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Title: Nanoparticles, their protein corona and impact on the immune function of human lung cells
Author: Whitwell, Harry James
ISNI:       0000 0004 8509 7509
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2016
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Particles with a single dimension smaller than 100 nm are called nanoparticles (NPs). There is a large amount of epidemiology that anthropogenic particles cause increased mortality, increased risk of asthma and increased incidence of lung adenocarcinoma. Inhaled NPs can reach the lung terminus, interacting with a lipid lining at the air-liquid interface (pulmonary surfactant (PSf)) and with an aqueous hydrophase beneath. Studies in serum have shown that upon contact with blood, proteins very rapidly adsorb to the particle surface, thus the particle accrues a biological identity. However, no such interaction studies have been performed in the pulmonary system, where there is a complex interplay of proteins and lipids. The interaction of NPs with PSf is poorly understood. Prior to reaching the lung epithelium, NPs must translocate through this layer. The aims of this thesis are to firstly explore the interactions of NPs with proteins and lipids in the lung and secondly investigate the toxicity and effect on the immunological action of lung cells. NPs were incubated with pulmonary lavage fluid and adsorbed proteins were analysed using state-of-the-art, high resolution, quantitative mass spectrometry. To investigate the interactions of NPs with PSf, particles were incubated with a porcine surfactant. The bound lipids were analysed by qualitative mass spectrometry. The effect of NPs and the NP-protein-corona was investigated in cell lines by a number of techniques. Unique proteins were observed on each particle type, however the main contributors contribution was from a few key proteins. There was no biophysical property of these bound proteins that could predict their affinity to a particle. Surfactant associated protein A, B and D (SP-A, B, D) were observed to be bound to the particle surface. SP-A was bound with high abundance, suggesting it is likely these particles may interfere with PSf in vivo. All particles retained lipids on their surface through binding mediated by electrostatic interactions. Aminated-polystyrene and titanium dioxide NPs were capable of interfering with PSf in vitro. There was little observed effect of the particles to induce inflammation. The key findings suggest that the protein corona does not predict particle toxicity. Any observed effect is due to the core particle chemistry, not an acquired bio-identity. The toxicity of particles observed through epidemiological surveys could be caused from the inhibition of pulmonary surfactant, not from direct toxicity of the particles themselves.
Supervisor: Madsen, Jens ; Clark, Howard ; Warner, Jane Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available