shown in Figure 1.
NP with different size, shape and surface chemistry will be tested for effects on LS's function by measuring the effect on surface tension of the artificial and natural lung fluids. In the case of inactivation, a thorough survey of the chemical substances adsorbed / bound to the surface of the particles will be carried out. The relevant physical-chemical properties for a given NPs ablility to interact with LS will be identified by examining four types of NP: NP with a surface that is either positive, negative or neutral at pH 7.4 (pH of the lung fluid), and carbon-based nanomaterials. Three representatives of each group are selected for further studies. It is also examined whether DLS (Dynamic Light Scattering) can be used for rapid screening of adsorption of LS on a particular NP.
Effektiv start/slut dato01/05/201230/12/2015