title: Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity.
abstract: Inhaled nanomaterials present a challenge to traditional methods and understanding of respiratory toxicology. In this study, a non-targeted metabolomics approach was used to investigate relationships between nanoparticle hydrophobicity, inflammatory outcomes and the metabolic fingerprint in bronchoalveolar fluid. Measures of acute lung toxicity were assessed following single-dose intratracheal administration of nanoparticles with varying surface hydrophobicity (i.e. pegylated lipid nanocapsules, polyvinyl acetate nanoparticles and polystyrene beads; listed in order of increasing hydrophobicity). Broncho-alveolar lavage (BAL) fluid was collected from mice exposed to nanoparticles at a surface area dose of 220 cm(2) and metabolite fingerprints were acquired via ultra pressure liquid chromatography-mass spectrometry-based metabolomics. Particles with high surface hydrophobicity were pro-inflammatory. Multivariate analysis of the resultant small molecule fingerprints revealed clear discrimination between the vehicle control and polystyrene beads (p < 0.05), as well as between nanoparticles of different surface hydrophobicity (p < 0.0001). Further investigation of the metabolic fingerprints revealed that adenosine monophosphate (AMP) concentration in BAL correlated with neutrophilia (p < 0.01), CXCL1 levels (p < 0.05) and nanoparticle surface hydrophobicity (p < 0.001). Our results suggest that extracellular AMP is an intermediary metabolite involved in adenine nucleotide-regulated neutrophilic inflammation as well as tissue damage, and could potentially be used to monitor nanoparticle-induced responses in the lung following pulmonary administration.
authors.affiliation: Institute of Pharmaceutical Science, King's College London , London , UK .
authors.forename: Lea Ann
authors.initials: LA
authors.lastname: Dailey
authors.forename: Raquel
authors.initials: R
authors.lastname: Hernández-Prieto
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Casas-Ferreira
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jones
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.forename: Encarnación
authors.initials: E
authors.lastname: Rodríguez-Gonzalo
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Jones
authors.forename: Norman W
authors.initials: NW
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.forename: Clive
authors.initials: C
authors.lastname: Page
authors.forename: Cristina
authors.initials: C
authors.lastname: Legido-Quigley
mesh_terms: D000249:Adenosine Monophosphate / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism*; D011137:Polystyrenes / Q000633:toxicity; D013499:Surface Properties
chemical_list: D011137:Polystyrenes; D000249:Adenosine Monophosphate
keywords: AMP; broncho-alveolar lavage; hydrophobicity; inflammation; lung; metabolomics; nanoparticles