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The pro-inflammatory effects of low-toxicity low-solubility particles, nanoparticles and fine particles, on epithelial cells in vitro: the role of surface area
  1. Claire Monteiller1,2,
  2. Lang Tran1,2,
  3. William MacNee2,
  4. Steve Faux2,
  5. Alan Jones1,
  6. Brian Miller1,
  7. Ken Donaldson2
  1. 1Institute of Occupational Medicine, Research Park North, Edinburgh, UK
  2. 2Edinburgh Lung and the Environment Group Initiative (ELEGI)/Colt Laboratory, The MRC/University of Edinburgh Centre for Inflammation Research, ELEGI Colt Laboratory, Queen’s Medical Research Institute, Edinburgh, UK
  1. Correspondence to:
 Dr Lang Tran
 Institute of Occupational Medicine, Research Avenue North, Edinburgh EH148 4AP, UK; lang.tran{at}


Objective: Rats exposed to high airborne mass concentrations of low-solubility low-toxicity particles (LSLTP) have been reported to develop lung disease such as fibrosis and lung cancer. These particles are regulated on a mass basis in occupational settings, but mass might not be the appropriate metric as animal studies have shown that nanoparticles (ultrafine particles) produce a stronger adverse effect than fine particles when delivered on an equal mass basis.

Methods: This study investigated whether the surface area is a better descriptor than mass of LSLTP of their ability to stimulate pro-inflammatory responses in vitro. In a human alveolar epithelial type II-like cell line, A549, we measured interleukin (IL)-8 mRNA, IL8 protein release and glutathione (GSH) depletion as markers of pro-inflammatory effects and oxidative stress after treatment with a range of LSLTP (fine and nanoparticles) and DQ12 quartz, a particle with a highly reactive surface.

Results: In all the assays, nanoparticle preparations of titanium dioxide (TiO2-np) and of carbon black (CB-np) produced much stronger pro-inflammatory responses than the same mass dose of fine TiO2 and CB. The results of the GSH assay confirmed that oxidative stress was involved in the response to all the particles, and two ultra-fine metal dusts (cobalt and nickel) produced GSH depletion similar to TiO2-np, for similar surface-area dose. As expected, DQ12 quartz was more inflammatory than the low toxicity dusts, on both a mass and surface-area basis.

Conclusion: Dose–response relationships observed in the in vitro assays appeared to be directly comparable with dose–response relationships in vivo when the doses were similarly standardised. Both sets of data suggested a threshold in dose measured as surface area of particles relative to the surface area of the exposed cells, at around 1–10 cm2/cm2.

These findings are consistent with the hypothesis that surface area is a more appropriate dose metric than mass for the pro-inflammatory effects of LSLTP in vitro and in vivo, and consequently that the high surface area of nanoparticles is a key factor in their inflammogenicity.

  • AM, alveolar macrophage
  • AP-1, activator protein-1
  • BaSO4, barium sulphate
  • CB, carbon black
  • Co, cobalt
  • DMEM, Dulbecco’s modified Eagle’s medium
  • IL, interleukin
  • FCS, fetal calf serum
  • GAPDH, glyceraldehyde-3-phosphate
  • GSH, glutathione
  • LDH, lactate dehydrogenase
  • LSLTP, low-solubility low-toxicity particles
  • NF, nuclear factor
  • Ni, nickel
  • np, nanoparticle
  • ROS, reactive oxygen species
  • TiO2, titanium dioxide
  • low-solubility low-toxicity particles
  • nanoparticles
  • surface area
  • inflammation
  • IL8

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  • Published Online First 18 April 2007

  • Competing interests: none declared